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‘Unheard of’ PAH improvement with novel drug: STELLAR
NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.
Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,
“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm−5 reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.
“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.
Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
‘A new hope’ for patients with PAH
Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.
“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.
“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.
But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.
The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
Death or clinical worsening cut by 84%
STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.
In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.
The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.
The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.
The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.
“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.
Drug binds activin, a pathologic driver of PAH
Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.
“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”
Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.
Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.
STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.
NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.
Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,
“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm−5 reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.
“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.
Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
‘A new hope’ for patients with PAH
Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.
“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.
“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.
But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.
The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
Death or clinical worsening cut by 84%
STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.
In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.
The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.
The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.
The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.
“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.
Drug binds activin, a pathologic driver of PAH
Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.
“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”
Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.
Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.
STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.
NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.
Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,
“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm−5 reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.
“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.
Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
‘A new hope’ for patients with PAH
Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.
“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.
“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.
But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.
The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
Death or clinical worsening cut by 84%
STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.
In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.
The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.
The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.
The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.
“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.
Drug binds activin, a pathologic driver of PAH
Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.
“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”
Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.
Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.
STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.
At ACC 2023
A surfing PA leads an intense beach rescue
There’s a famous surf spot called Old Man’s on San Onofre beach in north San Diego County. It has nice, gentle waves that people say are similar to Waikiki in Hawaii. Since the waves are so forgiving, a lot of older people surf there. I taught my boys and some friends how to surf there. Everyone enjoys the water. It’s just a really fun vibe.
In September of 2008, I was at Old Man’s surfing with friends. After a while, I told them I was going to catch the next wave in. When I rode the wave to the beach, I saw an older guy waving his arms above his head, trying to get the lifeguard’s attention. His friend was lying on the sand at the water’s edge, unconscious. The lifeguards were about 200 yards away in their truck. Since it was off-season, they weren’t in the nearby towers.
I threw my board down on the sand and ran over. The guy was blue in the face and had some secretions around his mouth. He wasn’t breathing and had no pulse. I told his friend to get the lifeguards.
I gave two rescue breaths, and then started CPR. The waves were still lapping against his feet. I could sense people gathering around, so I said, “Okay, we’re going to be hooking him up to electricity, let’s get him out of the water.” I didn’t want him in contact with the water that could potentially transmit that electricity to anyone else.
Many hands reached in and we dragged him up to dry sand. When we pulled down his wetsuit, I saw an old midline sternotomy incision on his chest and I thought: “Oh man, he’s got a cardiac history.” I said, “I need a towel,” and suddenly there was a towel in my hand. I dried him off and continued doing CPR.
The lifeguard truck pulled up and in my peripheral vision I saw two lifeguards running over with their first aid kit. While doing compressions, I yelled over my shoulder: “Bring your AED! Get your oxygen!” They ran back to the truck.
At that point, a young woman came up and said: “I’m a nuclear medicine tech. What can I do?” I asked her to help me keep his airway open. I positioned her at his head, and she did a chin lift.
The two lifeguards came running back. One was very experienced, and he started getting the AED ready and putting the pads on. The other lifeguard was younger. He was nervous and shaking, trying to figure out how to turn on the oxygen tank. I told him: “Buddy, you better figure that out real fast.”
The AED said there was a shockable rhythm so it delivered a shock. I started compressions again. The younger lifeguard finally figured out how to turn on the oxygen tank. Now we had oxygen, a bag valve mask, and an AED. We let our training take over and quickly melded together as an efficient team.
Two minutes later the AED analyzed the rhythm and administered another shock. More compressions. Then another shock and compressions. I had so much adrenaline going through my body that I wasn’t even getting tired.
By then I had been doing compressions for a good 10 minutes. Finally, I asked: “Hey, when are the paramedics going to get here?” And the lifeguard said: “They’re on their way.” But we were all the way down on a very remote section of beach.
We did CPR on him for what seemed like eternity, probably only 15-20 minutes. Sometimes he would get a pulse back and pink up, and we could stop and get a break. But then I would see him become cyanotic. His pulse would become thready, so I would start again.
The paramedics finally arrived and loaded him into the ambulance. He was still blue in the face, and I honestly thought he would probably not survive. I said a quick prayer for him as they drove off.
For the next week, I wondered what happened to him. The next time I was at the beach, I approached some older guys and said: “Hey, I was doing CPR on a guy here last week. Do you know what happened to him?” They gave me a thumbs up sign and said: “He’s doing great!” I was amazed!
While at the beach, I saw the nuclear med tech who helped with the airway and oxygen. She told me she’d called her hospital after the incident and asked if they had received a full arrest from the beach. They said: “Yes, he was sitting up, awake and talking when he came through the door.”
A few weeks later, the local paper called and wanted to do an interview and get some photos on the beach. We set up a time to meet, and I told the reporter that if he ever found out who the guy was, I would love to meet him. I had two reasons: First, because I had done mouth-to-mouth on him and I wanted to make sure he didn’t have any communicable diseases. Second, and this is a little weirder, I wanted to find out if he had an out-of-body experience. They fascinate me.
The reporter called back a few minutes later and said: “You’ll never believe this – while I was talking to you, my phone beeped with another call. The person left a message, and it was the guy. He wants to meet you.” I was amazed at the coincidence that he would call at exactly the same time.
Later that day, we all met at the beach. I gave him a big hug and told him he looked a lot better than the last time I saw him. He now had a pacemaker/defibrillator. I found out he was married and had three teenage boys (who still have a father). He told me on the day of the incident he developed chest pain, weakness, and shortness of breath while surfing, so he came in and sat down at the water’s edge to catch his breath. That was the last thing he remembered.
When I told him I did mouth-to-mouth on him, he laughed and reassured me that he didn’t have any contagious diseases. Then I asked him about an out-of-body experience, like hovering above his body and watching the CPR. “Did you see us doing that?” I asked. He said: “No, nothing but black. The next thing I remember is waking up in the back of the ambulance, and the paramedic asked me, ‘how does it feel to come back from the dead?’ ” He answered: “I think I have to throw up.”
He was cleared to surf 6 weeks later, and I thought it would be fun to surf with him. But when he started paddling out, he said his defibrillator went off, so he has now retired to golf.
I’ve been a PA in the emergency room for 28 years. I’ve done CPR for so long it’s instinctive for me. It really saves lives, especially with the AED. When people say: “You saved his life,” I say: “No, I didn’t. I just kept him alive and let the AED do its job.”
Ms. Westbrook-May is an emergency medicine physician assistant in Newport Beach, Calif.
A version of this article first appeared on Medscape.com.
There’s a famous surf spot called Old Man’s on San Onofre beach in north San Diego County. It has nice, gentle waves that people say are similar to Waikiki in Hawaii. Since the waves are so forgiving, a lot of older people surf there. I taught my boys and some friends how to surf there. Everyone enjoys the water. It’s just a really fun vibe.
In September of 2008, I was at Old Man’s surfing with friends. After a while, I told them I was going to catch the next wave in. When I rode the wave to the beach, I saw an older guy waving his arms above his head, trying to get the lifeguard’s attention. His friend was lying on the sand at the water’s edge, unconscious. The lifeguards were about 200 yards away in their truck. Since it was off-season, they weren’t in the nearby towers.
I threw my board down on the sand and ran over. The guy was blue in the face and had some secretions around his mouth. He wasn’t breathing and had no pulse. I told his friend to get the lifeguards.
I gave two rescue breaths, and then started CPR. The waves were still lapping against his feet. I could sense people gathering around, so I said, “Okay, we’re going to be hooking him up to electricity, let’s get him out of the water.” I didn’t want him in contact with the water that could potentially transmit that electricity to anyone else.
Many hands reached in and we dragged him up to dry sand. When we pulled down his wetsuit, I saw an old midline sternotomy incision on his chest and I thought: “Oh man, he’s got a cardiac history.” I said, “I need a towel,” and suddenly there was a towel in my hand. I dried him off and continued doing CPR.
The lifeguard truck pulled up and in my peripheral vision I saw two lifeguards running over with their first aid kit. While doing compressions, I yelled over my shoulder: “Bring your AED! Get your oxygen!” They ran back to the truck.
At that point, a young woman came up and said: “I’m a nuclear medicine tech. What can I do?” I asked her to help me keep his airway open. I positioned her at his head, and she did a chin lift.
The two lifeguards came running back. One was very experienced, and he started getting the AED ready and putting the pads on. The other lifeguard was younger. He was nervous and shaking, trying to figure out how to turn on the oxygen tank. I told him: “Buddy, you better figure that out real fast.”
The AED said there was a shockable rhythm so it delivered a shock. I started compressions again. The younger lifeguard finally figured out how to turn on the oxygen tank. Now we had oxygen, a bag valve mask, and an AED. We let our training take over and quickly melded together as an efficient team.
Two minutes later the AED analyzed the rhythm and administered another shock. More compressions. Then another shock and compressions. I had so much adrenaline going through my body that I wasn’t even getting tired.
By then I had been doing compressions for a good 10 minutes. Finally, I asked: “Hey, when are the paramedics going to get here?” And the lifeguard said: “They’re on their way.” But we were all the way down on a very remote section of beach.
We did CPR on him for what seemed like eternity, probably only 15-20 minutes. Sometimes he would get a pulse back and pink up, and we could stop and get a break. But then I would see him become cyanotic. His pulse would become thready, so I would start again.
The paramedics finally arrived and loaded him into the ambulance. He was still blue in the face, and I honestly thought he would probably not survive. I said a quick prayer for him as they drove off.
For the next week, I wondered what happened to him. The next time I was at the beach, I approached some older guys and said: “Hey, I was doing CPR on a guy here last week. Do you know what happened to him?” They gave me a thumbs up sign and said: “He’s doing great!” I was amazed!
While at the beach, I saw the nuclear med tech who helped with the airway and oxygen. She told me she’d called her hospital after the incident and asked if they had received a full arrest from the beach. They said: “Yes, he was sitting up, awake and talking when he came through the door.”
A few weeks later, the local paper called and wanted to do an interview and get some photos on the beach. We set up a time to meet, and I told the reporter that if he ever found out who the guy was, I would love to meet him. I had two reasons: First, because I had done mouth-to-mouth on him and I wanted to make sure he didn’t have any communicable diseases. Second, and this is a little weirder, I wanted to find out if he had an out-of-body experience. They fascinate me.
The reporter called back a few minutes later and said: “You’ll never believe this – while I was talking to you, my phone beeped with another call. The person left a message, and it was the guy. He wants to meet you.” I was amazed at the coincidence that he would call at exactly the same time.
Later that day, we all met at the beach. I gave him a big hug and told him he looked a lot better than the last time I saw him. He now had a pacemaker/defibrillator. I found out he was married and had three teenage boys (who still have a father). He told me on the day of the incident he developed chest pain, weakness, and shortness of breath while surfing, so he came in and sat down at the water’s edge to catch his breath. That was the last thing he remembered.
When I told him I did mouth-to-mouth on him, he laughed and reassured me that he didn’t have any contagious diseases. Then I asked him about an out-of-body experience, like hovering above his body and watching the CPR. “Did you see us doing that?” I asked. He said: “No, nothing but black. The next thing I remember is waking up in the back of the ambulance, and the paramedic asked me, ‘how does it feel to come back from the dead?’ ” He answered: “I think I have to throw up.”
He was cleared to surf 6 weeks later, and I thought it would be fun to surf with him. But when he started paddling out, he said his defibrillator went off, so he has now retired to golf.
I’ve been a PA in the emergency room for 28 years. I’ve done CPR for so long it’s instinctive for me. It really saves lives, especially with the AED. When people say: “You saved his life,” I say: “No, I didn’t. I just kept him alive and let the AED do its job.”
Ms. Westbrook-May is an emergency medicine physician assistant in Newport Beach, Calif.
A version of this article first appeared on Medscape.com.
There’s a famous surf spot called Old Man’s on San Onofre beach in north San Diego County. It has nice, gentle waves that people say are similar to Waikiki in Hawaii. Since the waves are so forgiving, a lot of older people surf there. I taught my boys and some friends how to surf there. Everyone enjoys the water. It’s just a really fun vibe.
In September of 2008, I was at Old Man’s surfing with friends. After a while, I told them I was going to catch the next wave in. When I rode the wave to the beach, I saw an older guy waving his arms above his head, trying to get the lifeguard’s attention. His friend was lying on the sand at the water’s edge, unconscious. The lifeguards were about 200 yards away in their truck. Since it was off-season, they weren’t in the nearby towers.
I threw my board down on the sand and ran over. The guy was blue in the face and had some secretions around his mouth. He wasn’t breathing and had no pulse. I told his friend to get the lifeguards.
