Cardiology

ST. LOUIS – Children who have background EEG asymmetry while on extracorporeal membrane oxygenation (ECMO) have worse outcomes even after adjustment for recent cardiac arrest and EEG suppression, according to a review of 41 children treated at Washington University, St. Louis.

ECMO is a last-ditch heart/lung bypass for patients near death, be it from infection, trauma, cardiac abnormalities, or any other issue. Children can be on it for days or weeks while problems are addressed and the body attempts to recover. Sometimes ECMO works, and children make a remarkable recovery, but other times they die or are left with severe disabilities, and no one really knows why.

Because of this, the investigators in this review sought to identify predictors of poor outcomes with an eye toward identifying modifiable risk factors, said senior investigator Kristin Guilliams, MD, an assistant professor of pediatric critical care medicine.

“We are trying to figure out why some kids do fantastically, and others don’t. We were looking at whether EEG can give us any clues and new ways to think about modifiable risk factors so that every kid rescued by ECMO can go back to their normal life,” she said at the American Neurological Association annual meeting.

The 41 children had an EEG within a day or 2 of starting ECMO; 22 did well, but 19 had bad outcomes, defined in the study as either dying in the hospital or being discharged with a Functional Status Score above 12, meaning mild dysfunction across six domains or more severe disability in particular ones.

The finding that all four children with EEG suppression – overall low brain activity – did poorly was not surprising, but the fact that EEG background asymmetry – one side of the brain being much less active than the other or giving different signals – in five children predicted poor outcomes, even after adjustment for cardiac arrest and overall suppression, was “a big surprise,” Dr. Guilliams said (odds ratio, 29.3; 95% confidence interval, 2.2-398.3; P = .003).

“The asymmetry tells me that we need to look more closely into brain blood flow patterns on ECMO,” she said. There might be a way to change delivery that could help, but “it’s not obvious right now.” The issue warrants further investigation, Dr. Guilliams said.

Twelve children had ECMO during chest compressions for cardiac arrest, which as expected, also predicted poor outcomes (OR, 9.5; 95% CI 1.6-58.2; P = .008).

Neuroimaging was available for 34 children. Abnormalities (n = 13; P = .2), including ischemia (n = 8; P = .1), hemorrhage (n = 8; P = .06), and seizures (n = 4; P = .2) did not predict poor outcomes, nor did sex, age, and mode of ECMO delivery (veno-arterial versus veno-venous).

As of about a year ago, EEGs at the university are now standard for children on ECMO, with special software to pick out asymmetries. “We are paying more attention to” EEGs, Dr. Guilliams said.

Children were a median of about 10 years old, and subjects were at least 1 year old. There were about equal numbers of boys and girls; 25 children were alive at discharge.

There was no external funding, and Dr. Guilliams didn’t have any disclosures.
 

aotto@mdedge.com

ST. LOUIS – Children who have background EEG asymmetry while on extracorporeal membrane oxygenation (ECMO) have worse outcomes even after adjustment for recent cardiac arrest and EEG suppression, according to a review of 41 children treated at Washington University, St. Louis.

ECMO is a last-ditch heart/lung bypass for patients near death, be it from infection, trauma, cardiac abnormalities, or any other issue. Children can be on it for days or weeks while problems are addressed and the body attempts to recover. Sometimes ECMO works, and children make a remarkable recovery, but other times they die or are left with severe disabilities, and no one really knows why.

Because of this, the investigators in this review sought to identify predictors of poor outcomes with an eye toward identifying modifiable risk factors, said senior investigator Kristin Guilliams, MD, an assistant professor of pediatric critical care medicine.

“We are trying to figure out why some kids do fantastically, and others don’t. We were looking at whether EEG can give us any clues and new ways to think about modifiable risk factors so that every kid rescued by ECMO can go back to their normal life,” she said at the American Neurological Association annual meeting.

The 41 children had an EEG within a day or 2 of starting ECMO; 22 did well, but 19 had bad outcomes, defined in the study as either dying in the hospital or being discharged with a Functional Status Score above 12, meaning mild dysfunction across six domains or more severe disability in particular ones.

The finding that all four children with EEG suppression – overall low brain activity – did poorly was not surprising, but the fact that EEG background asymmetry – one side of the brain being much less active than the other or giving different signals – in five children predicted poor outcomes, even after adjustment for cardiac arrest and overall suppression, was “a big surprise,” Dr. Guilliams said (odds ratio, 29.3; 95% confidence interval, 2.2-398.3; P = .003).

“The asymmetry tells me that we need to look more closely into brain blood flow patterns on ECMO,” she said. There might be a way to change delivery that could help, but “it’s not obvious right now.” The issue warrants further investigation, Dr. Guilliams said.

Twelve children had ECMO during chest compressions for cardiac arrest, which as expected, also predicted poor outcomes (OR, 9.5; 95% CI 1.6-58.2; P = .008).

Neuroimaging was available for 34 children. Abnormalities (n = 13; P = .2), including ischemia (n = 8; P = .1), hemorrhage (n = 8; P = .06), and seizures (n = 4; P = .2) did not predict poor outcomes, nor did sex, age, and mode of ECMO delivery (veno-arterial versus veno-venous).

As of about a year ago, EEGs at the university are now standard for children on ECMO, with special software to pick out asymmetries. “We are paying more attention to” EEGs, Dr. Guilliams said.

Children were a median of about 10 years old, and subjects were at least 1 year old. There were about equal numbers of boys and girls; 25 children were alive at discharge.

There was no external funding, and Dr. Guilliams didn’t have any disclosures.
 

aotto@mdedge.com

ST. LOUIS – Children who have background EEG asymmetry while on extracorporeal membrane oxygenation (ECMO) have worse outcomes even after adjustment for recent cardiac arrest and EEG suppression, according to a review of 41 children treated at Washington University, St. Louis.

ECMO is a last-ditch heart/lung bypass for patients near death, be it from infection, trauma, cardiac abnormalities, or any other issue. Children can be on it for days or weeks while problems are addressed and the body attempts to recover. Sometimes ECMO works, and children make a remarkable recovery, but other times they die or are left with severe disabilities, and no one really knows why.

Because of this, the investigators in this review sought to identify predictors of poor outcomes with an eye toward identifying modifiable risk factors, said senior investigator Kristin Guilliams, MD, an assistant professor of pediatric critical care medicine.

“We are trying to figure out why some kids do fantastically, and others don’t. We were looking at whether EEG can give us any clues and new ways to think about modifiable risk factors so that every kid rescued by ECMO can go back to their normal life,” she said at the American Neurological Association annual meeting.

The 41 children had an EEG within a day or 2 of starting ECMO; 22 did well, but 19 had bad outcomes, defined in the study as either dying in the hospital or being discharged with a Functional Status Score above 12, meaning mild dysfunction across six domains or more severe disability in particular ones.

The finding that all four children with EEG suppression – overall low brain activity – did poorly was not surprising, but the fact that EEG background asymmetry – one side of the brain being much less active than the other or giving different signals – in five children predicted poor outcomes, even after adjustment for cardiac arrest and overall suppression, was “a big surprise,” Dr. Guilliams said (odds ratio, 29.3; 95% confidence interval, 2.2-398.3; P = .003).

“The asymmetry tells me that we need to look more closely into brain blood flow patterns on ECMO,” she said. There might be a way to change delivery that could help, but “it’s not obvious right now.” The issue warrants further investigation, Dr. Guilliams said.

Twelve children had ECMO during chest compressions for cardiac arrest, which as expected, also predicted poor outcomes (OR, 9.5; 95% CI 1.6-58.2; P = .008).

Neuroimaging was available for 34 children. Abnormalities (n = 13; P = .2), including ischemia (n = 8; P = .1), hemorrhage (n = 8; P = .06), and seizures (n = 4; P = .2) did not predict poor outcomes, nor did sex, age, and mode of ECMO delivery (veno-arterial versus veno-venous).

As of about a year ago, EEGs at the university are now standard for children on ECMO, with special software to pick out asymmetries. “We are paying more attention to” EEGs, Dr. Guilliams said.

Children were a median of about 10 years old, and subjects were at least 1 year old. There were about equal numbers of boys and girls; 25 children were alive at discharge.

There was no external funding, and Dr. Guilliams didn’t have any disclosures.
 

aotto@mdedge.com

Regular low-level alcohol consumption may be a bigger risk factor for new-onset atrial fibrillation than binge drinking, according to a paper published online in EP Europace.

Nikada/iStockphoto

Alcohol consumption is known to have a dose-dependent association with the risk of new-onset atrial fibrillation (AFib), but the mechanism underlying this association was not clear, according to Yun Gi Kim, MD, from the Seoul National University (South Korea), and coauthors.

They analyzed data from the Korean National Health Insurance Service database for 9,776,956 individuals without atrial fibrillation at baseline, including health survey information about their alcohol consumption.

Overall, 51.3% of the study population were classified as nondrinkers, 32.1% were mild drinkers – defined as up to 105 g of alcohol consumed per week ­– 9.7% were moderate drinkers consuming 105-210 g/week, and 6.9% were heavy drinkers consuming 210 g or more per week.

The analysis revealed that heavy drinkers had the highest risk for new-onset AFib – 21.5% higher than mild drinkers – while nondrinkers had an 8.6% higher risk and moderate drinkers had a 7.7% higher risk, compared with mild drinkers.

It also showed an association between the number of drinking sessions per week and the development of new-onset atrial fibrillation. Individuals who only drank once per week had the lowest risk of AFib while those who drank every day had the highest.

“Although weekly alcohol intake was associated with the risk of new-onset [AFib], such association was lost when drinking frequency was included in the multivariate model,” the authors wrote.

They found a significant inverse relationship between the amount of alcohol consumed per drinking session, and the risk of new-onset AFib, such that individuals who consumed low amounts of alcohol per session had a higher risk, and the risk decreased as higher amounts were consumed.

“Regardless of whether weekly alcohol intake exceeded 210 g, the frequency of drinking was significantly associated with risk of new-onset [AFib],” they reported. “Patients who drink everyday represented the highest-risk group and those who drink once per week were the lowest-risk group for new-onset [AFib] in this investigation, respectively.”

The authors speculated that if alcohol consumption can trigger AFib, then multiple drinking episodes per week, regardless of amount, might trigger more episodes of AFib and potentially lead to the development of overt, new-onset disease. They also suggested that frequent drinking could lead to regular sleep disturbance, which might also contribute to the link with atrial fibrillation.

The study was supported by Korea University, Korea University Anam Hospital, Republic of Korea, the National Research Foundation of Korea, the Ministry of Education and the Ministry of Science, ICT, and Future Planning. No conflicts of interest were declared.

SOURCE: Kim YG et al. EP Europace. 2019 Oct 17. doi: 10.1093/europace/euz256.

Regular low-level alcohol consumption may be a bigger risk factor for new-onset atrial fibrillation than binge drinking, according to a paper published online in EP Europace.

Nikada/iStockphoto

Alcohol consumption is known to have a dose-dependent association with the risk of new-onset atrial fibrillation (AFib), but the mechanism underlying this association was not clear, according to Yun Gi Kim, MD, from the Seoul National University (South Korea), and coauthors.

They analyzed data from the Korean National Health Insurance Service database for 9,776,956 individuals without atrial fibrillation at baseline, including health survey information about their alcohol consumption.

Overall, 51.3% of the study population were classified as nondrinkers, 32.1% were mild drinkers – defined as up to 105 g of alcohol consumed per week ­– 9.7% were moderate drinkers consuming 105-210 g/week, and 6.9% were heavy drinkers consuming 210 g or more per week.

The analysis revealed that heavy drinkers had the highest risk for new-onset AFib – 21.5% higher than mild drinkers – while nondrinkers had an 8.6% higher risk and moderate drinkers had a 7.7% higher risk, compared with mild drinkers.

It also showed an association between the number of drinking sessions per week and the development of new-onset atrial fibrillation. Individuals who only drank once per week had the lowest risk of AFib while those who drank every day had the highest.

“Although weekly alcohol intake was associated with the risk of new-onset [AFib], such association was lost when drinking frequency was included in the multivariate model,” the authors wrote.

They found a significant inverse relationship between the amount of alcohol consumed per drinking session, and the risk of new-onset AFib, such that individuals who consumed low amounts of alcohol per session had a higher risk, and the risk decreased as higher amounts were consumed.

