Thrombosis

In patients with acute pulmonary embolism, using cutoff values other than 110 beats per minute might improve the prognostic value of heart rate at admission, a recent observational study suggests.

Courtesy of Mercy Medical Center

For identifying low-risk patients, a cutoff of 80 bpm increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from about 94% to nearly 99% among nonhypotensive patients with acute symptomatic pulmonary embolism (PE), according to results of the large, registry-based study.

Similarly, using a 140-bpm cutoff increased the specificity of the Bova score for identifying intermediate-high–risk patients from about 93% to 98% in the study, which was recently published in the journal CHEST.

“Although standard dichotomization of HR [i.e., HR less than 110 vs. greater than 110 bpm] may be useful for guideline recommendations, our results will allow for more accuracy regarding clinical decision-making,” wrote lead author Ana Jaureguízar, MD, of the University of Alcalá in Madrid, on behalf of the RIETE (Registro Informatizado de la Enfermedad TromboEmbólica) investigators.
 

Intuitive findings inform future research

These observational findings are intuitive and do at least have the potential to inform the design of future randomized clinical trials, according to Albert J. Polito, MD, chief of the division of pulmonary medicine and medical director for the lung center at Mercy Medical Center in Baltimore.

“In medicine, there is a spectrum of risk,” Dr. Polito said in an interview. “While we love our cutoffs, which in this case has traditionally always been that 110 beats per minute for heart rate, it makes sense that there would be some range of risks of bad outcomes.”

Building on the observations of the present study, subsequent prospective randomized studies could potentially aim to determine, for example, when thrombolytic therapy should be considered in nonhypotensive patients with acute PE and higher heart rates.

“It would not be easy to design, but it’s a straightforward question to ask whether patients with the highest heart rates are the ones who potentially might benefit the most from thrombolytic therapy,” Dr. Polito said.
 

Value of alternative HR cutoffs

Heart rate is a simple and easily available vital sign that is clearly linked to prognosis in patients with pulmonary embolism, authors of the RIETE registry study say in their report. Accordingly, a heart rate threshold of 110 bpm has made its way into scoring systems that seek to identify low-risk patients, such as the sPESI, and those focused on identifying higher-risk patients, such as the Bova score.

However, it has not been clear whether alternative HR cutoffs would improve upon the 110-bpm threshold, they added. At the low-risk end, more accurate scoring systems could optimize the selection of patients for home treatment, while at the intermediate-high–risk end, they could better select patients for close monitoring or advanced PE treatments.
 

Better granularity on heart rate risks?

To better define the prognostic value of different heart rate thresholds, investigators analyzed data from RIETE, a large, ongoing, multinational prospective registry including patients with objectively confirmed acute venous thromboembolism.

For 44,331 consecutive nonhypotensive symptomatic PEs, the overall rate of 30-day all-cause mortality was 5.1%, and the 30-day PE-related mortality was 1.9%, the authors report.

Significantly poorer outcomes were seen in patients with higher heart rates as compared to patients in the 80-99 bpm range, they also found. As compared to that reference range, odds ratios for 30-day all-cause death ranged from 1.5 for heart rates of 100-109, up to 2.4 for those with heart rates of 140 bpm or greater.

Likewise, patients with higher heart rates had a 1.7- to 2.4-fold greater risk of 30-day PE-related death as compared to the 80- to 99-bpm reference range, while patients with lower heart rates had lesser risk, the data published in CHEST show.
 

Toward refinement of prognostic scoring

Next, investigators sought to refine the prognostic scoring systems for low-risk PE (sPESI) and intermediate-high–risk PE (Bova).

For sPESI, they found that dropping the cutoff value from 110 to 100 bpm increased the sensitivity of the score from 93.4% to 95.3%. Going down even further to 80 bpm increased sensitivity to 98.8%, according to the report.

By going down from 110 to 80 bpm, the proportion of patients defined as low-risk dropped from 35% to 12%, according to the investigators.

For the Bova score, increasing the cutoff value from 110 to 120 bpm likewise increased specificity from 93.2% to 95%, while going up even further to 140 bpm increased specificity to 98.0%, the report shows.

In sensitivity analyses, the findings were not impacted by excluding younger patients, those who received reperfusion therapies, or those with atrial fibrillation, according to the study findings.
 

Potential implications for clinical practice

Taken together, these findings could serve as a resource to inform discussions regarding PE management that include whether home therapy or use of thrombolytic therapy is appropriate, investigators said in their report.

“For instance, among low-risk sPESI patients, those with borderline tachycardia [i.e., a heart rate between 100-109 bpm] might benefit from initial hospital observation for trending,” they wrote.

Dr. Jaureguízar reported no disclosures. One coinvestigator reported funding support from the Institute of Health Carlos III (ISCIII) and the European Development Regional Fund (ERDF). One coinvestigator reported consulting in litigation involving two models of inferior vena cava filters.

Dr. Polito reported no disclosures.

In patients with acute pulmonary embolism, using cutoff values other than 110 beats per minute might improve the prognostic value of heart rate at admission, a recent observational study suggests.