I gave two rescue breaths, and then started CPR. The waves were still lapping against his feet. I could sense people gathering around, so I said, “Okay, we’re going to be hooking him up to electricity, let’s get him out of the water.” I didn’t want him in contact with the water that could potentially transmit that electricity to anyone else.
Many hands reached in and we dragged him up to dry sand. When we pulled down his wetsuit, I saw an old midline sternotomy incision on his chest and I thought: “Oh man, he’s got a cardiac history.” I said, “I need a towel,” and suddenly there was a towel in my hand. I dried him off and continued doing CPR.
The lifeguard truck pulled up and in my peripheral vision I saw two lifeguards running over with their first aid kit. While doing compressions, I yelled over my shoulder: “Bring your AED! Get your oxygen!” They ran back to the truck.
At that point, a young woman came up and said: “I’m a nuclear medicine tech. What can I do?” I asked her to help me keep his airway open. I positioned her at his head, and she did a chin lift.
The two lifeguards came running back. One was very experienced, and he started getting the AED ready and putting the pads on. The other lifeguard was younger. He was nervous and shaking, trying to figure out how to turn on the oxygen tank. I told him: “Buddy, you better figure that out real fast.”
The AED said there was a shockable rhythm so it delivered a shock. I started compressions again. The younger lifeguard finally figured out how to turn on the oxygen tank. Now we had oxygen, a bag valve mask, and an AED. We let our training take over and quickly melded together as an efficient team.
Two minutes later the AED analyzed the rhythm and administered another shock. More compressions. Then another shock and compressions. I had so much adrenaline going through my body that I wasn’t even getting tired.
By then I had been doing compressions for a good 10 minutes. Finally, I asked: “Hey, when are the paramedics going to get here?” And the lifeguard said: “They’re on their way.” But we were all the way down on a very remote section of beach.
We did CPR on him for what seemed like eternity, probably only 15-20 minutes. Sometimes he would get a pulse back and pink up, and we could stop and get a break. But then I would see him become cyanotic. His pulse would become thready, so I would start again.
The paramedics finally arrived and loaded him into the ambulance. He was still blue in the face, and I honestly thought he would probably not survive. I said a quick prayer for him as they drove off.
For the next week, I wondered what happened to him. The next time I was at the beach, I approached some older guys and said: “Hey, I was doing CPR on a guy here last week. Do you know what happened to him?” They gave me a thumbs up sign and said: “He’s doing great!” I was amazed!
While at the beach, I saw the nuclear med tech who helped with the airway and oxygen. She told me she’d called her hospital after the incident and asked if they had received a full arrest from the beach. They said: “Yes, he was sitting up, awake and talking when he came through the door.”
A few weeks later, the local paper called and wanted to do an interview and get some photos on the beach. We set up a time to meet, and I told the reporter that if he ever found out who the guy was, I would love to meet him. I had two reasons: First, because I had done mouth-to-mouth on him and I wanted to make sure he didn’t have any communicable diseases. Second, and this is a little weirder, I wanted to find out if he had an out-of-body experience. They fascinate me.
The reporter called back a few minutes later and said: “You’ll never believe this – while I was talking to you, my phone beeped with another call. The person left a message, and it was the guy. He wants to meet you.” I was amazed at the coincidence that he would call at exactly the same time.
Later that day, we all met at the beach. I gave him a big hug and told him he looked a lot better than the last time I saw him. He now had a pacemaker/defibrillator. I found out he was married and had three teenage boys (who still have a father). He told me on the day of the incident he developed chest pain, weakness, and shortness of breath while surfing, so he came in and sat down at the water’s edge to catch his breath. That was the last thing he remembered.
When I told him I did mouth-to-mouth on him, he laughed and reassured me that he didn’t have any contagious diseases. Then I asked him about an out-of-body experience, like hovering above his body and watching the CPR. “Did you see us doing that?” I asked. He said: “No, nothing but black. The next thing I remember is waking up in the back of the ambulance, and the paramedic asked me, ‘how does it feel to come back from the dead?’ ” He answered: “I think I have to throw up.”
He was cleared to surf 6 weeks later, and I thought it would be fun to surf with him. But when he started paddling out, he said his defibrillator went off, so he has now retired to golf.
I’ve been a PA in the emergency room for 28 years. I’ve done CPR for so long it’s instinctive for me. It really saves lives, especially with the AED. When people say: “You saved his life,” I say: “No, I didn’t. I just kept him alive and let the AED do its job.”
Ms. Westbrook-May is an emergency medicine physician assistant in Newport Beach, Calif.
A version of this article first appeared on Medscape.com.
Endurance exercise tied to more coronary atherosclerosis
In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.
The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.
“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.
The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.
Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”
The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.
“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.
“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”
On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”
In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”
He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”
However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”
Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”
He noted that the Master@Heart study as an “important contribution” to the field.
“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”
It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”
He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”
However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”
Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.
But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.
“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”
In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.
He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.
The Master@Heart study aimed to look at this question in a more comprehensive way.
The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.
Maximal oxygen uptake (VO2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO2max than nonathletes (159 vs. 155 vs. 122).
There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).
The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.
Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).
In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:
- More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
- More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
- More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
- More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
- More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
- More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
- More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)
In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.
Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).
In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.
“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.
“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”
A version of this article first appeared on Medscape.com.
In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.
The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.
“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.
The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.
Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”
The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.
“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.
“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”
On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”
In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”
He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”
However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”
Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”
He noted that the Master@Heart study as an “important contribution” to the field.
“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”
It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”
He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”
However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”
Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.
But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.
“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”
In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.
He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.
The Master@Heart study aimed to look at this question in a more comprehensive way.
The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.
Maximal oxygen uptake (VO2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO2max than nonathletes (159 vs. 155 vs. 122).
There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).
The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.
Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).
In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:
- More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
- More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
- More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
- More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
- More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
- More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
- More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)
In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.
Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).
In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.
“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.
“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”
A version of this article first appeared on Medscape.com.
In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.
The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.
“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.
The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.
Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”
The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.
“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.
“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”
On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”
In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”
He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”
However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”
Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”
He noted that the Master@Heart study as an “important contribution” to the field.
“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”
It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”
He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”
However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”
Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.
But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.
“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”
In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.
He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.
The Master@Heart study aimed to look at this question in a more comprehensive way.
The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.
Maximal oxygen uptake (VO2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO2max than nonathletes (159 vs. 155 vs. 122).
There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).
The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.
Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).
In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:
- More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
- More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
- More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
- More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
- More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
- More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
- More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)
In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.
Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).
In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.
“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.
“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”
A version of this article first appeared on Medscape.com.
FROM ACC 2023
Can SGLT2 inhibitors limit acute kidney injury in type 2 diabetes?
Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.
The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.
The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.
Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.
Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.
More recent experience has calmed AKI concerns, however.
Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.
The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).
Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk
“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.
Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.
Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.
One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.
Early AKI concern has diminished
Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.
In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.
Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.
The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.
During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.
A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.
The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.
He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.
The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.
A version of this article originally appeared on Medscape.com.
Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.
The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.
The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.
Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.
Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.
More recent experience has calmed AKI concerns, however.
Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.
The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).
Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk
“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.
Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.
Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.
One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.
Early AKI concern has diminished
Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.
In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.
Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.
The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.
During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.
A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.
The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.
He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.
The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.
A version of this article originally appeared on Medscape.com.
Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.
The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.
The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.
Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.
Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.
More recent experience has calmed AKI concerns, however.
Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.
The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).
Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk
“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.
Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.
Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.
One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.
Early AKI concern has diminished
Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.
In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.
Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.
The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.
During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.
A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.
The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.
He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.
The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.
A version of this article originally appeared on Medscape.com.
Wearable fluid sensor lowers risk of HF rehospitalizations: BMAD
NEW ORLEANS – A wearable device that monitors thoracic fluid and can signal elevated levels can improve outcomes after heart failure hospitalization, according to a comparative but nonrandomized trial.
In this study, management adjustments made in response to a threshold alert from the device led to several improvements in outcome at 90 days, including a significant 38% reduction in the primary outcome of rehospitalization, relative to controls (P = .02), reported John P. Boehmer, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The same relative risk reduction at 90 days was observed for a composite outcome of time to first hospitalization, visit to an emergency room, or death (hazard ratio, 0.62; P = .03).
Quality of life, as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ), improved steadily in both the experimental and control arm over the 90-day study, but the curves separated at about 30 days, Dr. Boehmer reported. By the end of the study, the mean KCCQ difference was 12 points favoring the experimental arm on a scale in which 5 points is considered clinically meaningful.
70% report improved quality of life
“Responder analysis revealed that nearly 70% of patients in the arm managed with the monitor reported a clinically meaningful improvement in quality of life, compared to 50% of patients in the control arm,” said Dr. Boehmer, professor of medicine and surgery at Penn State Health, Hershey.
Fluid overload is an indication of worsening disease and a frequent cause of heart failure hospitalization. The Zoll Heart Failure Monitoring System (HFMS) that was tested in this study already has regulatory approval. It is equipped to monitor several biomarkers, including heart rate and respiration rate, but its ability to measure lung fluid through low electromagnetic radiofrequency pulses was the function of interest for this study.
In this nonrandomized study, called Benefits of Microcor in Ambulatory
Decompensated Heart Failure (BMAD), a control arm was enrolled first. By monitoring the initial patients enrolled in the control arm, the investigators established a threshold of thoracic fluid that would be used to trigger an alert in the intervention arm. This ultimately was defined as 3 standard deviations from the population mean.
Patients were eligible for this study if they were discharged from a hospital with heart failure in the previous 10 days. Of exclusion criteria, a short life expectancy (< 1 year) and a wearable cardiac defibrillator were notable. Left ventricular ejection fraction (LVEF) was not considered for inclusion or exclusion.
All subjects participated in weekly phone calls and monthly office visits. However, both investigators and patients were blinded to the device data in the control arm. Conversely, subjects and investigators in the intervention arm were able to access data generated by the device through a secure website.
Of the 245 eligible patients in the control arm, 168 were available for evaluation at 90 days. Among the 249 eligible patients in the intervention arm, 176 were included in the 90-day evaluation. Of those who were not available, the most common reason was study withdrawal. About 20% died before the 90-day evaluation.
The majority of patients in both arms were in class III or IV heart failure. About half had LVEF less than 40%, and more than 40% of patients in each group had chronic kidney disease (CKD). Roughly 55% of patients were at least 65 years of age.
At 90 days, the absolute risk reduction in rehospitalization was 7%, producing a number to treat with the device of 14.3 to prevent one rehospitalization. In a subgroup stratification, the benefit was similar by age, sex, presence or absence of CKD, LVEF greater or lower than 40%, Black or non-Black race, and ischemic or nonischemic etiology.
Patient access to data considered a plus
If lack of randomization is a weakness of this study, the decision to unblind the data for both investigators and patients might not be, according to Lynne Stevenson, MD, director of the cardiomyopathy program, Vanderbilt University Medical Center, Nashville, Tenn.
“You might be criticized for this [allowing patients to monitor their data], but I actually think this is a strength of the study,” said Dr. Stevenson, who believes the growing trend to involve heart failure patients in self-management has been a positive direction in clinical care.
She indicated that, despite the potential bias derived from being aware of fluid fluctuations, this information might also be contributing to patient motivation for adherence and appropriate lifestyle modifications.
Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, made a similar point but for a different reason. She expressed concern about the work that monitoring the wearable device creates for clinicians. Despite the positive data generated by this study, Dr. Bozkurt said the device as used in the study demanded “a lot of clinical time and effort” when these are both in short supply.
While she called for a larger and randomized study to corroborate the results of this investigation, she also thinks that it would make sense to compare the clinical value of this device against alternative methods for monitoring heart failure, including other wearable devices. Dr. Bozkurt asserted that some of the most helpful devices from a clinical perspective might be those that patients monitor themselves.
“Hopefully in the future, we will be offering tools that provide patients information they can use without the immediate need of a clinician,” she said.
Dr. Boehmer reports financial relationships with Abbott, Boston Scientific, Medtronic, and Zoll Medical Corporation, which provided the funding for this study. Dr. Stevenson reports no potential conflicts of interest. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.
NEW ORLEANS – A wearable device that monitors thoracic fluid and can signal elevated levels can improve outcomes after heart failure hospitalization, according to a comparative but nonrandomized trial.
In this study, management adjustments made in response to a threshold alert from the device led to several improvements in outcome at 90 days, including a significant 38% reduction in the primary outcome of rehospitalization, relative to controls (P = .02), reported John P. Boehmer, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The same relative risk reduction at 90 days was observed for a composite outcome of time to first hospitalization, visit to an emergency room, or death (hazard ratio, 0.62; P = .03).