“Regardless of whether weekly alcohol intake exceeded 210 g, the frequency of drinking was significantly associated with risk of new-onset [AFib],” they reported. “Patients who drink everyday represented the highest-risk group and those who drink once per week were the lowest-risk group for new-onset [AFib] in this investigation, respectively.”

The authors speculated that if alcohol consumption can trigger AFib, then multiple drinking episodes per week, regardless of amount, might trigger more episodes of AFib and potentially lead to the development of overt, new-onset disease. They also suggested that frequent drinking could lead to regular sleep disturbance, which might also contribute to the link with atrial fibrillation.

The study was supported by Korea University, Korea University Anam Hospital, Republic of Korea, the National Research Foundation of Korea, the Ministry of Education and the Ministry of Science, ICT, and Future Planning. No conflicts of interest were declared.

SOURCE: Kim YG et al. EP Europace. 2019 Oct 17. doi: 10.1093/europace/euz256.

Regular low-level alcohol consumption may be a bigger risk factor for new-onset atrial fibrillation than binge drinking, according to a paper published online in EP Europace.

Nikada/iStockphoto

Alcohol consumption is known to have a dose-dependent association with the risk of new-onset atrial fibrillation (AFib), but the mechanism underlying this association was not clear, according to Yun Gi Kim, MD, from the Seoul National University (South Korea), and coauthors.

They analyzed data from the Korean National Health Insurance Service database for 9,776,956 individuals without atrial fibrillation at baseline, including health survey information about their alcohol consumption.

Overall, 51.3% of the study population were classified as nondrinkers, 32.1% were mild drinkers – defined as up to 105 g of alcohol consumed per week ­– 9.7% were moderate drinkers consuming 105-210 g/week, and 6.9% were heavy drinkers consuming 210 g or more per week.

The analysis revealed that heavy drinkers had the highest risk for new-onset AFib – 21.5% higher than mild drinkers – while nondrinkers had an 8.6% higher risk and moderate drinkers had a 7.7% higher risk, compared with mild drinkers.

It also showed an association between the number of drinking sessions per week and the development of new-onset atrial fibrillation. Individuals who only drank once per week had the lowest risk of AFib while those who drank every day had the highest.

“Although weekly alcohol intake was associated with the risk of new-onset [AFib], such association was lost when drinking frequency was included in the multivariate model,” the authors wrote.

They found a significant inverse relationship between the amount of alcohol consumed per drinking session, and the risk of new-onset AFib, such that individuals who consumed low amounts of alcohol per session had a higher risk, and the risk decreased as higher amounts were consumed.

“Regardless of whether weekly alcohol intake exceeded 210 g, the frequency of drinking was significantly associated with risk of new-onset [AFib],” they reported. “Patients who drink everyday represented the highest-risk group and those who drink once per week were the lowest-risk group for new-onset [AFib] in this investigation, respectively.”

The authors speculated that if alcohol consumption can trigger AFib, then multiple drinking episodes per week, regardless of amount, might trigger more episodes of AFib and potentially lead to the development of overt, new-onset disease. They also suggested that frequent drinking could lead to regular sleep disturbance, which might also contribute to the link with atrial fibrillation.

The study was supported by Korea University, Korea University Anam Hospital, Republic of Korea, the National Research Foundation of Korea, the Ministry of Education and the Ministry of Science, ICT, and Future Planning. No conflicts of interest were declared.

SOURCE: Kim YG et al. EP Europace. 2019 Oct 17. doi: 10.1093/europace/euz256.

MADRID – For the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), balloon pulmonary angioplasty (BPA) is more effective than riociguat for reducing pulmonary vascular resistance (PVR) and improving functional class, according to a multicenter trial presented at the annual congress of the European Respiratory Congress.

Both therapies are widely used in the treatment of CTEPH, but this is the first controlled trial in which they were directly compared, according to Xavier Jaïs, MD, of the Pulmonology Service, Kremlin-Bicêtre Hospital, University of Paris-Sud.

In this randomized trial, called RACE, newly diagnosed and previously untreated patients with nonoperable CTEPH were enrolled. The key eligibility criteria included PVR greater than 320 dynes/sec per cm^–5 and a pulmonary capillary wedge pressure of 15 mm Hg or less.

The patients were randomized to BPA or riociguat and followed for 26 weeks. The primary endpoint was relative change in PVR from baseline. The 6-minute walk distance, change in functional class, time to clinical worsening and safety were among secondary endpoints.

As calculated by geometric mean from baseline, PVR was reduced by nearly 60% in the BPA group and by 32% in the riociguat group, providing a 40% (P less than .0001) relative advantage of BPA.

Although there was a small relative advantage in the 6-minute walk distance for the BPA group at the end of the study, it did not reach statistical significant. However, 88% of those randomized to BPA versus 49% of those treated with riociguat (P less than .0001) improved by at least one WHO class by the end of the study.

Clinical worsening events over the course of the trial were uncommon. All three of these events occurred in the riociguat group, but the difference was not significant.

The end-of-study reduction in brain natriuretic peptide, which was another secondary endpoint, was 67% greater in the BPA group (P less than .0001).

There was a safety cost for the greater efficacy of BPA. This included a higher proportion of patients in the BPA group with at least one serious adverse event (50% vs. 26%) and at least one serious treatment-related adverse event (14% vs. 9%). No patient in either arm discontinued therapy because of treatment-related adverse events, and there were no deaths over the course of the study in either arm.

The study has included a 6-month extension to allow patients symptomatic on their originally assigned therapy to switch to the opposite treatment. Results of the extension are not yet available, but Dr. Jaïs said that these data might provide insight about which therapy to start first.

“It was very important to do this trial,” according to the ERS-invited discussant, Martin Kolb, MD, of the Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ont. The most recent World Symposium on Pulmonary Hypertension identified BPA and medical therapy as reasonable choices in inoperable CTEPH, but Dr. Kolb said there has been an unmet need for comparative data.

“This was a very strong study that demonstrated a powerful impact for both interventions on pulmonary vascular resistance,” Dr. Kolb said, adding that, although BPA proved to be more effective, clinicians consider the greater risk of adverse events. He believes further work needs to be done in identifying the best candidates for each and to explore hybrid approaches.

“What do you think about doing these sequentially so that you lower the pressure first with medical therapy and then go in with the balloon?” Dr. Kolb asked Dr. Jaïs during a discussion that followed presentation of the RACE results.

Dr. Jaïs conceded this point, noting that the treatments have different targets and might be complementary.

“We plan to do a study like this in the future,” Dr. Jaïs said.

Dr. Jaïs reported no potential conflicts of interest.

MADRID – For the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), balloon pulmonary angioplasty (BPA) is more effective than riociguat for reducing pulmonary vascular resistance (PVR) and improving functional class, according to a multicenter trial presented at the annual congress of the European Respiratory Congress.

Both therapies are widely used in the treatment of CTEPH, but this is the first controlled trial in which they were directly compared, according to Xavier Jaïs, MD, of the Pulmonology Service, Kremlin-Bicêtre Hospital, University of Paris-Sud.

In this randomized trial, called RACE, newly diagnosed and previously untreated patients with nonoperable CTEPH were enrolled. The key eligibility criteria included PVR greater than 320 dynes/sec per cm^–5 and a pulmonary capillary wedge pressure of 15 mm Hg or less.

The patients were randomized to BPA or riociguat and followed for 26 weeks. The primary endpoint was relative change in PVR from baseline. The 6-minute walk distance, change in functional class, time to clinical worsening and safety were among secondary endpoints.

As calculated by geometric mean from baseline, PVR was reduced by nearly 60% in the BPA group and by 32% in the riociguat group, providing a 40% (P less than .0001) relative advantage of BPA.

Although there was a small relative advantage in the 6-minute walk distance for the BPA group at the end of the study, it did not reach statistical significant. However, 88% of those randomized to BPA versus 49% of those treated with riociguat (P less than .0001) improved by at least one WHO class by the end of the study.

Clinical worsening events over the course of the trial were uncommon. All three of these events occurred in the riociguat group, but the difference was not significant.

The end-of-study reduction in brain natriuretic peptide, which was another secondary endpoint, was 67% greater in the BPA group (P less than .0001).

There was a safety cost for the greater efficacy of BPA. This included a higher proportion of patients in the BPA group with at least one serious adverse event (50% vs. 26%) and at least one serious treatment-related adverse event (14% vs. 9%). No patient in either arm discontinued therapy because of treatment-related adverse events, and there were no deaths over the course of the study in either arm.

The study has included a 6-month extension to allow patients symptomatic on their originally assigned therapy to switch to the opposite treatment. Results of the extension are not yet available, but Dr. Jaïs said that these data might provide insight about which therapy to start first.

“It was very important to do this trial,” according to the ERS-invited discussant, Martin Kolb, MD, of the Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ont. The most recent World Symposium on Pulmonary Hypertension identified BPA and medical therapy as reasonable choices in inoperable CTEPH, but Dr. Kolb said there has been an unmet need for comparative data.

“This was a very strong study that demonstrated a powerful impact for both interventions on pulmonary vascular resistance,” Dr. Kolb said, adding that, although BPA proved to be more effective, clinicians consider the greater risk of adverse events. He believes further work needs to be done in identifying the best candidates for each and to explore hybrid approaches.

“What do you think about doing these sequentially so that you lower the pressure first with medical therapy and then go in with the balloon?” Dr. Kolb asked Dr. Jaïs during a discussion that followed presentation of the RACE results.

Dr. Jaïs conceded this point, noting that the treatments have different targets and might be complementary.

“We plan to do a study like this in the future,” Dr. Jaïs said.

Dr. Jaïs reported no potential conflicts of interest.

MADRID – For the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), balloon pulmonary angioplasty (BPA) is more effective than riociguat for reducing pulmonary vascular resistance (PVR) and improving functional class, according to a multicenter trial presented at the annual congress of the European Respiratory Congress.

Both therapies are widely used in the treatment of CTEPH, but this is the first controlled trial in which they were directly compared, according to Xavier Jaïs, MD, of the Pulmonology Service, Kremlin-Bicêtre Hospital, University of Paris-Sud.

In this randomized trial, called RACE, newly diagnosed and previously untreated patients with nonoperable CTEPH were enrolled. The key eligibility criteria included PVR greater than 320 dynes/sec per cm^–5 and a pulmonary capillary wedge pressure of 15 mm Hg or less.

The patients were randomized to BPA or riociguat and followed for 26 weeks. The primary endpoint was relative change in PVR from baseline. The 6-minute walk distance, change in functional class, time to clinical worsening and safety were among secondary endpoints.

As calculated by geometric mean from baseline, PVR was reduced by nearly 60% in the BPA group and by 32% in the riociguat group, providing a 40% (P less than .0001) relative advantage of BPA.

Although there was a small relative advantage in the 6-minute walk distance for the BPA group at the end of the study, it did not reach statistical significant. However, 88% of those randomized to BPA versus 49% of those treated with riociguat (P less than .0001) improved by at least one WHO class by the end of the study.

Clinical worsening events over the course of the trial were uncommon. All three of these events occurred in the riociguat group, but the difference was not significant.

The end-of-study reduction in brain natriuretic peptide, which was another secondary endpoint, was 67% greater in the BPA group (P less than .0001).

There was a safety cost for the greater efficacy of BPA. This included a higher proportion of patients in the BPA group with at least one serious adverse event (50% vs. 26%) and at least one serious treatment-related adverse event (14% vs. 9%). No patient in either arm discontinued therapy because of treatment-related adverse events, and there were no deaths over the course of the study in either arm.

The study has included a 6-month extension to allow patients symptomatic on their originally assigned therapy to switch to the opposite treatment. Results of the extension are not yet available, but Dr. Jaïs said that these data might provide insight about which therapy to start first.

“It was very important to do this trial,” according to the ERS-invited discussant, Martin Kolb, MD, of the Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ont. The most recent World Symposium on Pulmonary Hypertension identified BPA and medical therapy as reasonable choices in inoperable CTEPH, but Dr. Kolb said there has been an unmet need for comparative data.

“This was a very strong study that demonstrated a powerful impact for both interventions on pulmonary vascular resistance,” Dr. Kolb said, adding that, although BPA proved to be more effective, clinicians consider the greater risk of adverse events. He believes further work needs to be done in identifying the best candidates for each and to explore hybrid approaches.