Quality of life, as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ), improved steadily in both the experimental and control arm over the 90-day study, but the curves separated at about 30 days, Dr. Boehmer reported. By the end of the study, the mean KCCQ difference was 12 points favoring the experimental arm on a scale in which 5 points is considered clinically meaningful.
70% report improved quality of life
“Responder analysis revealed that nearly 70% of patients in the arm managed with the monitor reported a clinically meaningful improvement in quality of life, compared to 50% of patients in the control arm,” said Dr. Boehmer, professor of medicine and surgery at Penn State Health, Hershey.
Fluid overload is an indication of worsening disease and a frequent cause of heart failure hospitalization. The Zoll Heart Failure Monitoring System (HFMS) that was tested in this study already has regulatory approval. It is equipped to monitor several biomarkers, including heart rate and respiration rate, but its ability to measure lung fluid through low electromagnetic radiofrequency pulses was the function of interest for this study.
In this nonrandomized study, called Benefits of Microcor in Ambulatory
Decompensated Heart Failure (BMAD), a control arm was enrolled first. By monitoring the initial patients enrolled in the control arm, the investigators established a threshold of thoracic fluid that would be used to trigger an alert in the intervention arm. This ultimately was defined as 3 standard deviations from the population mean.
Patients were eligible for this study if they were discharged from a hospital with heart failure in the previous 10 days. Of exclusion criteria, a short life expectancy (< 1 year) and a wearable cardiac defibrillator were notable. Left ventricular ejection fraction (LVEF) was not considered for inclusion or exclusion.
All subjects participated in weekly phone calls and monthly office visits. However, both investigators and patients were blinded to the device data in the control arm. Conversely, subjects and investigators in the intervention arm were able to access data generated by the device through a secure website.
Of the 245 eligible patients in the control arm, 168 were available for evaluation at 90 days. Among the 249 eligible patients in the intervention arm, 176 were included in the 90-day evaluation. Of those who were not available, the most common reason was study withdrawal. About 20% died before the 90-day evaluation.
The majority of patients in both arms were in class III or IV heart failure. About half had LVEF less than 40%, and more than 40% of patients in each group had chronic kidney disease (CKD). Roughly 55% of patients were at least 65 years of age.
At 90 days, the absolute risk reduction in rehospitalization was 7%, producing a number to treat with the device of 14.3 to prevent one rehospitalization. In a subgroup stratification, the benefit was similar by age, sex, presence or absence of CKD, LVEF greater or lower than 40%, Black or non-Black race, and ischemic or nonischemic etiology.
Patient access to data considered a plus
If lack of randomization is a weakness of this study, the decision to unblind the data for both investigators and patients might not be, according to Lynne Stevenson, MD, director of the cardiomyopathy program, Vanderbilt University Medical Center, Nashville, Tenn.
“You might be criticized for this [allowing patients to monitor their data], but I actually think this is a strength of the study,” said Dr. Stevenson, who believes the growing trend to involve heart failure patients in self-management has been a positive direction in clinical care.
She indicated that, despite the potential bias derived from being aware of fluid fluctuations, this information might also be contributing to patient motivation for adherence and appropriate lifestyle modifications.
Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, made a similar point but for a different reason. She expressed concern about the work that monitoring the wearable device creates for clinicians. Despite the positive data generated by this study, Dr. Bozkurt said the device as used in the study demanded “a lot of clinical time and effort” when these are both in short supply.
While she called for a larger and randomized study to corroborate the results of this investigation, she also thinks that it would make sense to compare the clinical value of this device against alternative methods for monitoring heart failure, including other wearable devices. Dr. Bozkurt asserted that some of the most helpful devices from a clinical perspective might be those that patients monitor themselves.
“Hopefully in the future, we will be offering tools that provide patients information they can use without the immediate need of a clinician,” she said.
Dr. Boehmer reports financial relationships with Abbott, Boston Scientific, Medtronic, and Zoll Medical Corporation, which provided the funding for this study. Dr. Stevenson reports no potential conflicts of interest. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.
NEW ORLEANS – A wearable device that monitors thoracic fluid and can signal elevated levels can improve outcomes after heart failure hospitalization, according to a comparative but nonrandomized trial.
In this study, management adjustments made in response to a threshold alert from the device led to several improvements in outcome at 90 days, including a significant 38% reduction in the primary outcome of rehospitalization, relative to controls (P = .02), reported John P. Boehmer, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The same relative risk reduction at 90 days was observed for a composite outcome of time to first hospitalization, visit to an emergency room, or death (hazard ratio, 0.62; P = .03).
Quality of life, as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ), improved steadily in both the experimental and control arm over the 90-day study, but the curves separated at about 30 days, Dr. Boehmer reported. By the end of the study, the mean KCCQ difference was 12 points favoring the experimental arm on a scale in which 5 points is considered clinically meaningful.
70% report improved quality of life
“Responder analysis revealed that nearly 70% of patients in the arm managed with the monitor reported a clinically meaningful improvement in quality of life, compared to 50% of patients in the control arm,” said Dr. Boehmer, professor of medicine and surgery at Penn State Health, Hershey.
Fluid overload is an indication of worsening disease and a frequent cause of heart failure hospitalization. The Zoll Heart Failure Monitoring System (HFMS) that was tested in this study already has regulatory approval. It is equipped to monitor several biomarkers, including heart rate and respiration rate, but its ability to measure lung fluid through low electromagnetic radiofrequency pulses was the function of interest for this study.
In this nonrandomized study, called Benefits of Microcor in Ambulatory
Decompensated Heart Failure (BMAD), a control arm was enrolled first. By monitoring the initial patients enrolled in the control arm, the investigators established a threshold of thoracic fluid that would be used to trigger an alert in the intervention arm. This ultimately was defined as 3 standard deviations from the population mean.
Patients were eligible for this study if they were discharged from a hospital with heart failure in the previous 10 days. Of exclusion criteria, a short life expectancy (< 1 year) and a wearable cardiac defibrillator were notable. Left ventricular ejection fraction (LVEF) was not considered for inclusion or exclusion.
All subjects participated in weekly phone calls and monthly office visits. However, both investigators and patients were blinded to the device data in the control arm. Conversely, subjects and investigators in the intervention arm were able to access data generated by the device through a secure website.
Of the 245 eligible patients in the control arm, 168 were available for evaluation at 90 days. Among the 249 eligible patients in the intervention arm, 176 were included in the 90-day evaluation. Of those who were not available, the most common reason was study withdrawal. About 20% died before the 90-day evaluation.
The majority of patients in both arms were in class III or IV heart failure. About half had LVEF less than 40%, and more than 40% of patients in each group had chronic kidney disease (CKD). Roughly 55% of patients were at least 65 years of age.
At 90 days, the absolute risk reduction in rehospitalization was 7%, producing a number to treat with the device of 14.3 to prevent one rehospitalization. In a subgroup stratification, the benefit was similar by age, sex, presence or absence of CKD, LVEF greater or lower than 40%, Black or non-Black race, and ischemic or nonischemic etiology.
Patient access to data considered a plus
If lack of randomization is a weakness of this study, the decision to unblind the data for both investigators and patients might not be, according to Lynne Stevenson, MD, director of the cardiomyopathy program, Vanderbilt University Medical Center, Nashville, Tenn.
“You might be criticized for this [allowing patients to monitor their data], but I actually think this is a strength of the study,” said Dr. Stevenson, who believes the growing trend to involve heart failure patients in self-management has been a positive direction in clinical care.
She indicated that, despite the potential bias derived from being aware of fluid fluctuations, this information might also be contributing to patient motivation for adherence and appropriate lifestyle modifications.
Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, made a similar point but for a different reason. She expressed concern about the work that monitoring the wearable device creates for clinicians. Despite the positive data generated by this study, Dr. Bozkurt said the device as used in the study demanded “a lot of clinical time and effort” when these are both in short supply.
While she called for a larger and randomized study to corroborate the results of this investigation, she also thinks that it would make sense to compare the clinical value of this device against alternative methods for monitoring heart failure, including other wearable devices. Dr. Bozkurt asserted that some of the most helpful devices from a clinical perspective might be those that patients monitor themselves.
“Hopefully in the future, we will be offering tools that provide patients information they can use without the immediate need of a clinician,” she said.
Dr. Boehmer reports financial relationships with Abbott, Boston Scientific, Medtronic, and Zoll Medical Corporation, which provided the funding for this study. Dr. Stevenson reports no potential conflicts of interest. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.
AT ACC 2023
FREEDOM COVID: Full-dose anticoagulation cut mortality but missed primary endpoint
Study conducted in noncritically ill
NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.
The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
Missed primary endpoint blamed on low events
The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.
India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.
“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.
In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).
In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
Enoxaparin and apixaban are studied
In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).
The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.
The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).
Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).
The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
Bleeding rates did not differ between arms
Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.
Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.
Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.
“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.
COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.
“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”
Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.
Study conducted in noncritically ill
Study conducted in noncritically ill
NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.
The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
Missed primary endpoint blamed on low events
The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.
India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.
“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.
In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).
In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
Enoxaparin and apixaban are studied
In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).
The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.
The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).
Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).
The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
Bleeding rates did not differ between arms
Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.
Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.
Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.
“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.
COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.
“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”
Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.
NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.
The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
Missed primary endpoint blamed on low events
The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.
India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.
“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.
In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).
In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
Enoxaparin and apixaban are studied
In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).
The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.
The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).
Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).
The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
Bleeding rates did not differ between arms
Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.
Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.
Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.
“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.
COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.
“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”
Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.
AT ACC 2023
Clinician violence: Virtual reality to the rescue?
This discussion was recorded on Feb. 21, 2023. This transcript has been edited for clarity.
Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Welcome, Dr. Salazar. It’s a pleasure to have you join us today.
Gilberto A. Salazar, MD: The pleasure is all mine, Dr. Glatter. Thank you so much for having me.
Dr. Glatter: This is such an important topic, as you can imagine. Workplace violence is affecting so many providers in hospital emergency departments but also throughout other parts of the hospital.
First, can you describe how the virtual reality (VR) program was designed that you developed and what type of situations it simulates?
Dr. Salazar: We worked in conjunction with the University of Texas at Dallas. They help people like me, subject matter experts in health care, to bring ideas to reality. I worked very closely with a group of engineers from their department in designing a module specifically designed to tackle, as you mentioned, one of our biggest threats in workplace violence.
We decided to bring in a series of competencies and proficiencies that we wanted to bring into the virtual reality space. In leveraging the technology and the expertise from UT Dallas, we were able to make that happen.
Dr. Glatter: I think it’s important to understand, in terms of virtual reality, what type of environment the program creates. Can you describe what a provider who puts the goggles on is experiencing? Do they feel anything? Is there technology that enables this?
Dr. Salazar: Yes, absolutely. We were able to bring to reality a series of scenarios very common from what you and I see in the emergency department on a daily basis. We wanted to immerse a learner into that specific environment. We didn’t feel that a module or something on a computer or a slide set could really bring the reality of what it’s like to interact with a patient who may be escalating or may be aggressive.
We are immersing learners into an actual hospital room to our specifications, very similar to exactly where we practice each and every day, and taking the learners through different situations that we designed with various levels of escalation and aggression, and asking the learner to manage that situation as best as they possibly can using the competencies and proficiencies that we taught them.
Dr. Glatter: Haptic feedback is an important part of the program and also the approach and technique that you’re using. Can you describe what haptic feedback means and what people actually feel?
Dr. Salazar: Absolutely. One of the most unfortunate things in my professional career is physical abuse suffered by people like me and you and our colleagues, nursing personnel, technicians, and others, resulting in injury.
We wanted to provide the most realistic experience that we could design. Haptics engage digital senses other than your auditory and your visuals. They really engage your tactile senses. These haptic vests and gloves and technology allow us to provide a third set of sensory stimuli for the learner.
At one of the modules, we have an actual physical assault that takes place, and the learner is actually able to feel in their body the strikes – of course, not painful – but just bringing in those senses and that stimulus, really leaving the learner with an experience that’s going to be long-lasting.
Dr. Glatter: Feeling that stimulus certainly affects your vital signs. Do you monitor a provider’s vital signs, such as their blood pressure and heart rate, as the situation and the threat escalate? That could potentially trigger some issues in people with prior PTSD or people with other mental health issues. Has that ever been considered in the design of your program?
Dr. Salazar: Yes, 100%. The beautiful thing about haptics is that they can be tailored to our specific parameters. The sensory stimulus that’s provided is actually very mild. It feels more like a tap than an actual strike. It just reminds us that when we’re having or experiencing an actual physical attack, we’re really engaging the senses.
We have an emergency physician or an EMT-paramedic on site at all times during the training so that we can monitor our subjects and make sure that they’re comfortable and healthy.
Dr. Glatter: Do they have actual sensors attached to their bodies that are part of your program or distinct in terms of monitoring their vital signs?
Dr. Salazar: It’s completely different. We have two different systems that we are planning on utilizing. Frankly, in the final version of this virtual reality module, we may not even involve the haptics. We’re going to study it and see how our learners behave and how much information they’re able to acquire and retain.
It may be very possible that just the visuals – the auditory and the immersion taking place within the hospital room – may be enough. It’s very possible that, in the next final version of this, we may find that haptics bring in quite a bit of value, and we may incorporate that. If that is the case, then we will, of course, acquire different technology to monitor the patient’s vital signs.
Dr. Glatter: Clearly, when situations escalate in the department, everyone gets more concerned about the patient, but providers are part of this equation, as you allude to.
In 2022, there was a poll by the American College of Emergency Physicians that stated that 85% of emergency physicians reported an increase in violent activity in their ERs in the past 5 years. Nearly two-thirds of nearly 3,000 emergency physicians surveyed reported being assaulted in the past year. This is an important module that we integrate into training providers in terms of these types of tense situations that can result not only in mental anguish but also in physical injury.
Dr. Salazar: One hundred percent. I frankly got tired of seeing my friends and my colleagues suffer both the physical and mental effects of verbal and physical abuse, and I wanted to design a project that was very patient centric while allowing our personnel to really manage these situations a little bit better.
Frankly, we don’t receive great training in this space, and I wanted to rewrite that narrative and make things better for our clinicians out there while remaining patient centric. I wanted to do something about it, and hopefully this dream will become a reality.
Dr. Glatter: Absolutely. There are other data from the Bureau of Labor Statistics stating that health care workers are five times more likely than employees in any other area of work to experience workplace violence. This could, again, range from verbal to physical violence. This is a very important module that you’re developing.
Are there any thoughts to extend this to active-shooter scenarios or any other high-stakes scenarios that you can imagine in the department?
Dr. Salazar: We’re actually working with the same developer that’s helping us with this VR module in developing a mass-casualty incident module so that we can get better training in responding to these very unfortunate high-stakes situations.
Dr. Glatter: In terms of using the module remotely, certainly not requiring resources or having to be in a physical place, can providers in your plan be able to take such a headset home and practice on their own in the sense of being able to deal with a situation? Would this be more reserved for in-department use?
Dr. Salazar: That’s a phenomenal question. I wanted to create the most flexible module that I possibly could. Ideally, a dream scenario is leveraging a simulation center at an academic center and not just do the VR module but also have a brief didactics incorporating a small slide set, some feedback, and some standardized patients. I wanted it to be flexible enough so that folks here in my state, a different state, or even internationally could take advantage of this technology and do it from the comfort of their home.
As you mentioned, this is going to strike some people. It’s going to hit them heavier than others in terms of prior experience as PTSD. For some people, it may be more comfortable to do it in the comfort of their homes. I wanted to create something very flexible and dynamic.
Dr. Glatter: I think that’s ideal. Just one other point. Can you discuss the different levels of competencies involved in this module and how that would be attained?
Dr. Salazar: It’s all evidence based, so we borrowed from literature and the specialties of emergency medicine. We collaborated with psychiatrists within our medical center. We looked at all available literature and methods, proficiencies, competencies, and best practices, and we took all of them together to form something that we think is organized and concise.
We were able to create our own algorithm, but it’s not brand new. We’re just borrowing what we think is the best to create something that the majority of health care personnel are going to be able to relate to and be able to really be proficient at.
This includes things like active listening, bargaining, how to respond, where to put yourself in a situation, and the best possible situation to respond to a scenario, how to prevent things – how to get out of a chokehold, for example. We’re borrowing from several different disciplines and creating something that can be very concise and organized.
Dr. Glatter: Does this program that you’ve developed allow the provider to get feedback in the sense that when they’re in such a danger, their life could be at risk? For example, if they don’t remove themselves in a certain amount of time, this could be lethal.
Dr. Salazar: Yes, 100%. Probably the one thing that differentiates our project from any others is the ability to customize the experience so that a learner who is doing the things that we ask them to do in terms of safety and response is able to get out of a situation successfully within the environment. If they don’t, they get some kind of feedback.
Not to spoil the surprise here, but we’re going to be doing things like looking at decibel meters to see what the volume in the room is doing and how you’re managing the volume and the stimulation within the room. If you are able to maintain the decibel readings at a specific level, you’re going to succeed through the module. If you don’t, we keep the patient escalation going.
Dr. Glatter: There is a debrief built into this type of approach where, in other words, learning points are emphasized – where you could have done better and such.
Dr. Salazar: Yes, absolutely. We are going to be able to get individualized data for each learner so that we can tailor the debrief to their own performance and be able to give them actionable items to work on. It’s a debrief that’s productive and individualized, and folks can walk away with something useful in the end.
Dr. Glatter: Are the data shared or confidential at present?
Dr. Salazar: At this very moment, the data are confidential. We are going to look at how to best use this. We’re hoping to eventually write this up and see how this information can be best used to train personnel.
Eventually, we may see that some of the advice that we’re giving is very common to most folks. Others may require some individualized type of feedback. That said, it remains to be seen, but right now, it’s confidential.
Dr. Glatter: Is this currently being implemented as part of your curriculum for emergency medicine residents?
Dr. Salazar: We’re going to study it first. We’re very excited to include our emergency medicine residents as one of our cohorts that’s going to be undergoing the module, and we’re going to be studying other forms of workplace violence mitigation strategies. We’re really excited about the possibility of this eventually becoming the standard of education for not only our emergency medicine residents, but also health care personnel all over the world.
Dr. Glatter: I’m glad you mentioned that, because obviously nurses, clerks in the department, and anyone who’s working in the department, for that matter, and who interfaces with patients really should undergo such training.
Dr. Salazar: Absolutely. The folks at intake, at check-in, and at kiosks. Do they go through a separate area for screening? You’re absolutely right. There are many folks who interface with patients and all of us are potential victims of workplace violence. We want to give our health care family the best opportunity to succeed in these situations.
Dr. Glatter:: Absolutely. Even EMS providers, being on the front lines and encountering patients in such situations, would benefit, in my opinion.
Dr. Salazar: Yes, absolutely. Behavioral health emergencies and organically induced altered mental status results in injury, both physical and mental, to EMS professionals as well, and there’s good evidence of that. I’ll be very glad to see this type of education make it out to our initial and continuing education efforts for EMS as well.
Dr. Glatter: I want to thank you. This has been very helpful. It’s such an important task that you’ve started to explore, and I look forward to follow-up on this. Again, thank you for your time.
Dr. Salazar: It was my pleasure. Thank you so much for having me.
Dr. Glatter is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes. Dr. Salazar is a board-certified emergency physician and associate professor at UT Southwestern Medicine Center in Dallas. He is involved with the UTSW Emergency Medicine Education Program and serves as the medical director to teach both initial and continuing the emergency medicine education for emergency medical technicians and paramedics, which trains most of the Dallas Fire Rescue personnel and the vast majority for EMS providers in the Dallas County. In addition, he serves as an associate chief of service at Parkland’s emergency department, and liaison to surgical services. A version of this article originally appeared on Medscape.com.
This discussion was recorded on Feb. 21, 2023. This transcript has been edited for clarity.
Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Welcome, Dr. Salazar. It’s a pleasure to have you join us today.
Gilberto A. Salazar, MD: The pleasure is all mine, Dr. Glatter. Thank you so much for having me.
Dr. Glatter: This is such an important topic, as you can imagine. Workplace violence is affecting so many providers in hospital emergency departments but also throughout other parts of the hospital.
First, can you describe how the virtual reality (VR) program was designed that you developed and what type of situations it simulates?
Dr. Salazar: We worked in conjunction with the University of Texas at Dallas. They help people like me, subject matter experts in health care, to bring ideas to reality. I worked very closely with a group of engineers from their department in designing a module specifically designed to tackle, as you mentioned, one of our biggest threats in workplace violence.
We decided to bring in a series of competencies and proficiencies that we wanted to bring into the virtual reality space. In leveraging the technology and the expertise from UT Dallas, we were able to make that happen.
Dr. Glatter: I think it’s important to understand, in terms of virtual reality, what type of environment the program creates. Can you describe what a provider who puts the goggles on is experiencing? Do they feel anything? Is there technology that enables this?
Dr. Salazar: Yes, absolutely. We were able to bring to reality a series of scenarios very common from what you and I see in the emergency department on a daily basis. We wanted to immerse a learner into that specific environment. We didn’t feel that a module or something on a computer or a slide set could really bring the reality of what it’s like to interact with a patient who may be escalating or may be aggressive.
We are immersing learners into an actual hospital room to our specifications, very similar to exactly where we practice each and every day, and taking the learners through different situations that we designed with various levels of escalation and aggression, and asking the learner to manage that situation as best as they possibly can using the competencies and proficiencies that we taught them.
Dr. Glatter: Haptic feedback is an important part of the program and also the approach and technique that you’re using. Can you describe what haptic feedback means and what people actually feel?
Dr. Salazar: Absolutely. One of the most unfortunate things in my professional career is physical abuse suffered by people like me and you and our colleagues, nursing personnel, technicians, and others, resulting in injury.
We wanted to provide the most realistic experience that we could design. Haptics engage digital senses other than your auditory and your visuals. They really engage your tactile senses. These haptic vests and gloves and technology allow us to provide a third set of sensory stimuli for the learner.
At one of the modules, we have an actual physical assault that takes place, and the learner is actually able to feel in their body the strikes – of course, not painful – but just bringing in those senses and that stimulus, really leaving the learner with an experience that’s going to be long-lasting.
Dr. Glatter: Feeling that stimulus certainly affects your vital signs. Do you monitor a provider’s vital signs, such as their blood pressure and heart rate, as the situation and the threat escalate? That could potentially trigger some issues in people with prior PTSD or people with other mental health issues. Has that ever been considered in the design of your program?
Dr. Salazar: Yes, 100%. The beautiful thing about haptics is that they can be tailored to our specific parameters. The sensory stimulus that’s provided is actually very mild. It feels more like a tap than an actual strike. It just reminds us that when we’re having or experiencing an actual physical attack, we’re really engaging the senses.
We have an emergency physician or an EMT-paramedic on site at all times during the training so that we can monitor our subjects and make sure that they’re comfortable and healthy.
Dr. Glatter: Do they have actual sensors attached to their bodies that are part of your program or distinct in terms of monitoring their vital signs?
Dr. Salazar: It’s completely different. We have two different systems that we are planning on utilizing. Frankly, in the final version of this virtual reality module, we may not even involve the haptics. We’re going to study it and see how our learners behave and how much information they’re able to acquire and retain.
It may be very possible that just the visuals – the auditory and the immersion taking place within the hospital room – may be enough. It’s very possible that, in the next final version of this, we may find that haptics bring in quite a bit of value, and we may incorporate that. If that is the case, then we will, of course, acquire different technology to monitor the patient’s vital signs.
Dr. Glatter: Clearly, when situations escalate in the department, everyone gets more concerned about the patient, but providers are part of this equation, as you allude to.
In 2022, there was a poll by the American College of Emergency Physicians that stated that 85% of emergency physicians reported an increase in violent activity in their ERs in the past 5 years. Nearly two-thirds of nearly 3,000 emergency physicians surveyed reported being assaulted in the past year. This is an important module that we integrate into training providers in terms of these types of tense situations that can result not only in mental anguish but also in physical injury.
Dr. Salazar: One hundred percent. I frankly got tired of seeing my friends and my colleagues suffer both the physical and mental effects of verbal and physical abuse, and I wanted to design a project that was very patient centric while allowing our personnel to really manage these situations a little bit better.
Frankly, we don’t receive great training in this space, and I wanted to rewrite that narrative and make things better for our clinicians out there while remaining patient centric. I wanted to do something about it, and hopefully this dream will become a reality.
Dr. Glatter: Absolutely. There are other data from the Bureau of Labor Statistics stating that health care workers are five times more likely than employees in any other area of work to experience workplace violence. This could, again, range from verbal to physical violence. This is a very important module that you’re developing.
Are there any thoughts to extend this to active-shooter scenarios or any other high-stakes scenarios that you can imagine in the department?
Dr. Salazar: We’re actually working with the same developer that’s helping us with this VR module in developing a mass-casualty incident module so that we can get better training in responding to these very unfortunate high-stakes situations.
Dr. Glatter: In terms of using the module remotely, certainly not requiring resources or having to be in a physical place, can providers in your plan be able to take such a headset home and practice on their own in the sense of being able to deal with a situation? Would this be more reserved for in-department use?