“What do you think about doing these sequentially so that you lower the pressure first with medical therapy and then go in with the balloon?” Dr. Kolb asked Dr. Jaïs during a discussion that followed presentation of the RACE results.

Dr. Jaïs conceded this point, noting that the treatments have different targets and might be complementary.

“We plan to do a study like this in the future,” Dr. Jaïs said.

Dr. Jaïs reported no potential conflicts of interest.

SAN FRANCISCO – An investigational device exemption trial of the Portico valve with FlexNav delivery system showed 1-year clinical results on par with commercially available valves, Gregory P. Fontana, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

Doug Brunk/MDedge News

In a prospective, open-label study conducted at 52 sites known as PORTICO, Dr. Fontana and colleagues conducted a noninferiority intention-to-treat evaluation of the safety and effectiveness of the self-expanding Portico transcatheter aortic valve replacement system, compared with Food and Drug Administration–approved and commercially available TAVR systems for patients with severe aortic stenosis at high or extreme risk for surgery. Between May 2014 and June 2019, 750 patients from 69 sites were randomized 1:1 to each group. The prespecified primary safety composite endpoint was all-cause mortality, disabling stroke, life-threatening bleeding requiring blood transfusion, acute kidney injury requiring dialysis, or major vascular complications at 30 days, while the primary effectiveness composite endpoint was all-cause mortality or disabling stroke at 1 year.

The mean baseline age of patients was 83 years, 53% were female, and their mean Society of Thoracic Surgeons score was 6.5%. Dr. Fontana, director and chairman of cardiothoracic surgery at the CardioVascular Institute of Los Robles Regional Medical Center, Thousand Oaks, Calif., reported at the meeting sponsored by the Cardiovascular Research Foundation that procedural success was comparable between groups (96.5% for Portico vs, 98.3% for commercially available TAVR, respectively). In addition, patients in both groups met the prespecified primary safety composite endpoint (13.8% vs. 9.6%; P for noninferiority = .03) and the primary effectiveness composite endpoint (14.9% vs. 13.4%, P for noninferiority = .006).

However, the rate of moderate to severe paravalvular leak at 30 days was 6.3% among patients in the Portico valve group, compared with 2.1% of their counterparts in the commercially available TAVR group, a difference that did not reach noninferiority. Dr. Fontana said that a next-generation valve with design modifications to reduce paravalvular leak is being tested in clinical trials.

PORTICO included a separate cohort of 100 patients who underwent Portico valve implantation using the FlexNav Delivery System, which became available after the trial had launched. The primary safety endpoint for the FlexNav cohort was major vascular complication rate at 30 days. This cohort demonstrated no deaths or strokes, low rates of major vascular complications (7.0%) and new permanent pacemaker implants (14.6%), as well as a safety profile comparable with the commercially available valve group in the randomized study (8.0% vs. 9.6%).

“My sense of this device is that presumably it will be another valve we have available to us in the United States,” Pinak B. Shah, MD, a cardiologist at Brigham and Women’s Hospital, Boston, said during a media briefing. “The challenge to all of us is to figure out where it fits in our armamentarium. Is it going to be worth individuals to learn a whole new device when at this point it’s hard to say if there’s a major difference compared to the other self-expanding devices we have now?”

With the new FlexNav delivery system, the Portico valve is characterized by “a very calm, slow delivery,” said Dr. Fontana, who was the study’s coprincipal investigator, along with Raj R. Makkar, MD, director of interventional cardiology at Cedars-Sinai Medical Center, Los Angeles. “The operator can land the valve exactly where they want it. If they’re not happy, they can make some adjustments. I haven’t yet a system in my hands that is as stable as this. The option of having excellent hemodynamics and large cells to engage the coronary system is a unique combination for us in the United States.”

The Portico valve is not currently FDA approved. The PORTICO study was funded by Abbott. Dr. Fontana disclosed grant/research support from Abbott and Medtronic and consulting fees/honoraria from Abbott, Medtronic, and LivaNova.

dbrunk@mdedge.com

SAN FRANCISCO – An investigational device exemption trial of the Portico valve with FlexNav delivery system showed 1-year clinical results on par with commercially available valves, Gregory P. Fontana, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

Doug Brunk/MDedge News

In a prospective, open-label study conducted at 52 sites known as PORTICO, Dr. Fontana and colleagues conducted a noninferiority intention-to-treat evaluation of the safety and effectiveness of the self-expanding Portico transcatheter aortic valve replacement system, compared with Food and Drug Administration–approved and commercially available TAVR systems for patients with severe aortic stenosis at high or extreme risk for surgery. Between May 2014 and June 2019, 750 patients from 69 sites were randomized 1:1 to each group. The prespecified primary safety composite endpoint was all-cause mortality, disabling stroke, life-threatening bleeding requiring blood transfusion, acute kidney injury requiring dialysis, or major vascular complications at 30 days, while the primary effectiveness composite endpoint was all-cause mortality or disabling stroke at 1 year.

The mean baseline age of patients was 83 years, 53% were female, and their mean Society of Thoracic Surgeons score was 6.5%. Dr. Fontana, director and chairman of cardiothoracic surgery at the CardioVascular Institute of Los Robles Regional Medical Center, Thousand Oaks, Calif., reported at the meeting sponsored by the Cardiovascular Research Foundation that procedural success was comparable between groups (96.5% for Portico vs, 98.3% for commercially available TAVR, respectively). In addition, patients in both groups met the prespecified primary safety composite endpoint (13.8% vs. 9.6%; P for noninferiority = .03) and the primary effectiveness composite endpoint (14.9% vs. 13.4%, P for noninferiority = .006).

However, the rate of moderate to severe paravalvular leak at 30 days was 6.3% among patients in the Portico valve group, compared with 2.1% of their counterparts in the commercially available TAVR group, a difference that did not reach noninferiority. Dr. Fontana said that a next-generation valve with design modifications to reduce paravalvular leak is being tested in clinical trials.

PORTICO included a separate cohort of 100 patients who underwent Portico valve implantation using the FlexNav Delivery System, which became available after the trial had launched. The primary safety endpoint for the FlexNav cohort was major vascular complication rate at 30 days. This cohort demonstrated no deaths or strokes, low rates of major vascular complications (7.0%) and new permanent pacemaker implants (14.6%), as well as a safety profile comparable with the commercially available valve group in the randomized study (8.0% vs. 9.6%).

“My sense of this device is that presumably it will be another valve we have available to us in the United States,” Pinak B. Shah, MD, a cardiologist at Brigham and Women’s Hospital, Boston, said during a media briefing. “The challenge to all of us is to figure out where it fits in our armamentarium. Is it going to be worth individuals to learn a whole new device when at this point it’s hard to say if there’s a major difference compared to the other self-expanding devices we have now?”

With the new FlexNav delivery system, the Portico valve is characterized by “a very calm, slow delivery,” said Dr. Fontana, who was the study’s coprincipal investigator, along with Raj R. Makkar, MD, director of interventional cardiology at Cedars-Sinai Medical Center, Los Angeles. “The operator can land the valve exactly where they want it. If they’re not happy, they can make some adjustments. I haven’t yet a system in my hands that is as stable as this. The option of having excellent hemodynamics and large cells to engage the coronary system is a unique combination for us in the United States.”

The Portico valve is not currently FDA approved. The PORTICO study was funded by Abbott. Dr. Fontana disclosed grant/research support from Abbott and Medtronic and consulting fees/honoraria from Abbott, Medtronic, and LivaNova.

dbrunk@mdedge.com

SAN FRANCISCO – An investigational device exemption trial of the Portico valve with FlexNav delivery system showed 1-year clinical results on par with commercially available valves, Gregory P. Fontana, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

Doug Brunk/MDedge News

In a prospective, open-label study conducted at 52 sites known as PORTICO, Dr. Fontana and colleagues conducted a noninferiority intention-to-treat evaluation of the safety and effectiveness of the self-expanding Portico transcatheter aortic valve replacement system, compared with Food and Drug Administration–approved and commercially available TAVR systems for patients with severe aortic stenosis at high or extreme risk for surgery. Between May 2014 and June 2019, 750 patients from 69 sites were randomized 1:1 to each group. The prespecified primary safety composite endpoint was all-cause mortality, disabling stroke, life-threatening bleeding requiring blood transfusion, acute kidney injury requiring dialysis, or major vascular complications at 30 days, while the primary effectiveness composite endpoint was all-cause mortality or disabling stroke at 1 year.

The mean baseline age of patients was 83 years, 53% were female, and their mean Society of Thoracic Surgeons score was 6.5%. Dr. Fontana, director and chairman of cardiothoracic surgery at the CardioVascular Institute of Los Robles Regional Medical Center, Thousand Oaks, Calif., reported at the meeting sponsored by the Cardiovascular Research Foundation that procedural success was comparable between groups (96.5% for Portico vs, 98.3% for commercially available TAVR, respectively). In addition, patients in both groups met the prespecified primary safety composite endpoint (13.8% vs. 9.6%; P for noninferiority = .03) and the primary effectiveness composite endpoint (14.9% vs. 13.4%, P for noninferiority = .006).

However, the rate of moderate to severe paravalvular leak at 30 days was 6.3% among patients in the Portico valve group, compared with 2.1% of their counterparts in the commercially available TAVR group, a difference that did not reach noninferiority. Dr. Fontana said that a next-generation valve with design modifications to reduce paravalvular leak is being tested in clinical trials.

PORTICO included a separate cohort of 100 patients who underwent Portico valve implantation using the FlexNav Delivery System, which became available after the trial had launched. The primary safety endpoint for the FlexNav cohort was major vascular complication rate at 30 days. This cohort demonstrated no deaths or strokes, low rates of major vascular complications (7.0%) and new permanent pacemaker implants (14.6%), as well as a safety profile comparable with the commercially available valve group in the randomized study (8.0% vs. 9.6%).

“My sense of this device is that presumably it will be another valve we have available to us in the United States,” Pinak B. Shah, MD, a cardiologist at Brigham and Women’s Hospital, Boston, said during a media briefing. “The challenge to all of us is to figure out where it fits in our armamentarium. Is it going to be worth individuals to learn a whole new device when at this point it’s hard to say if there’s a major difference compared to the other self-expanding devices we have now?”

With the new FlexNav delivery system, the Portico valve is characterized by “a very calm, slow delivery,” said Dr. Fontana, who was the study’s coprincipal investigator, along with Raj R. Makkar, MD, director of interventional cardiology at Cedars-Sinai Medical Center, Los Angeles. “The operator can land the valve exactly where they want it. If they’re not happy, they can make some adjustments. I haven’t yet a system in my hands that is as stable as this. The option of having excellent hemodynamics and large cells to engage the coronary system is a unique combination for us in the United States.”

The Portico valve is not currently FDA approved. The PORTICO study was funded by Abbott. Dr. Fontana disclosed grant/research support from Abbott and Medtronic and consulting fees/honoraria from Abbott, Medtronic, and LivaNova.

dbrunk@mdedge.com

PARIS – A practical strategy of early and aggressive vasodilation and optimization of long-term medication for acute heart failure did not budge all-cause mortality or 180-day readmission rates, according to results of a pragmatic trial presented at the annual congress of the European Society of Cardiology.

“To our great disappointment, the curves were superimposable” between intervention and control arms in the GALACTIC (Goal-directed Afterload Reduction in Acute Congestive Cardiac Decompensation) trial, said lead investigator Christian Eugen Mueller, MD. “There was no signal of a benefit” for those receiving the targeted intervention: the adjusted hazard ratio was 1.07 for the composite primary endpoint of all-cause mortality or 6-month readmission for acute heart failure (P = 0.59).

GALACTIC, explained Dr. Mueller, was the largest investigator-initiated, randomized, controlled trial of pharmacologic therapy for acute heart failure (AHF).

“It is different in that it did not investigate a single drug, but a strategy of early, intensive, and sustained vasodilation. It is also unique in that it used individual doses of well-characterized, widely available, and mostly inexpensive drugs,” said Dr. Mueller, director of the Cardiovascular Research Institute at the University Hospital, Basel, Switzerland. “So this would have the beauty that, if it has a positive finding, you – in whatever country you come from – would be immediately able to apply it once you’re back home in your institution.”

The study attempted to address the gap between symptom amelioration and long-term outcomes when patients arrive in the ED with AHF. “Despite symptomatic improvement achieved from loop diuretics, mortality and morbidity remain unacceptably high,” said Dr. Mueller, with 40%-50% of AHF patients experiencing rehospitalization or death within 180 days of discharge.

Much remains unknown about the optimal treatment strategy for AHF. Aggressive vasodilation has been shown to improve outcomes in less-severe AHF, and intravenous nitrates are known to improve outcomes in AHF where severe pulmonary edema is present – “a phenotype representing only about 5% of patients,” noted Dr. Mueller. Still, “it is unknown whether aggressive vasodilation also improves outcomes in the much more common less-severe phenotype.”

Also, previous trials that ran intravenous vasodilators at a fixed dose for 48 hours did not improve AHF outcomes, so a one-size-fits-all strategy was not one the GALACTIC investigators sought to pursue.

In addition to a flexible regimen, “any strategy applied needs to take into consideration that the vast majority of patients with acute heart failure, after initial treatment in the ED, are then treated in a general cardiology ward,” added Dr. Mueller.

This meant that intravenous nitrate infusion was not part of the GALACTIC trial; rather, sublingual and transdermal nitrates were used, explained Dr. Mueller. “Transdermal application has the beauty that if you have an adverse effect – and hypotension is the most dangerous one – you can immediately remove the patch, and thereby avoid any further harm.”

The two-part strategy tested in GALACTIC involved reducing cardiac filling pressures by maintaining or increasing organ perfusion, while also increasing “long-term lifesaving therapy” targeting the renin-angiotensin-aldosterone system during hospitalization, with a goal to continue optimal treatment long term.

ACE inhibitors or angiotensin receptor blockers were added on the second day of hospitalization for the intervention group, said Dr. Mueller, and “in the ideal setting, up-titrated very aggressively from day to day.

“However, as you know, up-titration to target dose is sometimes wishful thinking in this frail population,” he said, so the GALACTIC trial protocol included a scheme to back dosing off for hypotension, hypokalemia, or worsening renal function. Systolic BP guided how aggressively vasodilation and ACE inhibitor/angiotensin receptor blocker therapy were escalated.

In the end, 382 patients randomized to the intervention arm received early, intensive, and sustained vasodilation, and the 399 patients in the control arm received standard-of-care treatment according to ESC guidelines. These figures omit two patients in the standard-of-care arm who withdrew consent, but follow-up was otherwise complete, said Dr. Mueller. Physicians treating patients in both study arms had discretion to use such other therapies as loop diuretics, beta-blockers, aldosterone antagonists, and cardiac devices.

Adult patients coming to the ED with acute dyspnea classified as New York Heart Association class III or IV were eligible if they had brain natriuretic peptide (BNP) levels of at least 500 ng/L, or N-terminal of the prohormone BNP (NT-proBNP) levels of at least 2,000 ng/L.

Overall, patients enrolled in GALACTIC were in their late 70s, and women made up 37% of the population.

The actual median BNP for enrollees was about 1,250 ng/L, and the median NT-proBNP was just under 6,000 ng/L. The median left ventricular ejection fraction was 37%. About a third of patients had diabetes, and 85% had hypertension. Over half had known chronic heart failure, about a third had prior history of MI, and half of patients had atrial fibrillation at baseline.

“Signs of congestion were present in all patients, and over 90% had rales on physical examination,” said Dr. Mueller.

Patients who were destined for the ICU, those who had systolic BP below 100 mm Hg or marked creatinine elevation, or who required cardiopulmonary resuscitation were excluded. Also excluded were patients with known structural defects such as severe valvular stenosis, congenital heart disease, or hypertrophic obstructive cardiomyopathy. GALACTIC also excluded patients with isolated right ventricular failure caused by pulmonary hypertension.

Prespecified subgroup analyses compared women with men, and those younger than 75 years with older participants. Women saw a significantly higher hazard ratio for readmission or death, indicating a potential harm from the intervention, said Dr. Mueller. An additional analysis stratified patients by left ventricular ejection fraction. Aside from the intervention’s negative effect on women participating in the trial, no other subgroups benefited or were harmed by an early vasodilation strategy.

Alexandre Mebazaa, MD, the designated discussant for the presentation, said that, although the GALACTIC trial was neutral, it represents “an important step forward in acute heart failure.

“Congratulations: First, because we know that in the critically ill condition it’s very difficult to do trials,” and the GALACTIC investigators succeeded in enrolling patients within the first 5 hours of presentation to EDs, noted Dr. Mebazaa, professor of anesthesiology and critical care medicine at the Paris Diderot School of Medicine.

He added that GALACTIC succeeded in continuing vasodilator use beyond the 48-hour mark. “For the first time, you had the courage to go a little bit further down, and we see that patients got the drug with vasodilator properties for 2 days or more.”

However, the long recruitment period for GALACTIC – first enrollment began in 2007 – meant that the study design reflected a thought process about AHF that doesn’t necessarily reflect current practice, noted Dr. Mebazaa. “The trial was designed many years ago, and at that time, we were still thinking that giving very aggressive treatment in the first hours could have an impact.

“Now, when we will be treating patients with vasodilators with acute heart failure – at least myself and my group – I would really wonder whether there is still evidence in the world to support the use of those agents.”

Dr. Mueller noted limitations of the GALACTIC trial, including the lack of generalizability to patients with systolic hypotension or severe renal dysfunction, since these populations were excluded. Also, “the open-label design, which was mandated by the aim to test a strategy, not a single drug, may have introduced a bias in the unblinded assessment of dyspnea” during inpatient stay.

The study was funded by several Swiss research institutions and had no industry support. Dr. Mueller reported no relevant conflicts of interest. Dr. Mebazaa reported financial relationships with Roche, Service, Novartis, AstraZeneca, S-Form Pharma, 4Teen$4, Adrenomed, and Sphingotec.

koakes@mdedge.com

SOURCE: Mueller C. ESC 2019, Hot Line Session 3.

PARIS – A practical strategy of early and aggressive vasodilation and optimization of long-term medication for acute heart failure did not budge all-cause mortality or 180-day readmission rates, according to results of a pragmatic trial presented at the annual congress of the European Society of Cardiology.

“To our great disappointment, the curves were superimposable” between intervention and control arms in the GALACTIC (Goal-directed Afterload Reduction in Acute Congestive Cardiac Decompensation) trial, said lead investigator Christian Eugen Mueller, MD. “There was no signal of a benefit” for those receiving the targeted intervention: the adjusted hazard ratio was 1.07 for the composite primary endpoint of all-cause mortality or 6-month readmission for acute heart failure (P = 0.59).

GALACTIC, explained Dr. Mueller, was the largest investigator-initiated, randomized, controlled trial of pharmacologic therapy for acute heart failure (AHF).

“It is different in that it did not investigate a single drug, but a strategy of early, intensive, and sustained vasodilation. It is also unique in that it used individual doses of well-characterized, widely available, and mostly inexpensive drugs,” said Dr. Mueller, director of the Cardiovascular Research Institute at the University Hospital, Basel, Switzerland. “So this would have the beauty that, if it has a positive finding, you – in whatever country you come from – would be immediately able to apply it once you’re back home in your institution.”

The study attempted to address the gap between symptom amelioration and long-term outcomes when patients arrive in the ED with AHF. “Despite symptomatic improvement achieved from loop diuretics, mortality and morbidity remain unacceptably high,” said Dr. Mueller, with 40%-50% of AHF patients experiencing rehospitalization or death within 180 days of discharge.

Much remains unknown about the optimal treatment strategy for AHF. Aggressive vasodilation has been shown to improve outcomes in less-severe AHF, and intravenous nitrates are known to improve outcomes in AHF where severe pulmonary edema is present – “a phenotype representing only about 5% of patients,” noted Dr. Mueller. Still, “it is unknown whether aggressive vasodilation also improves outcomes in the much more common less-severe phenotype.”

Also, previous trials that ran intravenous vasodilators at a fixed dose for 48 hours did not improve AHF outcomes, so a one-size-fits-all strategy was not one the GALACTIC investigators sought to pursue.

In addition to a flexible regimen, “any strategy applied needs to take into consideration that the vast majority of patients with acute heart failure, after initial treatment in the ED, are then treated in a general cardiology ward,” added Dr. Mueller.

This meant that intravenous nitrate infusion was not part of the GALACTIC trial; rather, sublingual and transdermal nitrates were used, explained Dr. Mueller. “Transdermal application has the beauty that if you have an adverse effect – and hypotension is the most dangerous one – you can immediately remove the patch, and thereby avoid any further harm.”

The two-part strategy tested in GALACTIC involved reducing cardiac filling pressures by maintaining or increasing organ perfusion, while also increasing “long-term lifesaving therapy” targeting the renin-angiotensin-aldosterone system during hospitalization, with a goal to continue optimal treatment long term.

ACE inhibitors or angiotensin receptor blockers were added on the second day of hospitalization for the intervention group, said Dr. Mueller, and “in the ideal setting, up-titrated very aggressively from day to day.

“However, as you know, up-titration to target dose is sometimes wishful thinking in this frail population,” he said, so the GALACTIC trial protocol included a scheme to back dosing off for hypotension, hypokalemia, or worsening renal function. Systolic BP guided how aggressively vasodilation and ACE inhibitor/angiotensin receptor blocker therapy were escalated.

In the end, 382 patients randomized to the intervention arm received early, intensive, and sustained vasodilation, and the 399 patients in the control arm received standard-of-care treatment according to ESC guidelines. These figures omit two patients in the standard-of-care arm who withdrew consent, but follow-up was otherwise complete, said Dr. Mueller. Physicians treating patients in both study arms had discretion to use such other therapies as loop diuretics, beta-blockers, aldosterone antagonists, and cardiac devices.

Adult patients coming to the ED with acute dyspnea classified as New York Heart Association class III or IV were eligible if they had brain natriuretic peptide (BNP) levels of at least 500 ng/L, or N-terminal of the prohormone BNP (NT-proBNP) levels of at least 2,000 ng/L.

Overall, patients enrolled in GALACTIC were in their late 70s, and women made up 37% of the population.

The actual median BNP for enrollees was about 1,250 ng/L, and the median NT-proBNP was just under 6,000 ng/L. The median left ventricular ejection fraction was 37%. About a third of patients had diabetes, and 85% had hypertension. Over half had known chronic heart failure, about a third had prior history of MI, and half of patients had atrial fibrillation at baseline.

“Signs of congestion were present in all patients, and over 90% had rales on physical examination,” said Dr. Mueller.

Patients who were destined for the ICU, those who had systolic BP below 100 mm Hg or marked creatinine elevation, or who required cardiopulmonary resuscitation were excluded. Also excluded were patients with known structural defects such as severe valvular stenosis, congenital heart disease, or hypertrophic obstructive cardiomyopathy. GALACTIC also excluded patients with isolated right ventricular failure caused by pulmonary hypertension.

Prespecified subgroup analyses compared women with men, and those younger than 75 years with older participants. Women saw a significantly higher hazard ratio for readmission or death, indicating a potential harm from the intervention, said Dr. Mueller. An additional analysis stratified patients by left ventricular ejection fraction. Aside from the intervention’s negative effect on women participating in the trial, no other subgroups benefited or were harmed by an early vasodilation strategy.

Alexandre Mebazaa, MD, the designated discussant for the presentation, said that, although the GALACTIC trial was neutral, it represents “an important step forward in acute heart failure.

“Congratulations: First, because we know that in the critically ill condition it’s very difficult to do trials,” and the GALACTIC investigators succeeded in enrolling patients within the first 5 hours of presentation to EDs, noted Dr. Mebazaa, professor of anesthesiology and critical care medicine at the Paris Diderot School of Medicine.

He added that GALACTIC succeeded in continuing vasodilator use beyond the 48-hour mark. “For the first time, you had the courage to go a little bit further down, and we see that patients got the drug with vasodilator properties for 2 days or more.”

However, the long recruitment period for GALACTIC – first enrollment began in 2007 – meant that the study design reflected a thought process about AHF that doesn’t necessarily reflect current practice, noted Dr. Mebazaa. “The trial was designed many years ago, and at that time, we were still thinking that giving very aggressive treatment in the first hours could have an impact.

“Now, when we will be treating patients with vasodilators with acute heart failure – at least myself and my group – I would really wonder whether there is still evidence in the world to support the use of those agents.”