Dr. Salazar: That’s a phenomenal question. I wanted to create the most flexible module that I possibly could. Ideally, a dream scenario is leveraging a simulation center at an academic center and not just do the VR module but also have a brief didactics incorporating a small slide set, some feedback, and some standardized patients. I wanted it to be flexible enough so that folks here in my state, a different state, or even internationally could take advantage of this technology and do it from the comfort of their home.
As you mentioned, this is going to strike some people. It’s going to hit them heavier than others in terms of prior experience as PTSD. For some people, it may be more comfortable to do it in the comfort of their homes. I wanted to create something very flexible and dynamic.
Dr. Glatter: I think that’s ideal. Just one other point. Can you discuss the different levels of competencies involved in this module and how that would be attained?
Dr. Salazar: It’s all evidence based, so we borrowed from literature and the specialties of emergency medicine. We collaborated with psychiatrists within our medical center. We looked at all available literature and methods, proficiencies, competencies, and best practices, and we took all of them together to form something that we think is organized and concise.
We were able to create our own algorithm, but it’s not brand new. We’re just borrowing what we think is the best to create something that the majority of health care personnel are going to be able to relate to and be able to really be proficient at.
This includes things like active listening, bargaining, how to respond, where to put yourself in a situation, and the best possible situation to respond to a scenario, how to prevent things – how to get out of a chokehold, for example. We’re borrowing from several different disciplines and creating something that can be very concise and organized.
Dr. Glatter: Does this program that you’ve developed allow the provider to get feedback in the sense that when they’re in such a danger, their life could be at risk? For example, if they don’t remove themselves in a certain amount of time, this could be lethal.
Dr. Salazar: Yes, 100%. Probably the one thing that differentiates our project from any others is the ability to customize the experience so that a learner who is doing the things that we ask them to do in terms of safety and response is able to get out of a situation successfully within the environment. If they don’t, they get some kind of feedback.
Not to spoil the surprise here, but we’re going to be doing things like looking at decibel meters to see what the volume in the room is doing and how you’re managing the volume and the stimulation within the room. If you are able to maintain the decibel readings at a specific level, you’re going to succeed through the module. If you don’t, we keep the patient escalation going.
Dr. Glatter: There is a debrief built into this type of approach where, in other words, learning points are emphasized – where you could have done better and such.
Dr. Salazar: Yes, absolutely. We are going to be able to get individualized data for each learner so that we can tailor the debrief to their own performance and be able to give them actionable items to work on. It’s a debrief that’s productive and individualized, and folks can walk away with something useful in the end.
Dr. Glatter: Are the data shared or confidential at present?
Dr. Salazar: At this very moment, the data are confidential. We are going to look at how to best use this. We’re hoping to eventually write this up and see how this information can be best used to train personnel.
Eventually, we may see that some of the advice that we’re giving is very common to most folks. Others may require some individualized type of feedback. That said, it remains to be seen, but right now, it’s confidential.
Dr. Glatter: Is this currently being implemented as part of your curriculum for emergency medicine residents?
Dr. Salazar: We’re going to study it first. We’re very excited to include our emergency medicine residents as one of our cohorts that’s going to be undergoing the module, and we’re going to be studying other forms of workplace violence mitigation strategies. We’re really excited about the possibility of this eventually becoming the standard of education for not only our emergency medicine residents, but also health care personnel all over the world.
Dr. Glatter: I’m glad you mentioned that, because obviously nurses, clerks in the department, and anyone who’s working in the department, for that matter, and who interfaces with patients really should undergo such training.
Dr. Salazar: Absolutely. The folks at intake, at check-in, and at kiosks. Do they go through a separate area for screening? You’re absolutely right. There are many folks who interface with patients and all of us are potential victims of workplace violence. We want to give our health care family the best opportunity to succeed in these situations.
Dr. Glatter:: Absolutely. Even EMS providers, being on the front lines and encountering patients in such situations, would benefit, in my opinion.
Dr. Salazar: Yes, absolutely. Behavioral health emergencies and organically induced altered mental status results in injury, both physical and mental, to EMS professionals as well, and there’s good evidence of that. I’ll be very glad to see this type of education make it out to our initial and continuing education efforts for EMS as well.
Dr. Glatter: I want to thank you. This has been very helpful. It’s such an important task that you’ve started to explore, and I look forward to follow-up on this. Again, thank you for your time.
Dr. Salazar: It was my pleasure. Thank you so much for having me.
Dr. Glatter is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes. Dr. Salazar is a board-certified emergency physician and associate professor at UT Southwestern Medicine Center in Dallas. He is involved with the UTSW Emergency Medicine Education Program and serves as the medical director to teach both initial and continuing the emergency medicine education for emergency medical technicians and paramedics, which trains most of the Dallas Fire Rescue personnel and the vast majority for EMS providers in the Dallas County. In addition, he serves as an associate chief of service at Parkland’s emergency department, and liaison to surgical services. A version of this article originally appeared on Medscape.com.
This discussion was recorded on Feb. 21, 2023. This transcript has been edited for clarity.
Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Welcome, Dr. Salazar. It’s a pleasure to have you join us today.
Gilberto A. Salazar, MD: The pleasure is all mine, Dr. Glatter. Thank you so much for having me.
Dr. Glatter: This is such an important topic, as you can imagine. Workplace violence is affecting so many providers in hospital emergency departments but also throughout other parts of the hospital.
First, can you describe how the virtual reality (VR) program was designed that you developed and what type of situations it simulates?
Dr. Salazar: We worked in conjunction with the University of Texas at Dallas. They help people like me, subject matter experts in health care, to bring ideas to reality. I worked very closely with a group of engineers from their department in designing a module specifically designed to tackle, as you mentioned, one of our biggest threats in workplace violence.
We decided to bring in a series of competencies and proficiencies that we wanted to bring into the virtual reality space. In leveraging the technology and the expertise from UT Dallas, we were able to make that happen.
Dr. Glatter: I think it’s important to understand, in terms of virtual reality, what type of environment the program creates. Can you describe what a provider who puts the goggles on is experiencing? Do they feel anything? Is there technology that enables this?
Dr. Salazar: Yes, absolutely. We were able to bring to reality a series of scenarios very common from what you and I see in the emergency department on a daily basis. We wanted to immerse a learner into that specific environment. We didn’t feel that a module or something on a computer or a slide set could really bring the reality of what it’s like to interact with a patient who may be escalating or may be aggressive.
We are immersing learners into an actual hospital room to our specifications, very similar to exactly where we practice each and every day, and taking the learners through different situations that we designed with various levels of escalation and aggression, and asking the learner to manage that situation as best as they possibly can using the competencies and proficiencies that we taught them.
Dr. Glatter: Haptic feedback is an important part of the program and also the approach and technique that you’re using. Can you describe what haptic feedback means and what people actually feel?
Dr. Salazar: Absolutely. One of the most unfortunate things in my professional career is physical abuse suffered by people like me and you and our colleagues, nursing personnel, technicians, and others, resulting in injury.
We wanted to provide the most realistic experience that we could design. Haptics engage digital senses other than your auditory and your visuals. They really engage your tactile senses. These haptic vests and gloves and technology allow us to provide a third set of sensory stimuli for the learner.
At one of the modules, we have an actual physical assault that takes place, and the learner is actually able to feel in their body the strikes – of course, not painful – but just bringing in those senses and that stimulus, really leaving the learner with an experience that’s going to be long-lasting.
Dr. Glatter: Feeling that stimulus certainly affects your vital signs. Do you monitor a provider’s vital signs, such as their blood pressure and heart rate, as the situation and the threat escalate? That could potentially trigger some issues in people with prior PTSD or people with other mental health issues. Has that ever been considered in the design of your program?
Dr. Salazar: Yes, 100%. The beautiful thing about haptics is that they can be tailored to our specific parameters. The sensory stimulus that’s provided is actually very mild. It feels more like a tap than an actual strike. It just reminds us that when we’re having or experiencing an actual physical attack, we’re really engaging the senses.
We have an emergency physician or an EMT-paramedic on site at all times during the training so that we can monitor our subjects and make sure that they’re comfortable and healthy.
Dr. Glatter: Do they have actual sensors attached to their bodies that are part of your program or distinct in terms of monitoring their vital signs?
Dr. Salazar: It’s completely different. We have two different systems that we are planning on utilizing. Frankly, in the final version of this virtual reality module, we may not even involve the haptics. We’re going to study it and see how our learners behave and how much information they’re able to acquire and retain.
It may be very possible that just the visuals – the auditory and the immersion taking place within the hospital room – may be enough. It’s very possible that, in the next final version of this, we may find that haptics bring in quite a bit of value, and we may incorporate that. If that is the case, then we will, of course, acquire different technology to monitor the patient’s vital signs.
Dr. Glatter: Clearly, when situations escalate in the department, everyone gets more concerned about the patient, but providers are part of this equation, as you allude to.
In 2022, there was a poll by the American College of Emergency Physicians that stated that 85% of emergency physicians reported an increase in violent activity in their ERs in the past 5 years. Nearly two-thirds of nearly 3,000 emergency physicians surveyed reported being assaulted in the past year. This is an important module that we integrate into training providers in terms of these types of tense situations that can result not only in mental anguish but also in physical injury.
Dr. Salazar: One hundred percent. I frankly got tired of seeing my friends and my colleagues suffer both the physical and mental effects of verbal and physical abuse, and I wanted to design a project that was very patient centric while allowing our personnel to really manage these situations a little bit better.
Frankly, we don’t receive great training in this space, and I wanted to rewrite that narrative and make things better for our clinicians out there while remaining patient centric. I wanted to do something about it, and hopefully this dream will become a reality.
Dr. Glatter: Absolutely. There are other data from the Bureau of Labor Statistics stating that health care workers are five times more likely than employees in any other area of work to experience workplace violence. This could, again, range from verbal to physical violence. This is a very important module that you’re developing.
Are there any thoughts to extend this to active-shooter scenarios or any other high-stakes scenarios that you can imagine in the department?
Dr. Salazar: We’re actually working with the same developer that’s helping us with this VR module in developing a mass-casualty incident module so that we can get better training in responding to these very unfortunate high-stakes situations.
Dr. Glatter: In terms of using the module remotely, certainly not requiring resources or having to be in a physical place, can providers in your plan be able to take such a headset home and practice on their own in the sense of being able to deal with a situation? Would this be more reserved for in-department use?
Dr. Salazar: That’s a phenomenal question. I wanted to create the most flexible module that I possibly could. Ideally, a dream scenario is leveraging a simulation center at an academic center and not just do the VR module but also have a brief didactics incorporating a small slide set, some feedback, and some standardized patients. I wanted it to be flexible enough so that folks here in my state, a different state, or even internationally could take advantage of this technology and do it from the comfort of their home.
As you mentioned, this is going to strike some people. It’s going to hit them heavier than others in terms of prior experience as PTSD. For some people, it may be more comfortable to do it in the comfort of their homes. I wanted to create something very flexible and dynamic.
Dr. Glatter: I think that’s ideal. Just one other point. Can you discuss the different levels of competencies involved in this module and how that would be attained?
Dr. Salazar: It’s all evidence based, so we borrowed from literature and the specialties of emergency medicine. We collaborated with psychiatrists within our medical center. We looked at all available literature and methods, proficiencies, competencies, and best practices, and we took all of them together to form something that we think is organized and concise.
We were able to create our own algorithm, but it’s not brand new. We’re just borrowing what we think is the best to create something that the majority of health care personnel are going to be able to relate to and be able to really be proficient at.
This includes things like active listening, bargaining, how to respond, where to put yourself in a situation, and the best possible situation to respond to a scenario, how to prevent things – how to get out of a chokehold, for example. We’re borrowing from several different disciplines and creating something that can be very concise and organized.
Dr. Glatter: Does this program that you’ve developed allow the provider to get feedback in the sense that when they’re in such a danger, their life could be at risk? For example, if they don’t remove themselves in a certain amount of time, this could be lethal.
Dr. Salazar: Yes, 100%. Probably the one thing that differentiates our project from any others is the ability to customize the experience so that a learner who is doing the things that we ask them to do in terms of safety and response is able to get out of a situation successfully within the environment. If they don’t, they get some kind of feedback.
Not to spoil the surprise here, but we’re going to be doing things like looking at decibel meters to see what the volume in the room is doing and how you’re managing the volume and the stimulation within the room. If you are able to maintain the decibel readings at a specific level, you’re going to succeed through the module. If you don’t, we keep the patient escalation going.
Dr. Glatter: There is a debrief built into this type of approach where, in other words, learning points are emphasized – where you could have done better and such.
Dr. Salazar: Yes, absolutely. We are going to be able to get individualized data for each learner so that we can tailor the debrief to their own performance and be able to give them actionable items to work on. It’s a debrief that’s productive and individualized, and folks can walk away with something useful in the end.