Dr. Mueller noted limitations of the GALACTIC trial, including the lack of generalizability to patients with systolic hypotension or severe renal dysfunction, since these populations were excluded. Also, “the open-label design, which was mandated by the aim to test a strategy, not a single drug, may have introduced a bias in the unblinded assessment of dyspnea” during inpatient stay.

The study was funded by several Swiss research institutions and had no industry support. Dr. Mueller reported no relevant conflicts of interest. Dr. Mebazaa reported financial relationships with Roche, Service, Novartis, AstraZeneca, S-Form Pharma, 4Teen$4, Adrenomed, and Sphingotec.

koakes@mdedge.com

SOURCE: Mueller C. ESC 2019, Hot Line Session 3.

PARIS – A practical strategy of early and aggressive vasodilation and optimization of long-term medication for acute heart failure did not budge all-cause mortality or 180-day readmission rates, according to results of a pragmatic trial presented at the annual congress of the European Society of Cardiology.

“To our great disappointment, the curves were superimposable” between intervention and control arms in the GALACTIC (Goal-directed Afterload Reduction in Acute Congestive Cardiac Decompensation) trial, said lead investigator Christian Eugen Mueller, MD. “There was no signal of a benefit” for those receiving the targeted intervention: the adjusted hazard ratio was 1.07 for the composite primary endpoint of all-cause mortality or 6-month readmission for acute heart failure (P = 0.59).

GALACTIC, explained Dr. Mueller, was the largest investigator-initiated, randomized, controlled trial of pharmacologic therapy for acute heart failure (AHF).

“It is different in that it did not investigate a single drug, but a strategy of early, intensive, and sustained vasodilation. It is also unique in that it used individual doses of well-characterized, widely available, and mostly inexpensive drugs,” said Dr. Mueller, director of the Cardiovascular Research Institute at the University Hospital, Basel, Switzerland. “So this would have the beauty that, if it has a positive finding, you – in whatever country you come from – would be immediately able to apply it once you’re back home in your institution.”

The study attempted to address the gap between symptom amelioration and long-term outcomes when patients arrive in the ED with AHF. “Despite symptomatic improvement achieved from loop diuretics, mortality and morbidity remain unacceptably high,” said Dr. Mueller, with 40%-50% of AHF patients experiencing rehospitalization or death within 180 days of discharge.

Much remains unknown about the optimal treatment strategy for AHF. Aggressive vasodilation has been shown to improve outcomes in less-severe AHF, and intravenous nitrates are known to improve outcomes in AHF where severe pulmonary edema is present – “a phenotype representing only about 5% of patients,” noted Dr. Mueller. Still, “it is unknown whether aggressive vasodilation also improves outcomes in the much more common less-severe phenotype.”

Also, previous trials that ran intravenous vasodilators at a fixed dose for 48 hours did not improve AHF outcomes, so a one-size-fits-all strategy was not one the GALACTIC investigators sought to pursue.

In addition to a flexible regimen, “any strategy applied needs to take into consideration that the vast majority of patients with acute heart failure, after initial treatment in the ED, are then treated in a general cardiology ward,” added Dr. Mueller.

This meant that intravenous nitrate infusion was not part of the GALACTIC trial; rather, sublingual and transdermal nitrates were used, explained Dr. Mueller. “Transdermal application has the beauty that if you have an adverse effect – and hypotension is the most dangerous one – you can immediately remove the patch, and thereby avoid any further harm.”

The two-part strategy tested in GALACTIC involved reducing cardiac filling pressures by maintaining or increasing organ perfusion, while also increasing “long-term lifesaving therapy” targeting the renin-angiotensin-aldosterone system during hospitalization, with a goal to continue optimal treatment long term.

ACE inhibitors or angiotensin receptor blockers were added on the second day of hospitalization for the intervention group, said Dr. Mueller, and “in the ideal setting, up-titrated very aggressively from day to day.

“However, as you know, up-titration to target dose is sometimes wishful thinking in this frail population,” he said, so the GALACTIC trial protocol included a scheme to back dosing off for hypotension, hypokalemia, or worsening renal function. Systolic BP guided how aggressively vasodilation and ACE inhibitor/angiotensin receptor blocker therapy were escalated.

In the end, 382 patients randomized to the intervention arm received early, intensive, and sustained vasodilation, and the 399 patients in the control arm received standard-of-care treatment according to ESC guidelines. These figures omit two patients in the standard-of-care arm who withdrew consent, but follow-up was otherwise complete, said Dr. Mueller. Physicians treating patients in both study arms had discretion to use such other therapies as loop diuretics, beta-blockers, aldosterone antagonists, and cardiac devices.

Adult patients coming to the ED with acute dyspnea classified as New York Heart Association class III or IV were eligible if they had brain natriuretic peptide (BNP) levels of at least 500 ng/L, or N-terminal of the prohormone BNP (NT-proBNP) levels of at least 2,000 ng/L.

Overall, patients enrolled in GALACTIC were in their late 70s, and women made up 37% of the population.

The actual median BNP for enrollees was about 1,250 ng/L, and the median NT-proBNP was just under 6,000 ng/L. The median left ventricular ejection fraction was 37%. About a third of patients had diabetes, and 85% had hypertension. Over half had known chronic heart failure, about a third had prior history of MI, and half of patients had atrial fibrillation at baseline.

“Signs of congestion were present in all patients, and over 90% had rales on physical examination,” said Dr. Mueller.

Patients who were destined for the ICU, those who had systolic BP below 100 mm Hg or marked creatinine elevation, or who required cardiopulmonary resuscitation were excluded. Also excluded were patients with known structural defects such as severe valvular stenosis, congenital heart disease, or hypertrophic obstructive cardiomyopathy. GALACTIC also excluded patients with isolated right ventricular failure caused by pulmonary hypertension.

Prespecified subgroup analyses compared women with men, and those younger than 75 years with older participants. Women saw a significantly higher hazard ratio for readmission or death, indicating a potential harm from the intervention, said Dr. Mueller. An additional analysis stratified patients by left ventricular ejection fraction. Aside from the intervention’s negative effect on women participating in the trial, no other subgroups benefited or were harmed by an early vasodilation strategy.

Alexandre Mebazaa, MD, the designated discussant for the presentation, said that, although the GALACTIC trial was neutral, it represents “an important step forward in acute heart failure.

“Congratulations: First, because we know that in the critically ill condition it’s very difficult to do trials,” and the GALACTIC investigators succeeded in enrolling patients within the first 5 hours of presentation to EDs, noted Dr. Mebazaa, professor of anesthesiology and critical care medicine at the Paris Diderot School of Medicine.

He added that GALACTIC succeeded in continuing vasodilator use beyond the 48-hour mark. “For the first time, you had the courage to go a little bit further down, and we see that patients got the drug with vasodilator properties for 2 days or more.”

However, the long recruitment period for GALACTIC – first enrollment began in 2007 – meant that the study design reflected a thought process about AHF that doesn’t necessarily reflect current practice, noted Dr. Mebazaa. “The trial was designed many years ago, and at that time, we were still thinking that giving very aggressive treatment in the first hours could have an impact.

“Now, when we will be treating patients with vasodilators with acute heart failure – at least myself and my group – I would really wonder whether there is still evidence in the world to support the use of those agents.”

Dr. Mueller noted limitations of the GALACTIC trial, including the lack of generalizability to patients with systolic hypotension or severe renal dysfunction, since these populations were excluded. Also, “the open-label design, which was mandated by the aim to test a strategy, not a single drug, may have introduced a bias in the unblinded assessment of dyspnea” during inpatient stay.

The study was funded by several Swiss research institutions and had no industry support. Dr. Mueller reported no relevant conflicts of interest. Dr. Mebazaa reported financial relationships with Roche, Service, Novartis, AstraZeneca, S-Form Pharma, 4Teen$4, Adrenomed, and Sphingotec.

koakes@mdedge.com

SOURCE: Mueller C. ESC 2019, Hot Line Session 3.

ST. LOUIS – The lower the blood pressure peaks and variability in the first 24 hours after ischemic stroke reperfusion, the better the outcomes, according to a review of 140 patients at the University of New Mexico, Albuquerque. Investigators found that every 10–mm Hg increase in peak systolic pressure boosted the risk of in-hospital death 24% (P = .01) and reduced the chance of being discharged home or to a inpatient rehabilitation facility 13% (P = .03). Results were even stronger for peak mean arterial pressure, at 76% (P = .01) and 29% (P = .04), respectively; trends in the same direction for peak diastolic pressure were not statistically significant.

Also, every 10–mm Hg increase in blood pressure variability again increased the risk of dying in the hospital, whether it was systolic (33%; P = .002), diastolic (33%; P = .03), or mean arterial pressure variability (58%; P = .02). Higher variability also reduced the chance of being discharged home or to a rehab 10%-20%, but the findings, although close, were not statistically significant.

Neurologists generally do what they can to control blood pressure after stroke, and the study confirms the need to do that. What’s new is that the work was limited to reperfusion patients – intravenous thrombolysis with alteplase in 83.5%, mechanical thrombectomy in 60%, with some having both – which has not been the specific focus of much research.

“Be much more aggressive in terms of making sure the variability is limited and limiting the peaks,” especially within 24 hours of reperfusion, said lead investigator and stroke neurologist Dinesh Jillella, MD, of Emory University, Atlanta, at the annual meeting of the American Neurological Association. “We want to be much more aggressive [with these patients]; it might limit our worse outcomes,” Dr. Jillella said. He conducted the review while in training at the University of New Mexico.

What led to the study is that Dr. Jillella and colleagues noticed that similar reperfusion patients can have very different outcomes, and he wanted to find modifiable risk factors that could account for the differences. The study did not address why high peaks and variability lead to worse outcomes, but he said hemorrhagic conversion might play a role.

It is also possible that higher pressures could be a marker of bad outcomes, as opposed to a direct cause, but the findings were adjusted for two significant confounders: age and the National Institutes of Health Stroke Scale score, which were both significantly higher in patients who did not do well. But after adjustment, “we [still] found an independent association with blood pressures and worse outcomes,” he said.

Higher peak systolic pressures and variability were also associated with about a 15% lower odds of leaving the hospital with a modified Rankin Scale score of 3 or less, which means the patient has some moderate disability but is still able to walk without assistance.

Patients were 69 years old on average, and about 60% were men. The majority were white. About a third had a modified Rankin Scale score at or below 3 at discharge, and about two-thirds were discharged home or to a rehabilitation facility; 17% of patients died in the hospital.

Differences in antihypertensive regimens were not associated with outcomes on univariate analysis. Dr. Jillella said that, ideally, he would like to run a multicenter, prospective trial of blood pressure reduction targets after reperfusion.

There was no external funding, and Dr. Jillella didn’t have any relevant disclosures.
 

aotto@mdedge.com

ST. LOUIS – The lower the blood pressure peaks and variability in the first 24 hours after ischemic stroke reperfusion, the better the outcomes, according to a review of 140 patients at the University of New Mexico, Albuquerque. Investigators found that every 10–mm Hg increase in peak systolic pressure boosted the risk of in-hospital death 24% (P = .01) and reduced the chance of being discharged home or to a inpatient rehabilitation facility 13% (P = .03). Results were even stronger for peak mean arterial pressure, at 76% (P = .01) and 29% (P = .04), respectively; trends in the same direction for peak diastolic pressure were not statistically significant.

Also, every 10–mm Hg increase in blood pressure variability again increased the risk of dying in the hospital, whether it was systolic (33%; P = .002), diastolic (33%; P = .03), or mean arterial pressure variability (58%; P = .02). Higher variability also reduced the chance of being discharged home or to a rehab 10%-20%, but the findings, although close, were not statistically significant.

Neurologists generally do what they can to control blood pressure after stroke, and the study confirms the need to do that. What’s new is that the work was limited to reperfusion patients – intravenous thrombolysis with alteplase in 83.5%, mechanical thrombectomy in 60%, with some having both – which has not been the specific focus of much research.

“Be much more aggressive in terms of making sure the variability is limited and limiting the peaks,” especially within 24 hours of reperfusion, said lead investigator and stroke neurologist Dinesh Jillella, MD, of Emory University, Atlanta, at the annual meeting of the American Neurological Association. “We want to be much more aggressive [with these patients]; it might limit our worse outcomes,” Dr. Jillella said. He conducted the review while in training at the University of New Mexico.

What led to the study is that Dr. Jillella and colleagues noticed that similar reperfusion patients can have very different outcomes, and he wanted to find modifiable risk factors that could account for the differences. The study did not address why high peaks and variability lead to worse outcomes, but he said hemorrhagic conversion might play a role.

It is also possible that higher pressures could be a marker of bad outcomes, as opposed to a direct cause, but the findings were adjusted for two significant confounders: age and the National Institutes of Health Stroke Scale score, which were both significantly higher in patients who did not do well. But after adjustment, “we [still] found an independent association with blood pressures and worse outcomes,” he said.

Higher peak systolic pressures and variability were also associated with about a 15% lower odds of leaving the hospital with a modified Rankin Scale score of 3 or less, which means the patient has some moderate disability but is still able to walk without assistance.

Patients were 69 years old on average, and about 60% were men. The majority were white. About a third had a modified Rankin Scale score at or below 3 at discharge, and about two-thirds were discharged home or to a rehabilitation facility; 17% of patients died in the hospital.

Differences in antihypertensive regimens were not associated with outcomes on univariate analysis. Dr. Jillella said that, ideally, he would like to run a multicenter, prospective trial of blood pressure reduction targets after reperfusion.

There was no external funding, and Dr. Jillella didn’t have any relevant disclosures.
 

aotto@mdedge.com

ST. LOUIS – The lower the blood pressure peaks and variability in the first 24 hours after ischemic stroke reperfusion, the better the outcomes, according to a review of 140 patients at the University of New Mexico, Albuquerque. Investigators found that every 10–mm Hg increase in peak systolic pressure boosted the risk of in-hospital death 24% (P = .01) and reduced the chance of being discharged home or to a inpatient rehabilitation facility 13% (P = .03). Results were even stronger for peak mean arterial pressure, at 76% (P = .01) and 29% (P = .04), respectively; trends in the same direction for peak diastolic pressure were not statistically significant.

Also, every 10–mm Hg increase in blood pressure variability again increased the risk of dying in the hospital, whether it was systolic (33%; P = .002), diastolic (33%; P = .03), or mean arterial pressure variability (58%; P = .02). Higher variability also reduced the chance of being discharged home or to a rehab 10%-20%, but the findings, although close, were not statistically significant.

Neurologists generally do what they can to control blood pressure after stroke, and the study confirms the need to do that. What’s new is that the work was limited to reperfusion patients – intravenous thrombolysis with alteplase in 83.5%, mechanical thrombectomy in 60%, with some having both – which has not been the specific focus of much research.

“Be much more aggressive in terms of making sure the variability is limited and limiting the peaks,” especially within 24 hours of reperfusion, said lead investigator and stroke neurologist Dinesh Jillella, MD, of Emory University, Atlanta, at the annual meeting of the American Neurological Association. “We want to be much more aggressive [with these patients]; it might limit our worse outcomes,” Dr. Jillella said. He conducted the review while in training at the University of New Mexico.

What led to the study is that Dr. Jillella and colleagues noticed that similar reperfusion patients can have very different outcomes, and he wanted to find modifiable risk factors that could account for the differences. The study did not address why high peaks and variability lead to worse outcomes, but he said hemorrhagic conversion might play a role.

It is also possible that higher pressures could be a marker of bad outcomes, as opposed to a direct cause, but the findings were adjusted for two significant confounders: age and the National Institutes of Health Stroke Scale score, which were both significantly higher in patients who did not do well. But after adjustment, “we [still] found an independent association with blood pressures and worse outcomes,” he said.

Higher peak systolic pressures and variability were also associated with about a 15% lower odds of leaving the hospital with a modified Rankin Scale score of 3 or less, which means the patient has some moderate disability but is still able to walk without assistance.

Patients were 69 years old on average, and about 60% were men. The majority were white. About a third had a modified Rankin Scale score at or below 3 at discharge, and about two-thirds were discharged home or to a rehabilitation facility; 17% of patients died in the hospital.

Differences in antihypertensive regimens were not associated with outcomes on univariate analysis. Dr. Jillella said that, ideally, he would like to run a multicenter, prospective trial of blood pressure reduction targets after reperfusion.

There was no external funding, and Dr. Jillella didn’t have any relevant disclosures.
 

aotto@mdedge.com

The Food and Drug Administration has approved rivaroxaban (Xarelto) for the prevention of venous thromboembolism (VTE) in hospitalized, acutely ill patients at risk for thromboembolic complications who do not have a high bleeding risk, according to a release from Janssen.

FDA approval for the new indication is based on results from the phase 3 MAGELLAN and MARINER trials, which included more than 20,000 hospitalized, acutely ill patients. In MAGELLAN, rivaroxaban demonstrated noninferiority to enoxaparin, a low-molecular-weight heparin, in short-term usage, and it was superior over the long term, compared with short-term enoxaparin followed by placebo.

While VTE and VTE-related deaths were not reduced in MARINER, compared with placebo, patients who received rivaroxaban did see a significantly reduction in symptomatic VTE with a favorable safety profile.

According to the indication, rivaroxaban can be administered to patients during hospitalization and can be continued after discharge for 31-39 days. The safety profile in MAGELLAN and MARINER was consistent with that already seen, with the most common adverse event being bleeding.

The new indication is the eighth for rivaroxaban, the most of any direct oral anticoagulant; six of these are specifically for the treatment, prevention, and reduction in the risk of VTE recurrence.

“With this new approval, Xarelto as an oral-only option now has the potential to change how acutely ill medical patients are managed for the prevention of blood clots, both in the hospital and for an extended period after discharge,” said Alex C. Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital, New York, and a member of the steering committee of the MAGELLAN trial.

Find the full press release on the Janssen website.

lfranki@mdedge.com

The Food and Drug Administration has approved rivaroxaban (Xarelto) for the prevention of venous thromboembolism (VTE) in hospitalized, acutely ill patients at risk for thromboembolic complications who do not have a high bleeding risk, according to a release from Janssen.

FDA approval for the new indication is based on results from the phase 3 MAGELLAN and MARINER trials, which included more than 20,000 hospitalized, acutely ill patients. In MAGELLAN, rivaroxaban demonstrated noninferiority to enoxaparin, a low-molecular-weight heparin, in short-term usage, and it was superior over the long term, compared with short-term enoxaparin followed by placebo.

While VTE and VTE-related deaths were not reduced in MARINER, compared with placebo, patients who received rivaroxaban did see a significantly reduction in symptomatic VTE with a favorable safety profile.

According to the indication, rivaroxaban can be administered to patients during hospitalization and can be continued after discharge for 31-39 days. The safety profile in MAGELLAN and MARINER was consistent with that already seen, with the most common adverse event being bleeding.

The new indication is the eighth for rivaroxaban, the most of any direct oral anticoagulant; six of these are specifically for the treatment, prevention, and reduction in the risk of VTE recurrence.

“With this new approval, Xarelto as an oral-only option now has the potential to change how acutely ill medical patients are managed for the prevention of blood clots, both in the hospital and for an extended period after discharge,” said Alex C. Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital, New York, and a member of the steering committee of the MAGELLAN trial.

Find the full press release on the Janssen website.

lfranki@mdedge.com

The Food and Drug Administration has approved rivaroxaban (Xarelto) for the prevention of venous thromboembolism (VTE) in hospitalized, acutely ill patients at risk for thromboembolic complications who do not have a high bleeding risk, according to a release from Janssen.

FDA approval for the new indication is based on results from the phase 3 MAGELLAN and MARINER trials, which included more than 20,000 hospitalized, acutely ill patients. In MAGELLAN, rivaroxaban demonstrated noninferiority to enoxaparin, a low-molecular-weight heparin, in short-term usage, and it was superior over the long term, compared with short-term enoxaparin followed by placebo.

While VTE and VTE-related deaths were not reduced in MARINER, compared with placebo, patients who received rivaroxaban did see a significantly reduction in symptomatic VTE with a favorable safety profile.

According to the indication, rivaroxaban can be administered to patients during hospitalization and can be continued after discharge for 31-39 days. The safety profile in MAGELLAN and MARINER was consistent with that already seen, with the most common adverse event being bleeding.

The new indication is the eighth for rivaroxaban, the most of any direct oral anticoagulant; six of these are specifically for the treatment, prevention, and reduction in the risk of VTE recurrence.

“With this new approval, Xarelto as an oral-only option now has the potential to change how acutely ill medical patients are managed for the prevention of blood clots, both in the hospital and for an extended period after discharge,” said Alex C. Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital, New York, and a member of the steering committee of the MAGELLAN trial.

Find the full press release on the Janssen website.

lfranki@mdedge.com

Patients with thrombotic antiphospholipid syndrome (APS) may have a greater risk of recurrent thrombosis when taking rivaroxaban instead of a vitamin K antagonist, suggests a recent trial conducted in Spain.

Stroke was also more common among those taking rivaroxaban, while major bleeding was slightly less common, reported lead author Josep Ordi-Ros, MD, PhD, of Vall d’Hebrón University Hospital Research Institute in Barcelona, and colleagues in Annals of Internal Medicine.

“Two randomized, controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation but showed an increased thrombotic risk in those with triple-positive antiphospholipid antibodies,” the investigators wrote. However, they also noted that these findings required a cautious interpretation because of study limitations, such as premature termination caused by an excess of study events and the use of a laboratory surrogate marker as a primary outcome.

To learn more, the investigators performed an open-label, phase 3 trial involving 190 patients with thrombotic APS. Patients were randomized in a 1:1 ratio to receive either rivaroxaban (20 mg per day, or 15 mg per day for patients with a creatinine clearance of 30-49 mL/min per 1.73 m²) or an adjusted dosage of vitamin K antagonists (target international normalized ratio of 2.0-3.0, or 3.1-4.0 for those with a history of recurrent thrombosis).

Patients underwent evaluations every month for the first 3 months and then every 3 months thereafter, each of which involved a variety of laboratory diagnostics such as checks for antinuclear antibodies and lupus anticoagulant, among others. Statistical analyses aimed to determine if rivaroxaban was noninferior to therapy with vitamin K antagonists based on parameters drawn from previous meta-analyses, as no studies had compared the two types of treatment when the present study was designed.

After 3 years of follow-up, almost twice as many patients in the rivaroxaban group had experienced recurrent thrombosis (11.6% vs. 6.3%), although this finding lacked statistical significance for both noninferiority of rivaroxaban (P = .29) and superiority of vitamin K antagonists (P = .20). Still, supporting a similar trend toward differences in efficacy, stroke was more common in the rivaroxaban group, in which nine events occurred, compared with none in the vitamin K antagonist group. In contrast, major bleeding was slightly less common with rivaroxaban than vitamin K antagonists (6.3% vs. 7.4%).

“In conclusion, rivaroxaban did not demonstrate noninferiority to dose-adjusted vitamin K antagonists for secondary thromboprophylaxis in patients with thrombotic APS,” the investigators wrote. “Instead, our results indicate a recurrent thrombotic rate that is nearly double, albeit without statistical significance.”

The study was funded by Bayer Hispania. One coauthor reported additional relationships with Pfizer, Lilly, Janssen, and others.

SOURCE: Ordi-Ros J et al. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291.

Patients with thrombotic antiphospholipid syndrome (APS) may have a greater risk of recurrent thrombosis when taking rivaroxaban instead of a vitamin K antagonist, suggests a recent trial conducted in Spain.

Stroke was also more common among those taking rivaroxaban, while major bleeding was slightly less common, reported lead author Josep Ordi-Ros, MD, PhD, of Vall d’Hebrón University Hospital Research Institute in Barcelona, and colleagues in Annals of Internal Medicine.

“Two randomized, controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation but showed an increased thrombotic risk in those with triple-positive antiphospholipid antibodies,” the investigators wrote. However, they also noted that these findings required a cautious interpretation because of study limitations, such as premature termination caused by an excess of study events and the use of a laboratory surrogate marker as a primary outcome.

To learn more, the investigators performed an open-label, phase 3 trial involving 190 patients with thrombotic APS. Patients were randomized in a 1:1 ratio to receive either rivaroxaban (20 mg per day, or 15 mg per day for patients with a creatinine clearance of 30-49 mL/min per 1.73 m²) or an adjusted dosage of vitamin K antagonists (target international normalized ratio of 2.0-3.0, or 3.1-4.0 for those with a history of recurrent thrombosis).