Dr. Glatter: Are the data shared or confidential at present?
Dr. Salazar: At this very moment, the data are confidential. We are going to look at how to best use this. We’re hoping to eventually write this up and see how this information can be best used to train personnel.
Eventually, we may see that some of the advice that we’re giving is very common to most folks. Others may require some individualized type of feedback. That said, it remains to be seen, but right now, it’s confidential.
Dr. Glatter: Is this currently being implemented as part of your curriculum for emergency medicine residents?
Dr. Salazar: We’re going to study it first. We’re very excited to include our emergency medicine residents as one of our cohorts that’s going to be undergoing the module, and we’re going to be studying other forms of workplace violence mitigation strategies. We’re really excited about the possibility of this eventually becoming the standard of education for not only our emergency medicine residents, but also health care personnel all over the world.
Dr. Glatter: I’m glad you mentioned that, because obviously nurses, clerks in the department, and anyone who’s working in the department, for that matter, and who interfaces with patients really should undergo such training.
Dr. Salazar: Absolutely. The folks at intake, at check-in, and at kiosks. Do they go through a separate area for screening? You’re absolutely right. There are many folks who interface with patients and all of us are potential victims of workplace violence. We want to give our health care family the best opportunity to succeed in these situations.
Dr. Glatter:: Absolutely. Even EMS providers, being on the front lines and encountering patients in such situations, would benefit, in my opinion.
Dr. Salazar: Yes, absolutely. Behavioral health emergencies and organically induced altered mental status results in injury, both physical and mental, to EMS professionals as well, and there’s good evidence of that. I’ll be very glad to see this type of education make it out to our initial and continuing education efforts for EMS as well.
Dr. Glatter: I want to thank you. This has been very helpful. It’s such an important task that you’ve started to explore, and I look forward to follow-up on this. Again, thank you for your time.
Dr. Salazar: It was my pleasure. Thank you so much for having me.
Dr. Glatter is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes. Dr. Salazar is a board-certified emergency physician and associate professor at UT Southwestern Medicine Center in Dallas. He is involved with the UTSW Emergency Medicine Education Program and serves as the medical director to teach both initial and continuing the emergency medicine education for emergency medical technicians and paramedics, which trains most of the Dallas Fire Rescue personnel and the vast majority for EMS providers in the Dallas County. In addition, he serves as an associate chief of service at Parkland’s emergency department, and liaison to surgical services. A version of this article originally appeared on Medscape.com.
Fixed-dose combo pill for PAH promises accelerated benefit: A DUE
Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.
The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
Guidelines encourage rapid PVR reductions
In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).
In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.
Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
PVR reduced twofold on combination therapy
Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).
For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).
The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.
The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.
Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.
Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
Anemia risk unexpected
Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.
In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.
Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.
Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.
Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.
The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
Guidelines encourage rapid PVR reductions
In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).
In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.
Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
PVR reduced twofold on combination therapy
Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).
For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).
The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.
The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.
Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.
Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
Anemia risk unexpected
Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.
In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.
Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.
Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.
Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.
The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
Guidelines encourage rapid PVR reductions
In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).
In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.
Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
PVR reduced twofold on combination therapy
Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).
For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).
The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.
The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.
Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.
Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
Anemia risk unexpected
Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.
In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.
Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.
Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.
AT ACC 2023
Depressive symptoms tied to higher stroke risk, worse outcomes
new research suggests.
Data from the international INTERSTROKE study also showed that those with depressive symptoms before a stroke had worse outcomes, including a significantly higher mortality rate in the first month after a stroke.
These findings build on prior research on the link between depression and stroke, including one study that showed an increased risk for incident stroke among those with a high number of depressive symptoms and another that found that worsening depression can precede stroke in older adults.
“Depression is an important risk factor for acute stroke and is potentially a modifiable contributor to the global burden of stroke,” lead investigator Robert Murphy, MB, a consultant in stroke and geriatric medicine and a researcher with the clinical research facility at the University of Galway, Ireland, told this news organization. “Even mild depressive symptoms were found in this study to be associated with increased risk of stroke and this adds to the literature that across the full range of depressive symptoms there is an association with increased risk of stroke.”
The findings were published online March 8 in Neurology.
Significant stroke risk
For the analysis, investigators collected data on 26,877 cases and controls across 32 countries who participated in INTERSTROKE, an international case-control study of risk factors for a first acute stroke. Participants were recruited between 2007 and 2015 and completed a series of questionnaires about stroke risk factors, including measures of depressive symptoms experienced in the past 12 months.
After adjustment for occupation, education, wealth index, diet, physical activity, alcohol consumption, and smoking history, having prestroke depressive symptoms was associated with greater odds for acute stroke (adjusted odds ratio [aOR], 1.46; 95% confidence interval [CI], 1.34-1.58), including both intracerebral hemorrhage (aOR, 1.56; 95% CI, 1.28-1.91) and ischemic stroke (aOR, 1.44; 95% CI, 1.31-1.58).
Stroke risk increased with increasing severity of depression, but even those with mild depression had a 35% increased risk (aOR, 1.35; 95% CI, 1.19-1.53).
The increased risk held even after the researchers adjusted further for diabetes, hypertension, atrial fibrillation, and body mass index, and work, home, and financial stress.
The association was consistent across geographical regions and age groups, but was stronger in men and in those without hypertension.
“This study looks at different constructs of depression and identifies that across the spectrum of mild, moderate, and severe depressive symptoms that there is an association present with acute stroke and that a biological gradient emerges with increasing burden of depressive symptoms associated with increasing risk,” Dr. Murphy said.
An antidepressant mediating effect?
While prestroke depressive symptoms were not associated with a greater odds of worse stroke severity, they were associated with worse outcomes (P < .001) and higher mortality (10% vs. 8.1%; P = .003) 1 month after a stroke.
In a subgroup analysis, researchers found no association between depressive symptoms and stroke risk in patients who were taking antidepressants.
While no assumptions of causality can be drawn from these findings, “this subgroup analysis does suggest that an increased risk of stroke in those with depression may be attenuated if a patient is on appropriate treatment,” Dr. Murphy said. “This is an area that warrants further exploration.”
The mechanisms that link depression to stroke are unclear, but these findings offer strong evidence that this link exists, Dr. Murphy said.
“We adjusted for potential confounders in sequential models and after adjusting for traditional cardiovascular risk factors there was a consistent association between depressive symptoms and stroke identifying that there is likely an independent association between depression and stroke,” Dr. Murphy said.
Questions remain
Commenting on the study, Daniel T. Lackland DrPH, professor, division of translational neurosciences and population studies, department of neurology, Medical University of South Carolina, Charleston, said it adds to a growing body of work on the association of stroke and depression.
“In this case, depression may be a risk factor for having a stroke,” said Dr. Lackland, who was not part of the study. In addition, the study suggests that “treating depression can have additional benefits beyond mental health, in this case, reduced stroke risks.”
However, it’s important, as with any observational study, that there may be confounding factors that may offer an alternative explanation for the findings.
“Further, it is often difficult to accurately assess depression in all individuals, and specifically in individuals who have had a stroke,” Dr. Lackland said. “While this particular study adds depression as a risk factor and suggests treatment of depression in reducing risks, it is important to emphasize that the traditional stroke risk factors including hypertension should [be] continually recognized and treat[ed] with high rigor.”
The INTERSTROKE study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Stroke Network, the Swedish Research Council, the Swedish Heart Lung Foundation, AFA Insurance, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), Merck Sharp & Dohme, the Swedish Heart Lung Foundation, Chest Heart & Stroke Scotland, and the Stroke Association (United Kingdom). Dr. Murphy and Dr. Lackland have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
Data from the international INTERSTROKE study also showed that those with depressive symptoms before a stroke had worse outcomes, including a significantly higher mortality rate in the first month after a stroke.
These findings build on prior research on the link between depression and stroke, including one study that showed an increased risk for incident stroke among those with a high number of depressive symptoms and another that found that worsening depression can precede stroke in older adults.
“Depression is an important risk factor for acute stroke and is potentially a modifiable contributor to the global burden of stroke,” lead investigator Robert Murphy, MB, a consultant in stroke and geriatric medicine and a researcher with the clinical research facility at the University of Galway, Ireland, told this news organization. “Even mild depressive symptoms were found in this study to be associated with increased risk of stroke and this adds to the literature that across the full range of depressive symptoms there is an association with increased risk of stroke.”
The findings were published online March 8 in Neurology.
Significant stroke risk
For the analysis, investigators collected data on 26,877 cases and controls across 32 countries who participated in INTERSTROKE, an international case-control study of risk factors for a first acute stroke. Participants were recruited between 2007 and 2015 and completed a series of questionnaires about stroke risk factors, including measures of depressive symptoms experienced in the past 12 months.
After adjustment for occupation, education, wealth index, diet, physical activity, alcohol consumption, and smoking history, having prestroke depressive symptoms was associated with greater odds for acute stroke (adjusted odds ratio [aOR], 1.46; 95% confidence interval [CI], 1.34-1.58), including both intracerebral hemorrhage (aOR, 1.56; 95% CI, 1.28-1.91) and ischemic stroke (aOR, 1.44; 95% CI, 1.31-1.58).
Stroke risk increased with increasing severity of depression, but even those with mild depression had a 35% increased risk (aOR, 1.35; 95% CI, 1.19-1.53).
The increased risk held even after the researchers adjusted further for diabetes, hypertension, atrial fibrillation, and body mass index, and work, home, and financial stress.
The association was consistent across geographical regions and age groups, but was stronger in men and in those without hypertension.
“This study looks at different constructs of depression and identifies that across the spectrum of mild, moderate, and severe depressive symptoms that there is an association present with acute stroke and that a biological gradient emerges with increasing burden of depressive symptoms associated with increasing risk,” Dr. Murphy said.
An antidepressant mediating effect?
While prestroke depressive symptoms were not associated with a greater odds of worse stroke severity, they were associated with worse outcomes (P < .001) and higher mortality (10% vs. 8.1%; P = .003) 1 month after a stroke.
In a subgroup analysis, researchers found no association between depressive symptoms and stroke risk in patients who were taking antidepressants.
While no assumptions of causality can be drawn from these findings, “this subgroup analysis does suggest that an increased risk of stroke in those with depression may be attenuated if a patient is on appropriate treatment,” Dr. Murphy said. “This is an area that warrants further exploration.”
The mechanisms that link depression to stroke are unclear, but these findings offer strong evidence that this link exists, Dr. Murphy said.
“We adjusted for potential confounders in sequential models and after adjusting for traditional cardiovascular risk factors there was a consistent association between depressive symptoms and stroke identifying that there is likely an independent association between depression and stroke,” Dr. Murphy said.
Questions remain
Commenting on the study, Daniel T. Lackland DrPH, professor, division of translational neurosciences and population studies, department of neurology, Medical University of South Carolina, Charleston, said it adds to a growing body of work on the association of stroke and depression.
“In this case, depression may be a risk factor for having a stroke,” said Dr. Lackland, who was not part of the study. In addition, the study suggests that “treating depression can have additional benefits beyond mental health, in this case, reduced stroke risks.”
However, it’s important, as with any observational study, that there may be confounding factors that may offer an alternative explanation for the findings.
“Further, it is often difficult to accurately assess depression in all individuals, and specifically in individuals who have had a stroke,” Dr. Lackland said. “While this particular study adds depression as a risk factor and suggests treatment of depression in reducing risks, it is important to emphasize that the traditional stroke risk factors including hypertension should [be] continually recognized and treat[ed] with high rigor.”
The INTERSTROKE study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Stroke Network, the Swedish Research Council, the Swedish Heart Lung Foundation, AFA Insurance, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), Merck Sharp & Dohme, the Swedish Heart Lung Foundation, Chest Heart & Stroke Scotland, and the Stroke Association (United Kingdom). Dr. Murphy and Dr. Lackland have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
Data from the international INTERSTROKE study also showed that those with depressive symptoms before a stroke had worse outcomes, including a significantly higher mortality rate in the first month after a stroke.
These findings build on prior research on the link between depression and stroke, including one study that showed an increased risk for incident stroke among those with a high number of depressive symptoms and another that found that worsening depression can precede stroke in older adults.
“Depression is an important risk factor for acute stroke and is potentially a modifiable contributor to the global burden of stroke,” lead investigator Robert Murphy, MB, a consultant in stroke and geriatric medicine and a researcher with the clinical research facility at the University of Galway, Ireland, told this news organization. “Even mild depressive symptoms were found in this study to be associated with increased risk of stroke and this adds to the literature that across the full range of depressive symptoms there is an association with increased risk of stroke.”
The findings were published online March 8 in Neurology.
Significant stroke risk
For the analysis, investigators collected data on 26,877 cases and controls across 32 countries who participated in INTERSTROKE, an international case-control study of risk factors for a first acute stroke. Participants were recruited between 2007 and 2015 and completed a series of questionnaires about stroke risk factors, including measures of depressive symptoms experienced in the past 12 months.
After adjustment for occupation, education, wealth index, diet, physical activity, alcohol consumption, and smoking history, having prestroke depressive symptoms was associated with greater odds for acute stroke (adjusted odds ratio [aOR], 1.46; 95% confidence interval [CI], 1.34-1.58), including both intracerebral hemorrhage (aOR, 1.56; 95% CI, 1.28-1.91) and ischemic stroke (aOR, 1.44; 95% CI, 1.31-1.58).
Stroke risk increased with increasing severity of depression, but even those with mild depression had a 35% increased risk (aOR, 1.35; 95% CI, 1.19-1.53).
The increased risk held even after the researchers adjusted further for diabetes, hypertension, atrial fibrillation, and body mass index, and work, home, and financial stress.
The association was consistent across geographical regions and age groups, but was stronger in men and in those without hypertension.
“This study looks at different constructs of depression and identifies that across the spectrum of mild, moderate, and severe depressive symptoms that there is an association present with acute stroke and that a biological gradient emerges with increasing burden of depressive symptoms associated with increasing risk,” Dr. Murphy said.
An antidepressant mediating effect?
While prestroke depressive symptoms were not associated with a greater odds of worse stroke severity, they were associated with worse outcomes (P < .001) and higher mortality (10% vs. 8.1%; P = .003) 1 month after a stroke.
In a subgroup analysis, researchers found no association between depressive symptoms and stroke risk in patients who were taking antidepressants.
While no assumptions of causality can be drawn from these findings, “this subgroup analysis does suggest that an increased risk of stroke in those with depression may be attenuated if a patient is on appropriate treatment,” Dr. Murphy said. “This is an area that warrants further exploration.”
The mechanisms that link depression to stroke are unclear, but these findings offer strong evidence that this link exists, Dr. Murphy said.
“We adjusted for potential confounders in sequential models and after adjusting for traditional cardiovascular risk factors there was a consistent association between depressive symptoms and stroke identifying that there is likely an independent association between depression and stroke,” Dr. Murphy said.
Questions remain
Commenting on the study, Daniel T. Lackland DrPH, professor, division of translational neurosciences and population studies, department of neurology, Medical University of South Carolina, Charleston, said it adds to a growing body of work on the association of stroke and depression.
“In this case, depression may be a risk factor for having a stroke,” said Dr. Lackland, who was not part of the study. In addition, the study suggests that “treating depression can have additional benefits beyond mental health, in this case, reduced stroke risks.”
However, it’s important, as with any observational study, that there may be confounding factors that may offer an alternative explanation for the findings.
“Further, it is often difficult to accurately assess depression in all individuals, and specifically in individuals who have had a stroke,” Dr. Lackland said. “While this particular study adds depression as a risk factor and suggests treatment of depression in reducing risks, it is important to emphasize that the traditional stroke risk factors including hypertension should [be] continually recognized and treat[ed] with high rigor.”
The INTERSTROKE study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Stroke Network, the Swedish Research Council, the Swedish Heart Lung Foundation, AFA Insurance, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), Merck Sharp & Dohme, the Swedish Heart Lung Foundation, Chest Heart & Stroke Scotland, and the Stroke Association (United Kingdom). Dr. Murphy and Dr. Lackland have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Encouraging 3-year data for TAVR in low-risk patients: EVOLUT
Three-year results from the Evolut trial seem to provide more reassurance on the use of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients.
The 3-year results show that low-surgical-risk patients undergoing aortic valve replacement continue to show lower rates of all-cause mortality and disabling stroke with TAVR, compared with surgery.
The rates of all-cause mortality or disabling stroke (the primary endpoint) at 3 years were 7.4% with TAVR and 10.4% with surgery.
Rates of new pacemaker implantation continued to be higher after TAVR and the frequency of new onset atrial fibrillation was more common after surgery.
“At 3 years, the rate of all-cause mortality or disabling stroke after TAVR with the Evolut valve compared very favorably to surgery. The absolute difference between treatment arms remained consistent with a 30% relative reduction in the hazard of death or disabling stroke, with a P value that just missed statistical significance,” said Evolut investigator John Forrest, MD, Yale University School of Medicine, New Haven, Conn.
“The Kaplan-Meier curves show what we’ve come to expect – an early separation of the curves – but what’s unique here, and seen for the first time, is that the early separation is maintained at year 1 and year 2, and between years 2 and 3 the curve didn’t start to come together, but, if anything, separated a little,” Dr. Forrest commented.
“Both components of the primary endpoint – all cause mortality and disabling stroke – numerically favor TAVR. The separation of the curves for stroke are maintained, and if anything, we see a further slight separation of the curves as we go forward out to 3 years in terms of all-cause mortality,” he added.
Dr. Forrest presented the 3-year results from the Evolut trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. They were simultaneously published online in the Journal of the American College of Cardiology.
Dr. Forrest also reported that TAVR patients continued to have better valve hemodynamics at 3 years and very low rates of valve thrombosis; moreover, rates of moderate or greater paravalvular regurgitation and paravalvular leak (factors that can affect valve durability) were also low, although mild paravalvular regurgitation was higher with TAVR.
“In these low-risk patients, the durability of the valve is going to be critically important,” Dr. Forrest commented. “The excellent valve performance and durable outcomes out to 3 years in low-risk patients affirms the role of TAVR in this population,” he concluded.
On how these results may affect clinical practice, Dr. Forrest said: “I think in the U.S. these results reaffirm what we are doing. It gives us confidence to continue treating low-risk patients and being comfortable with that.”
He added: “Outside the U.S., the guidelines are a little different. Maybe we should reconsider some of these guidelines based on these data.”
David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., who is not involved in the TAVR studies, said: “The results provide a little more reassurance ... that will go a little way further.”
“Uncertainty remains regarding long-term durability of the transcatheter valve in low-risk patients who are generally younger and likely more active than higher-risk cohorts,” he added. “The current 3-year results provide more confidence as the outcome curves for death and disabling stroke are trending in the right direction for TAVR versus surgery.”
Dr. Moliterno pointed out that while rates of paravalvular regurgitation and permanent pacemaker placement are decreasing with newer generation Evolut devices and implantation techniques, he noted that according to the U.S. Social Security Administration, patients aged 74 years as enrolled in this low-risk cohort have an additional life expectancy of approximately 12 years. “So, we have more device durability (and coronary access feasibility) to prove.”
In his presentation, Dr. Forrest explained that TAVR is now approved in the United States for all patients with aortic stenosis regardless of surgical risk and has become the dominant form of aortic valve replacement. Current ACC/AHA guidelines recommend that heart teams utilize a shared decision-making process when discussing aortic valve replacement with patients aged 65-80 years. In younger, lower-risk patients, the faster recovery and short-term benefits after TAVR must be balanced with long-term durability; however, only limited intermediate and long-term data exist to guide such discussions in this patient population.
The Evolut Low Risk trial randomly assigned 1,414 patients in need of aortic valve replacement to TAVR with a self-expanding, supra-annular valve or surgery. Results at 1 and 2 years have shown a similar benefit in the primary endpoint of all-cause mortality/disabling stroke for the less invasive TAVR procedure.
The current 3-year results suggest the benefit appears to be maintained out for another year.
The main results show that the rate of death or disabling stroke was 7.4% in the TAVR group versus 10.4% in the surgery group, giving a hazard ratio of 0.70 (P = .051).
In the JACC paper, the authors report that the absolute difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: –1.8% at year 1; –2.0% at year 2; and –2.9% at year 3.
Other key results on valve durability show that mild paravalvular regurgitation was increased in the TAVR group (20.3%) versus 2.5% with surgery. However, rates of moderate or greater paravalvular regurgitation for both groups were below 1% and not significantly different between groups.
Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs. 12.1 mm Hg surgery; P < .001) at 3 years.
However, pacemaker placement was much higher in the TAVR group (23.2%), compared with 9.1% in the surgery group.
On the other hand, the surgery group had a greater incidence of atrial fibrillation (40%) versus 13% with TAVR.
Quality-of-life results looked good in both groups.
“As we’ve come to expect, patients recover more quickly after TAVR, so at 30 days their quality of life is better than those who have undergone surgery,” Dr. Forrest commented. “But by 1 year, both groups are doing exceptionally well and, remarkably, here by 3 years both groups have greater than a 20-point increase in their KCCQ score, showing a very large improvement in quality of life.”
Discussant of these latest results at the ACC late-breaking trials session, James Hermiller, MD, St. Vincent Ascension Heart Center, Indianapolis, said: “This 3-year data continues to demonstrate that the gift of TAVR keeps giving.”
Noting that the divergence in the effect curves was primarily driven by mortality rather than stroke, he asked whether this was cardiac or noncardiac mortality that was reduced.
Dr. Forrest responded: “It was a fairly equal contribution – a little bit more cardiac death. We have to remember that although the average age in this study was 74, there were some patients over 80 who were still low-surgical-risk included so we are going to see noncardiac death as well.”
Dr. Hermiller drew attention to the high pacemaker rate in the TAVR group and asked how these patients fared in comparison to those who didn’t need a pacemaker.
Dr. Forrest replied: “I think it’s fair to say that putting in a pacemaker is not a benign procedure. Patients who got a pacemaker did slightly worse than those who didn’t get a pacemaker, so we need to try to drive that rate down.”
He added that the number of patients needing a pacemaker after TAVR has come down with new implantation techniques and new generation valves.
“We realize that using a cusp overlap technique can significantly reduce the need for a pacemaker, and we see from registry data that with the use of this new technique the need for a pacemaker has dropped down to 8%-9%, significantly less than seen in this study,” Dr. Forrest commented.
Dr. Hermiller also asked about how TAVR affects future access for catheterization or percutaneous coronary intervention.
Dr. Forrest noted that 24 patients in the TAVR group required PCI in first 3 years, and all the PCI procedures had been successful. He noted that operators reported the procedure to be easy or moderately easy in about 75%-80% of cases and difficult in about 20% of patients. “So, it is slightly more challenging to engage the coronaries and have to go through the frame, but it is very feasible.”
Dr. Forrest concluded that: “These results provide patients and heart teams important data to aid in the shared decision-making process.”
But he acknowledged that longer term data are still needed. “And the potential impact that hemodynamics, valve design, new pacemakers, and other secondary endpoints have on long-term outcomes will be important to follow in this group of low-risk patients.”
The Evolut Low Risk trial was funded by Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees/honoraria/speakers bureau fees from Edwards Lifesciences and Medtronic.
A version of this article first appeared on Medscape.com.
Three-year results from the Evolut trial seem to provide more reassurance on the use of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients.
The 3-year results show that low-surgical-risk patients undergoing aortic valve replacement continue to show lower rates of all-cause mortality and disabling stroke with TAVR, compared with surgery.
The rates of all-cause mortality or disabling stroke (the primary endpoint) at 3 years were 7.4% with TAVR and 10.4% with surgery.
Rates of new pacemaker implantation continued to be higher after TAVR and the frequency of new onset atrial fibrillation was more common after surgery.
“At 3 years, the rate of all-cause mortality or disabling stroke after TAVR with the Evolut valve compared very favorably to surgery. The absolute difference between treatment arms remained consistent with a 30% relative reduction in the hazard of death or disabling stroke, with a P value that just missed statistical significance,” said Evolut investigator John Forrest, MD, Yale University School of Medicine, New Haven, Conn.
“The Kaplan-Meier curves show what we’ve come to expect – an early separation of the curves – but what’s unique here, and seen for the first time, is that the early separation is maintained at year 1 and year 2, and between years 2 and 3 the curve didn’t start to come together, but, if anything, separated a little,” Dr. Forrest commented.
“Both components of the primary endpoint – all cause mortality and disabling stroke – numerically favor TAVR. The separation of the curves for stroke are maintained, and if anything, we see a further slight separation of the curves as we go forward out to 3 years in terms of all-cause mortality,” he added.
Dr. Forrest presented the 3-year results from the Evolut trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. They were simultaneously published online in the Journal of the American College of Cardiology.
Dr. Forrest also reported that TAVR patients continued to have better valve hemodynamics at 3 years and very low rates of valve thrombosis; moreover, rates of moderate or greater paravalvular regurgitation and paravalvular leak (factors that can affect valve durability) were also low, although mild paravalvular regurgitation was higher with TAVR.