Patients underwent evaluations every month for the first 3 months and then every 3 months thereafter, each of which involved a variety of laboratory diagnostics such as checks for antinuclear antibodies and lupus anticoagulant, among others. Statistical analyses aimed to determine if rivaroxaban was noninferior to therapy with vitamin K antagonists based on parameters drawn from previous meta-analyses, as no studies had compared the two types of treatment when the present study was designed.

After 3 years of follow-up, almost twice as many patients in the rivaroxaban group had experienced recurrent thrombosis (11.6% vs. 6.3%), although this finding lacked statistical significance for both noninferiority of rivaroxaban (P = .29) and superiority of vitamin K antagonists (P = .20). Still, supporting a similar trend toward differences in efficacy, stroke was more common in the rivaroxaban group, in which nine events occurred, compared with none in the vitamin K antagonist group. In contrast, major bleeding was slightly less common with rivaroxaban than vitamin K antagonists (6.3% vs. 7.4%).

“In conclusion, rivaroxaban did not demonstrate noninferiority to dose-adjusted vitamin K antagonists for secondary thromboprophylaxis in patients with thrombotic APS,” the investigators wrote. “Instead, our results indicate a recurrent thrombotic rate that is nearly double, albeit without statistical significance.”

The study was funded by Bayer Hispania. One coauthor reported additional relationships with Pfizer, Lilly, Janssen, and others.

SOURCE: Ordi-Ros J et al. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291.

Patients with thrombotic antiphospholipid syndrome (APS) may have a greater risk of recurrent thrombosis when taking rivaroxaban instead of a vitamin K antagonist, suggests a recent trial conducted in Spain.

Stroke was also more common among those taking rivaroxaban, while major bleeding was slightly less common, reported lead author Josep Ordi-Ros, MD, PhD, of Vall d’Hebrón University Hospital Research Institute in Barcelona, and colleagues in Annals of Internal Medicine.

“Two randomized, controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation but showed an increased thrombotic risk in those with triple-positive antiphospholipid antibodies,” the investigators wrote. However, they also noted that these findings required a cautious interpretation because of study limitations, such as premature termination caused by an excess of study events and the use of a laboratory surrogate marker as a primary outcome.

To learn more, the investigators performed an open-label, phase 3 trial involving 190 patients with thrombotic APS. Patients were randomized in a 1:1 ratio to receive either rivaroxaban (20 mg per day, or 15 mg per day for patients with a creatinine clearance of 30-49 mL/min per 1.73 m²) or an adjusted dosage of vitamin K antagonists (target international normalized ratio of 2.0-3.0, or 3.1-4.0 for those with a history of recurrent thrombosis).

Patients underwent evaluations every month for the first 3 months and then every 3 months thereafter, each of which involved a variety of laboratory diagnostics such as checks for antinuclear antibodies and lupus anticoagulant, among others. Statistical analyses aimed to determine if rivaroxaban was noninferior to therapy with vitamin K antagonists based on parameters drawn from previous meta-analyses, as no studies had compared the two types of treatment when the present study was designed.

After 3 years of follow-up, almost twice as many patients in the rivaroxaban group had experienced recurrent thrombosis (11.6% vs. 6.3%), although this finding lacked statistical significance for both noninferiority of rivaroxaban (P = .29) and superiority of vitamin K antagonists (P = .20). Still, supporting a similar trend toward differences in efficacy, stroke was more common in the rivaroxaban group, in which nine events occurred, compared with none in the vitamin K antagonist group. In contrast, major bleeding was slightly less common with rivaroxaban than vitamin K antagonists (6.3% vs. 7.4%).

“In conclusion, rivaroxaban did not demonstrate noninferiority to dose-adjusted vitamin K antagonists for secondary thromboprophylaxis in patients with thrombotic APS,” the investigators wrote. “Instead, our results indicate a recurrent thrombotic rate that is nearly double, albeit without statistical significance.”

The study was funded by Bayer Hispania. One coauthor reported additional relationships with Pfizer, Lilly, Janssen, and others.

SOURCE: Ordi-Ros J et al. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291.

MADRID – In patients managed on mechanical ventilation in an intensive care unit following cardiac surgery, a fully automated system provides more reliable ventilatory support than highly experienced ICU nurses, suggest results of a randomized trial.

The study’s control group received usual care, which means that nurses adjusted mechanical ventilation manually in response to respiratory rate, tidal volume, positive end-respiratory pressure (PEEP), and other factors to maintain ventilation within parameters associated with safe respiration. The experimental group was managed with a fully automated closed-loop system to make these adjustments without any nurse intervention.

For those in the experimental group “the proportion of time in the optimal zone was increased and the proportion of time in the unsafe zone was decreased” relative to those randomized to conventional nursing care, Marcus J. Schultz, MD, reported at the annual congress of the European Respiratory Society.

Conducted at a hospital with an experienced ICU staff, the study had a control arm that was managed by “dedicated nurses who, I can tell you, are very eager to provide the best level of care possible,” said Dr. Schultz, professor of experimental intensive care, University of Amsterdam, the Netherlands..

The investigator-initiated POSITiVE trial randomized 220 cardiac surgery patients scheduled to receive postoperative mechanical ventilation in the ICU. Exclusions included those with class III or higher chronic obstructive pulmonary disease (COPD), a requirement for extracorporeal membrane oxygenation (ECMO), or a history of lung surgery.

The primary endpoint was the proportion of time spent in an optimal zone, an acceptable zone, or a dangerous zone of ventilation based on predefined values for tidal volume, maximum airway pressure, end-tidal CO₂, and oxygen saturation (SpO₂).

The greatest between-group difference was seen in the proportion of time spent in the optimal zone. This climbed from approximately 35% in the control arm to slightly more than 70% in the experimental arm, a significant difference. The proportion of time in the dangerous zone was reduced from approximately 6% in the control arm to 3% in the automated arm. On average nurse-managed patients spent nearly 60% of the time in the acceptable zone versus less than 30% of those in the automated experimental arm.

A heat map using green, yellow, and red to represent optimal, acceptable, and dangerous zones, respectively, for individual participants in the trial provided a more stark global impression. For the control group, the heat map was primarily yellow with scattered dashes of green and red. For the experimental group, the map was primarily green with dashes of yellow and a much smaller number of red dashes relative to the control group.

In addition, the time to spontaneous breathing was 38% shorter for those randomized to automated ventilation than to conventional care, a significant difference.

There are now many devices marketed for automated ventilation, according to Dr. Schultz. The device used in this study was the proprietary INTELLiVENT-ASV system, marketed by Hamilton Medical, which was selected based on prior satisfactory experience. Although not unique, this system has sophisticated software to adjust ventilation to reach targets set by the clinician on the basis of information it is receiving from physiologic sensors for such variables as respiratory rate, tidal volume, and inspiratory pressure.

“It is frequently adjusting the PEEP levels to reach the lowest driving pressure,” said Dr. Schultz. Among its many other features, it also “gives spontaneous breathing trials automatically.”

Uncomplicated patients were selected purposefully to test this system, but Dr. Schultz said that a second trial, called POSITiVE 2, is now being planned that will enroll more complex patients. Keeping complex patients within the optimal zone as defined by tidal volume and other critical variables has the potential to reduce the lung damage that is known to occur when these are not optimized.

“Applying safe ventilatory support in clinical practice remains a serious challenge and is extremely time consuming,” Dr. Schultz said. He reported that fully automated ventilation appears to be reliable, and “it takes out the human factor” in regard to diligence in monitoring and potential for error.

Overall, these results support the potential for a fully automated system to improve optimal ventilatory support, reduce risk of lung injury, and reduce staffing required for monitoring of mechanical ventilation, according to Dr. Schultz.

Relative costs were not evaluated in this analysis, but might be another factor relevant to the value of fully automated ventilation in ICU patients.
 

MADRID – In patients managed on mechanical ventilation in an intensive care unit following cardiac surgery, a fully automated system provides more reliable ventilatory support than highly experienced ICU nurses, suggest results of a randomized trial.

The study’s control group received usual care, which means that nurses adjusted mechanical ventilation manually in response to respiratory rate, tidal volume, positive end-respiratory pressure (PEEP), and other factors to maintain ventilation within parameters associated with safe respiration. The experimental group was managed with a fully automated closed-loop system to make these adjustments without any nurse intervention.

For those in the experimental group “the proportion of time in the optimal zone was increased and the proportion of time in the unsafe zone was decreased” relative to those randomized to conventional nursing care, Marcus J. Schultz, MD, reported at the annual congress of the European Respiratory Society.

Conducted at a hospital with an experienced ICU staff, the study had a control arm that was managed by “dedicated nurses who, I can tell you, are very eager to provide the best level of care possible,” said Dr. Schultz, professor of experimental intensive care, University of Amsterdam, the Netherlands..

The investigator-initiated POSITiVE trial randomized 220 cardiac surgery patients scheduled to receive postoperative mechanical ventilation in the ICU. Exclusions included those with class III or higher chronic obstructive pulmonary disease (COPD), a requirement for extracorporeal membrane oxygenation (ECMO), or a history of lung surgery.

The primary endpoint was the proportion of time spent in an optimal zone, an acceptable zone, or a dangerous zone of ventilation based on predefined values for tidal volume, maximum airway pressure, end-tidal CO₂, and oxygen saturation (SpO₂).

The greatest between-group difference was seen in the proportion of time spent in the optimal zone. This climbed from approximately 35% in the control arm to slightly more than 70% in the experimental arm, a significant difference. The proportion of time in the dangerous zone was reduced from approximately 6% in the control arm to 3% in the automated arm. On average nurse-managed patients spent nearly 60% of the time in the acceptable zone versus less than 30% of those in the automated experimental arm.

A heat map using green, yellow, and red to represent optimal, acceptable, and dangerous zones, respectively, for individual participants in the trial provided a more stark global impression. For the control group, the heat map was primarily yellow with scattered dashes of green and red. For the experimental group, the map was primarily green with dashes of yellow and a much smaller number of red dashes relative to the control group.

In addition, the time to spontaneous breathing was 38% shorter for those randomized to automated ventilation than to conventional care, a significant difference.

There are now many devices marketed for automated ventilation, according to Dr. Schultz. The device used in this study was the proprietary INTELLiVENT-ASV system, marketed by Hamilton Medical, which was selected based on prior satisfactory experience. Although not unique, this system has sophisticated software to adjust ventilation to reach targets set by the clinician on the basis of information it is receiving from physiologic sensors for such variables as respiratory rate, tidal volume, and inspiratory pressure.

“It is frequently adjusting the PEEP levels to reach the lowest driving pressure,” said Dr. Schultz. Among its many other features, it also “gives spontaneous breathing trials automatically.”

Uncomplicated patients were selected purposefully to test this system, but Dr. Schultz said that a second trial, called POSITiVE 2, is now being planned that will enroll more complex patients. Keeping complex patients within the optimal zone as defined by tidal volume and other critical variables has the potential to reduce the lung damage that is known to occur when these are not optimized.

“Applying safe ventilatory support in clinical practice remains a serious challenge and is extremely time consuming,” Dr. Schultz said. He reported that fully automated ventilation appears to be reliable, and “it takes out the human factor” in regard to diligence in monitoring and potential for error.

Overall, these results support the potential for a fully automated system to improve optimal ventilatory support, reduce risk of lung injury, and reduce staffing required for monitoring of mechanical ventilation, according to Dr. Schultz.

Relative costs were not evaluated in this analysis, but might be another factor relevant to the value of fully automated ventilation in ICU patients.
 

MADRID – In patients managed on mechanical ventilation in an intensive care unit following cardiac surgery, a fully automated system provides more reliable ventilatory support than highly experienced ICU nurses, suggest results of a randomized trial.

The study’s control group received usual care, which means that nurses adjusted mechanical ventilation manually in response to respiratory rate, tidal volume, positive end-respiratory pressure (PEEP), and other factors to maintain ventilation within parameters associated with safe respiration. The experimental group was managed with a fully automated closed-loop system to make these adjustments without any nurse intervention.

For those in the experimental group “the proportion of time in the optimal zone was increased and the proportion of time in the unsafe zone was decreased” relative to those randomized to conventional nursing care, Marcus J. Schultz, MD, reported at the annual congress of the European Respiratory Society.

Conducted at a hospital with an experienced ICU staff, the study had a control arm that was managed by “dedicated nurses who, I can tell you, are very eager to provide the best level of care possible,” said Dr. Schultz, professor of experimental intensive care, University of Amsterdam, the Netherlands..

The investigator-initiated POSITiVE trial randomized 220 cardiac surgery patients scheduled to receive postoperative mechanical ventilation in the ICU. Exclusions included those with class III or higher chronic obstructive pulmonary disease (COPD), a requirement for extracorporeal membrane oxygenation (ECMO), or a history of lung surgery.

The primary endpoint was the proportion of time spent in an optimal zone, an acceptable zone, or a dangerous zone of ventilation based on predefined values for tidal volume, maximum airway pressure, end-tidal CO₂, and oxygen saturation (SpO₂).

The greatest between-group difference was seen in the proportion of time spent in the optimal zone. This climbed from approximately 35% in the control arm to slightly more than 70% in the experimental arm, a significant difference. The proportion of time in the dangerous zone was reduced from approximately 6% in the control arm to 3% in the automated arm. On average nurse-managed patients spent nearly 60% of the time in the acceptable zone versus less than 30% of those in the automated experimental arm.

A heat map using green, yellow, and red to represent optimal, acceptable, and dangerous zones, respectively, for individual participants in the trial provided a more stark global impression. For the control group, the heat map was primarily yellow with scattered dashes of green and red. For the experimental group, the map was primarily green with dashes of yellow and a much smaller number of red dashes relative to the control group.

In addition, the time to spontaneous breathing was 38% shorter for those randomized to automated ventilation than to conventional care, a significant difference.

There are now many devices marketed for automated ventilation, according to Dr. Schultz. The device used in this study was the proprietary INTELLiVENT-ASV system, marketed by Hamilton Medical, which was selected based on prior satisfactory experience. Although not unique, this system has sophisticated software to adjust ventilation to reach targets set by the clinician on the basis of information it is receiving from physiologic sensors for such variables as respiratory rate, tidal volume, and inspiratory pressure.

“It is frequently adjusting the PEEP levels to reach the lowest driving pressure,” said Dr. Schultz. Among its many other features, it also “gives spontaneous breathing trials automatically.”

Uncomplicated patients were selected purposefully to test this system, but Dr. Schultz said that a second trial, called POSITiVE 2, is now being planned that will enroll more complex patients. Keeping complex patients within the optimal zone as defined by tidal volume and other critical variables has the potential to reduce the lung damage that is known to occur when these are not optimized.

“Applying safe ventilatory support in clinical practice remains a serious challenge and is extremely time consuming,” Dr. Schultz said. He reported that fully automated ventilation appears to be reliable, and “it takes out the human factor” in regard to diligence in monitoring and potential for error.

Overall, these results support the potential for a fully automated system to improve optimal ventilatory support, reduce risk of lung injury, and reduce staffing required for monitoring of mechanical ventilation, according to Dr. Schultz.

Relative costs were not evaluated in this analysis, but might be another factor relevant to the value of fully automated ventilation in ICU patients.
 

Statin use for a minimum of 3 months was significantly associated with an increased risk of skin and soft tissue infections (SSTIs), according to a sequence symmetry analysis of prescription claims over a 10-year period reported in the British Journal of Clinical Pharmacology.

In the study, statin use for as little as 91 days was linked with elevated risks of SSTIs and diabetes. However, the increased risk of infection was seen in individuals who did and did not develop diabetes, wrote Humphrey Ko, of the school of pharmacy and biomedical sciences, Curtin University, Perth, Australia, and colleagues.

The current literature on the impact of statins on SSTIs is conflicted, they noted. Previous research shows that statins “may reduce the risk of community-acquired [Staphylococcus aureus] bacteremia and exert antibacterial effects against S. aureus,” and therefore may have potential for reducing SSTI risk “or evolve into promising novel treatments for SSTIs,” the researchers said; they noted, however, that other data show that statins may induce new-onset diabetes.

They examined prescription claims (for statins, antidiabetic medications, and antistaphylococcal antibiotics) from 2001 to 2011 from the Australian Department of Veterans’ Affairs that included more than 228,000 veterans, war widows, and widowers. Prescriptions for antistaphylococcal antibiotics were used as a marker of SSTIs.

Overall, statins were significantly associated with an increased risk of SSTIs at 91 days (adjusted sequence ratio, 1.40). The risk of SSTIs from statin use was similar at 182 (ASR, 1.41) and 365 days (ASR, 1.40). In this case, the ASRs represent the incidence rate ratios of prescribing antibiotics in statin-exposed versus statin-nonexposed person-time.

Statins were associated with a significantly increased risk of new onset diabetes, but the SSTI risk was not significantly different between statin users with and without diabetes. Statin users who did not have diabetes had significant SSTI risks at 91, 182, and 365 days (ASR, 1.39, 1.41, and 1.37, respectively) and statin users with diabetes had similarly significant risks of SSTIs (ASR,1.43, 1.42, and 1.49, respectively).

In addition, socioeconomic status appeared to have no significant effect on the relationship between statin use, SSTIs, and diabetes, the researchers noted.

The findings were limited by several factors including the inability to account for patient compliance in taking the medications, a lack of dosage data to determine the impact of dosage on outcomes, and potential confounding by the presence of diabetes, they said. However, the results suggest that “it would seem prudent for clinicians to monitor blood glucose levels of statin users who are predisposed to diabetes, and be mindful of possible increased SSTI risks in such patients,” they concluded. Statins, they added, “may increase SSTI risk via direct or indirect mechanisms.”

More clinical trials are needed to confirm the mechanisms, and “to ascertain the effect of statins on gut dysbiosis, impaired bile acid metabolism, vitamin D levels, and cholesterol inhibition on skin function,” they wrote.

The study was supported in part by the Australian Government Research Training Program Scholarship, the Curtin Health Innovation Research Institute Biosciences Research Precinct Core Facility, and the School of Pharmacy and Biomedical Sciences (Curtin University). The researchers had no financial conflicts to disclose.

SOURCE: Ko H et al. Br J Clin Pharmacol. 2019 Oct 9. doi: 10.1111/bcp.14077.

Statin use for a minimum of 3 months was significantly associated with an increased risk of skin and soft tissue infections (SSTIs), according to a sequence symmetry analysis of prescription claims over a 10-year period reported in the British Journal of Clinical Pharmacology.

In the study, statin use for as little as 91 days was linked with elevated risks of SSTIs and diabetes. However, the increased risk of infection was seen in individuals who did and did not develop diabetes, wrote Humphrey Ko, of the school of pharmacy and biomedical sciences, Curtin University, Perth, Australia, and colleagues.

The current literature on the impact of statins on SSTIs is conflicted, they noted. Previous research shows that statins “may reduce the risk of community-acquired [Staphylococcus aureus] bacteremia and exert antibacterial effects against S. aureus,” and therefore may have potential for reducing SSTI risk “or evolve into promising novel treatments for SSTIs,” the researchers said; they noted, however, that other data show that statins may induce new-onset diabetes.

They examined prescription claims (for statins, antidiabetic medications, and antistaphylococcal antibiotics) from 2001 to 2011 from the Australian Department of Veterans’ Affairs that included more than 228,000 veterans, war widows, and widowers. Prescriptions for antistaphylococcal antibiotics were used as a marker of SSTIs.

Overall, statins were significantly associated with an increased risk of SSTIs at 91 days (adjusted sequence ratio, 1.40). The risk of SSTIs from statin use was similar at 182 (ASR, 1.41) and 365 days (ASR, 1.40). In this case, the ASRs represent the incidence rate ratios of prescribing antibiotics in statin-exposed versus statin-nonexposed person-time.

Statins were associated with a significantly increased risk of new onset diabetes, but the SSTI risk was not significantly different between statin users with and without diabetes. Statin users who did not have diabetes had significant SSTI risks at 91, 182, and 365 days (ASR, 1.39, 1.41, and 1.37, respectively) and statin users with diabetes had similarly significant risks of SSTIs (ASR,1.43, 1.42, and 1.49, respectively).

In addition, socioeconomic status appeared to have no significant effect on the relationship between statin use, SSTIs, and diabetes, the researchers noted.

The findings were limited by several factors including the inability to account for patient compliance in taking the medications, a lack of dosage data to determine the impact of dosage on outcomes, and potential confounding by the presence of diabetes, they said. However, the results suggest that “it would seem prudent for clinicians to monitor blood glucose levels of statin users who are predisposed to diabetes, and be mindful of possible increased SSTI risks in such patients,” they concluded. Statins, they added, “may increase SSTI risk via direct or indirect mechanisms.”

More clinical trials are needed to confirm the mechanisms, and “to ascertain the effect of statins on gut dysbiosis, impaired bile acid metabolism, vitamin D levels, and cholesterol inhibition on skin function,” they wrote.

The study was supported in part by the Australian Government Research Training Program Scholarship, the Curtin Health Innovation Research Institute Biosciences Research Precinct Core Facility, and the School of Pharmacy and Biomedical Sciences (Curtin University). The researchers had no financial conflicts to disclose.

SOURCE: Ko H et al. Br J Clin Pharmacol. 2019 Oct 9. doi: 10.1111/bcp.14077.

Statin use for a minimum of 3 months was significantly associated with an increased risk of skin and soft tissue infections (SSTIs), according to a sequence symmetry analysis of prescription claims over a 10-year period reported in the British Journal of Clinical Pharmacology.

In the study, statin use for as little as 91 days was linked with elevated risks of SSTIs and diabetes. However, the increased risk of infection was seen in individuals who did and did not develop diabetes, wrote Humphrey Ko, of the school of pharmacy and biomedical sciences, Curtin University, Perth, Australia, and colleagues.

The current literature on the impact of statins on SSTIs is conflicted, they noted. Previous research shows that statins “may reduce the risk of community-acquired [Staphylococcus aureus] bacteremia and exert antibacterial effects against S. aureus,” and therefore may have potential for reducing SSTI risk “or evolve into promising novel treatments for SSTIs,” the researchers said; they noted, however, that other data show that statins may induce new-onset diabetes.

They examined prescription claims (for statins, antidiabetic medications, and antistaphylococcal antibiotics) from 2001 to 2011 from the Australian Department of Veterans’ Affairs that included more than 228,000 veterans, war widows, and widowers. Prescriptions for antistaphylococcal antibiotics were used as a marker of SSTIs.

Overall, statins were significantly associated with an increased risk of SSTIs at 91 days (adjusted sequence ratio, 1.40). The risk of SSTIs from statin use was similar at 182 (ASR, 1.41) and 365 days (ASR, 1.40). In this case, the ASRs represent the incidence rate ratios of prescribing antibiotics in statin-exposed versus statin-nonexposed person-time.

Statins were associated with a significantly increased risk of new onset diabetes, but the SSTI risk was not significantly different between statin users with and without diabetes. Statin users who did not have diabetes had significant SSTI risks at 91, 182, and 365 days (ASR, 1.39, 1.41, and 1.37, respectively) and statin users with diabetes had similarly significant risks of SSTIs (ASR,1.43, 1.42, and 1.49, respectively).

In addition, socioeconomic status appeared to have no significant effect on the relationship between statin use, SSTIs, and diabetes, the researchers noted.

The findings were limited by several factors including the inability to account for patient compliance in taking the medications, a lack of dosage data to determine the impact of dosage on outcomes, and potential confounding by the presence of diabetes, they said. However, the results suggest that “it would seem prudent for clinicians to monitor blood glucose levels of statin users who are predisposed to diabetes, and be mindful of possible increased SSTI risks in such patients,” they concluded. Statins, they added, “may increase SSTI risk via direct or indirect mechanisms.”

More clinical trials are needed to confirm the mechanisms, and “to ascertain the effect of statins on gut dysbiosis, impaired bile acid metabolism, vitamin D levels, and cholesterol inhibition on skin function,” they wrote.

The study was supported in part by the Australian Government Research Training Program Scholarship, the Curtin Health Innovation Research Institute Biosciences Research Precinct Core Facility, and the School of Pharmacy and Biomedical Sciences (Curtin University). The researchers had no financial conflicts to disclose.

SOURCE: Ko H et al. Br J Clin Pharmacol. 2019 Oct 9. doi: 10.1111/bcp.14077.