“In these low-risk patients, the durability of the valve is going to be critically important,” Dr. Forrest commented. “The excellent valve performance and durable outcomes out to 3 years in low-risk patients affirms the role of TAVR in this population,” he concluded.
On how these results may affect clinical practice, Dr. Forrest said: “I think in the U.S. these results reaffirm what we are doing. It gives us confidence to continue treating low-risk patients and being comfortable with that.”
He added: “Outside the U.S., the guidelines are a little different. Maybe we should reconsider some of these guidelines based on these data.”
David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., who is not involved in the TAVR studies, said: “The results provide a little more reassurance ... that will go a little way further.”
“Uncertainty remains regarding long-term durability of the transcatheter valve in low-risk patients who are generally younger and likely more active than higher-risk cohorts,” he added. “The current 3-year results provide more confidence as the outcome curves for death and disabling stroke are trending in the right direction for TAVR versus surgery.”
Dr. Moliterno pointed out that while rates of paravalvular regurgitation and permanent pacemaker placement are decreasing with newer generation Evolut devices and implantation techniques, he noted that according to the U.S. Social Security Administration, patients aged 74 years as enrolled in this low-risk cohort have an additional life expectancy of approximately 12 years. “So, we have more device durability (and coronary access feasibility) to prove.”
In his presentation, Dr. Forrest explained that TAVR is now approved in the United States for all patients with aortic stenosis regardless of surgical risk and has become the dominant form of aortic valve replacement. Current ACC/AHA guidelines recommend that heart teams utilize a shared decision-making process when discussing aortic valve replacement with patients aged 65-80 years. In younger, lower-risk patients, the faster recovery and short-term benefits after TAVR must be balanced with long-term durability; however, only limited intermediate and long-term data exist to guide such discussions in this patient population.
The Evolut Low Risk trial randomly assigned 1,414 patients in need of aortic valve replacement to TAVR with a self-expanding, supra-annular valve or surgery. Results at 1 and 2 years have shown a similar benefit in the primary endpoint of all-cause mortality/disabling stroke for the less invasive TAVR procedure.
The current 3-year results suggest the benefit appears to be maintained out for another year.
The main results show that the rate of death or disabling stroke was 7.4% in the TAVR group versus 10.4% in the surgery group, giving a hazard ratio of 0.70 (P = .051).
In the JACC paper, the authors report that the absolute difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: –1.8% at year 1; –2.0% at year 2; and –2.9% at year 3.
Other key results on valve durability show that mild paravalvular regurgitation was increased in the TAVR group (20.3%) versus 2.5% with surgery. However, rates of moderate or greater paravalvular regurgitation for both groups were below 1% and not significantly different between groups.
Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs. 12.1 mm Hg surgery; P < .001) at 3 years.
However, pacemaker placement was much higher in the TAVR group (23.2%), compared with 9.1% in the surgery group.
On the other hand, the surgery group had a greater incidence of atrial fibrillation (40%) versus 13% with TAVR.
Quality-of-life results looked good in both groups.
“As we’ve come to expect, patients recover more quickly after TAVR, so at 30 days their quality of life is better than those who have undergone surgery,” Dr. Forrest commented. “But by 1 year, both groups are doing exceptionally well and, remarkably, here by 3 years both groups have greater than a 20-point increase in their KCCQ score, showing a very large improvement in quality of life.”
Discussant of these latest results at the ACC late-breaking trials session, James Hermiller, MD, St. Vincent Ascension Heart Center, Indianapolis, said: “This 3-year data continues to demonstrate that the gift of TAVR keeps giving.”
Noting that the divergence in the effect curves was primarily driven by mortality rather than stroke, he asked whether this was cardiac or noncardiac mortality that was reduced.
Dr. Forrest responded: “It was a fairly equal contribution – a little bit more cardiac death. We have to remember that although the average age in this study was 74, there were some patients over 80 who were still low-surgical-risk included so we are going to see noncardiac death as well.”
Dr. Hermiller drew attention to the high pacemaker rate in the TAVR group and asked how these patients fared in comparison to those who didn’t need a pacemaker.
Dr. Forrest replied: “I think it’s fair to say that putting in a pacemaker is not a benign procedure. Patients who got a pacemaker did slightly worse than those who didn’t get a pacemaker, so we need to try to drive that rate down.”
He added that the number of patients needing a pacemaker after TAVR has come down with new implantation techniques and new generation valves.
“We realize that using a cusp overlap technique can significantly reduce the need for a pacemaker, and we see from registry data that with the use of this new technique the need for a pacemaker has dropped down to 8%-9%, significantly less than seen in this study,” Dr. Forrest commented.
Dr. Hermiller also asked about how TAVR affects future access for catheterization or percutaneous coronary intervention.
Dr. Forrest noted that 24 patients in the TAVR group required PCI in first 3 years, and all the PCI procedures had been successful. He noted that operators reported the procedure to be easy or moderately easy in about 75%-80% of cases and difficult in about 20% of patients. “So, it is slightly more challenging to engage the coronaries and have to go through the frame, but it is very feasible.”
Dr. Forrest concluded that: “These results provide patients and heart teams important data to aid in the shared decision-making process.”
But he acknowledged that longer term data are still needed. “And the potential impact that hemodynamics, valve design, new pacemakers, and other secondary endpoints have on long-term outcomes will be important to follow in this group of low-risk patients.”
The Evolut Low Risk trial was funded by Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees/honoraria/speakers bureau fees from Edwards Lifesciences and Medtronic.
A version of this article first appeared on Medscape.com.
Three-year results from the Evolut trial seem to provide more reassurance on the use of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients.
The 3-year results show that low-surgical-risk patients undergoing aortic valve replacement continue to show lower rates of all-cause mortality and disabling stroke with TAVR, compared with surgery.
The rates of all-cause mortality or disabling stroke (the primary endpoint) at 3 years were 7.4% with TAVR and 10.4% with surgery.
Rates of new pacemaker implantation continued to be higher after TAVR and the frequency of new onset atrial fibrillation was more common after surgery.
“At 3 years, the rate of all-cause mortality or disabling stroke after TAVR with the Evolut valve compared very favorably to surgery. The absolute difference between treatment arms remained consistent with a 30% relative reduction in the hazard of death or disabling stroke, with a P value that just missed statistical significance,” said Evolut investigator John Forrest, MD, Yale University School of Medicine, New Haven, Conn.
“The Kaplan-Meier curves show what we’ve come to expect – an early separation of the curves – but what’s unique here, and seen for the first time, is that the early separation is maintained at year 1 and year 2, and between years 2 and 3 the curve didn’t start to come together, but, if anything, separated a little,” Dr. Forrest commented.
“Both components of the primary endpoint – all cause mortality and disabling stroke – numerically favor TAVR. The separation of the curves for stroke are maintained, and if anything, we see a further slight separation of the curves as we go forward out to 3 years in terms of all-cause mortality,” he added.
Dr. Forrest presented the 3-year results from the Evolut trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. They were simultaneously published online in the Journal of the American College of Cardiology.
Dr. Forrest also reported that TAVR patients continued to have better valve hemodynamics at 3 years and very low rates of valve thrombosis; moreover, rates of moderate or greater paravalvular regurgitation and paravalvular leak (factors that can affect valve durability) were also low, although mild paravalvular regurgitation was higher with TAVR.
“In these low-risk patients, the durability of the valve is going to be critically important,” Dr. Forrest commented. “The excellent valve performance and durable outcomes out to 3 years in low-risk patients affirms the role of TAVR in this population,” he concluded.
On how these results may affect clinical practice, Dr. Forrest said: “I think in the U.S. these results reaffirm what we are doing. It gives us confidence to continue treating low-risk patients and being comfortable with that.”
He added: “Outside the U.S., the guidelines are a little different. Maybe we should reconsider some of these guidelines based on these data.”
David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., who is not involved in the TAVR studies, said: “The results provide a little more reassurance ... that will go a little way further.”
“Uncertainty remains regarding long-term durability of the transcatheter valve in low-risk patients who are generally younger and likely more active than higher-risk cohorts,” he added. “The current 3-year results provide more confidence as the outcome curves for death and disabling stroke are trending in the right direction for TAVR versus surgery.”
Dr. Moliterno pointed out that while rates of paravalvular regurgitation and permanent pacemaker placement are decreasing with newer generation Evolut devices and implantation techniques, he noted that according to the U.S. Social Security Administration, patients aged 74 years as enrolled in this low-risk cohort have an additional life expectancy of approximately 12 years. “So, we have more device durability (and coronary access feasibility) to prove.”
In his presentation, Dr. Forrest explained that TAVR is now approved in the United States for all patients with aortic stenosis regardless of surgical risk and has become the dominant form of aortic valve replacement. Current ACC/AHA guidelines recommend that heart teams utilize a shared decision-making process when discussing aortic valve replacement with patients aged 65-80 years. In younger, lower-risk patients, the faster recovery and short-term benefits after TAVR must be balanced with long-term durability; however, only limited intermediate and long-term data exist to guide such discussions in this patient population.
The Evolut Low Risk trial randomly assigned 1,414 patients in need of aortic valve replacement to TAVR with a self-expanding, supra-annular valve or surgery. Results at 1 and 2 years have shown a similar benefit in the primary endpoint of all-cause mortality/disabling stroke for the less invasive TAVR procedure.
The current 3-year results suggest the benefit appears to be maintained out for another year.
The main results show that the rate of death or disabling stroke was 7.4% in the TAVR group versus 10.4% in the surgery group, giving a hazard ratio of 0.70 (P = .051).
In the JACC paper, the authors report that the absolute difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: –1.8% at year 1; –2.0% at year 2; and –2.9% at year 3.
Other key results on valve durability show that mild paravalvular regurgitation was increased in the TAVR group (20.3%) versus 2.5% with surgery. However, rates of moderate or greater paravalvular regurgitation for both groups were below 1% and not significantly different between groups.
Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs. 12.1 mm Hg surgery; P < .001) at 3 years.
However, pacemaker placement was much higher in the TAVR group (23.2%), compared with 9.1% in the surgery group.
On the other hand, the surgery group had a greater incidence of atrial fibrillation (40%) versus 13% with TAVR.
Quality-of-life results looked good in both groups.
“As we’ve come to expect, patients recover more quickly after TAVR, so at 30 days their quality of life is better than those who have undergone surgery,” Dr. Forrest commented. “But by 1 year, both groups are doing exceptionally well and, remarkably, here by 3 years both groups have greater than a 20-point increase in their KCCQ score, showing a very large improvement in quality of life.”
Discussant of these latest results at the ACC late-breaking trials session, James Hermiller, MD, St. Vincent Ascension Heart Center, Indianapolis, said: “This 3-year data continues to demonstrate that the gift of TAVR keeps giving.”
Noting that the divergence in the effect curves was primarily driven by mortality rather than stroke, he asked whether this was cardiac or noncardiac mortality that was reduced.
Dr. Forrest responded: “It was a fairly equal contribution – a little bit more cardiac death. We have to remember that although the average age in this study was 74, there were some patients over 80 who were still low-surgical-risk included so we are going to see noncardiac death as well.”
Dr. Hermiller drew attention to the high pacemaker rate in the TAVR group and asked how these patients fared in comparison to those who didn’t need a pacemaker.
Dr. Forrest replied: “I think it’s fair to say that putting in a pacemaker is not a benign procedure. Patients who got a pacemaker did slightly worse than those who didn’t get a pacemaker, so we need to try to drive that rate down.”
He added that the number of patients needing a pacemaker after TAVR has come down with new implantation techniques and new generation valves.
“We realize that using a cusp overlap technique can significantly reduce the need for a pacemaker, and we see from registry data that with the use of this new technique the need for a pacemaker has dropped down to 8%-9%, significantly less than seen in this study,” Dr. Forrest commented.
Dr. Hermiller also asked about how TAVR affects future access for catheterization or percutaneous coronary intervention.
Dr. Forrest noted that 24 patients in the TAVR group required PCI in first 3 years, and all the PCI procedures had been successful. He noted that operators reported the procedure to be easy or moderately easy in about 75%-80% of cases and difficult in about 20% of patients. “So, it is slightly more challenging to engage the coronaries and have to go through the frame, but it is very feasible.”
Dr. Forrest concluded that: “These results provide patients and heart teams important data to aid in the shared decision-making process.”
But he acknowledged that longer term data are still needed. “And the potential impact that hemodynamics, valve design, new pacemakers, and other secondary endpoints have on long-term outcomes will be important to follow in this group of low-risk patients.”
The Evolut Low Risk trial was funded by Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees/honoraria/speakers bureau fees from Edwards Lifesciences and Medtronic.
A version of this article first appeared on Medscape.com.
FROM ACC 2023