Courtesy of Mercy Medical Center

For identifying low-risk patients, a cutoff of 80 bpm increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from about 94% to nearly 99% among nonhypotensive patients with acute symptomatic pulmonary embolism (PE), according to results of the large, registry-based study.

Similarly, using a 140-bpm cutoff increased the specificity of the Bova score for identifying intermediate-high–risk patients from about 93% to 98% in the study, which was recently published in the journal CHEST.

“Although standard dichotomization of HR [i.e., HR less than 110 vs. greater than 110 bpm] may be useful for guideline recommendations, our results will allow for more accuracy regarding clinical decision-making,” wrote lead author Ana Jaureguízar, MD, of the University of Alcalá in Madrid, on behalf of the RIETE (Registro Informatizado de la Enfermedad TromboEmbólica) investigators.
 

Intuitive findings inform future research

These observational findings are intuitive and do at least have the potential to inform the design of future randomized clinical trials, according to Albert J. Polito, MD, chief of the division of pulmonary medicine and medical director for the lung center at Mercy Medical Center in Baltimore.

“In medicine, there is a spectrum of risk,” Dr. Polito said in an interview. “While we love our cutoffs, which in this case has traditionally always been that 110 beats per minute for heart rate, it makes sense that there would be some range of risks of bad outcomes.”

Building on the observations of the present study, subsequent prospective randomized studies could potentially aim to determine, for example, when thrombolytic therapy should be considered in nonhypotensive patients with acute PE and higher heart rates.

“It would not be easy to design, but it’s a straightforward question to ask whether patients with the highest heart rates are the ones who potentially might benefit the most from thrombolytic therapy,” Dr. Polito said.
 

Value of alternative HR cutoffs

Heart rate is a simple and easily available vital sign that is clearly linked to prognosis in patients with pulmonary embolism, authors of the RIETE registry study say in their report. Accordingly, a heart rate threshold of 110 bpm has made its way into scoring systems that seek to identify low-risk patients, such as the sPESI, and those focused on identifying higher-risk patients, such as the Bova score.

However, it has not been clear whether alternative HR cutoffs would improve upon the 110-bpm threshold, they added. At the low-risk end, more accurate scoring systems could optimize the selection of patients for home treatment, while at the intermediate-high–risk end, they could better select patients for close monitoring or advanced PE treatments.
 

Better granularity on heart rate risks?

To better define the prognostic value of different heart rate thresholds, investigators analyzed data from RIETE, a large, ongoing, multinational prospective registry including patients with objectively confirmed acute venous thromboembolism.

For 44,331 consecutive nonhypotensive symptomatic PEs, the overall rate of 30-day all-cause mortality was 5.1%, and the 30-day PE-related mortality was 1.9%, the authors report.

Significantly poorer outcomes were seen in patients with higher heart rates as compared to patients in the 80-99 bpm range, they also found. As compared to that reference range, odds ratios for 30-day all-cause death ranged from 1.5 for heart rates of 100-109, up to 2.4 for those with heart rates of 140 bpm or greater.

Likewise, patients with higher heart rates had a 1.7- to 2.4-fold greater risk of 30-day PE-related death as compared to the 80- to 99-bpm reference range, while patients with lower heart rates had lesser risk, the data published in CHEST show.
 

Toward refinement of prognostic scoring

Next, investigators sought to refine the prognostic scoring systems for low-risk PE (sPESI) and intermediate-high–risk PE (Bova).

For sPESI, they found that dropping the cutoff value from 110 to 100 bpm increased the sensitivity of the score from 93.4% to 95.3%. Going down even further to 80 bpm increased sensitivity to 98.8%, according to the report.

By going down from 110 to 80 bpm, the proportion of patients defined as low-risk dropped from 35% to 12%, according to the investigators.

For the Bova score, increasing the cutoff value from 110 to 120 bpm likewise increased specificity from 93.2% to 95%, while going up even further to 140 bpm increased specificity to 98.0%, the report shows.

In sensitivity analyses, the findings were not impacted by excluding younger patients, those who received reperfusion therapies, or those with atrial fibrillation, according to the study findings.
 

Potential implications for clinical practice

Taken together, these findings could serve as a resource to inform discussions regarding PE management that include whether home therapy or use of thrombolytic therapy is appropriate, investigators said in their report.

“For instance, among low-risk sPESI patients, those with borderline tachycardia [i.e., a heart rate between 100-109 bpm] might benefit from initial hospital observation for trending,” they wrote.

Dr. Jaureguízar reported no disclosures. One coinvestigator reported funding support from the Institute of Health Carlos III (ISCIII) and the European Development Regional Fund (ERDF). One coinvestigator reported consulting in litigation involving two models of inferior vena cava filters.

Dr. Polito reported no disclosures.

In patients with acute pulmonary embolism, using cutoff values other than 110 beats per minute might improve the prognostic value of heart rate at admission, a recent observational study suggests.

Courtesy of Mercy Medical Center

For identifying low-risk patients, a cutoff of 80 bpm increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from about 94% to nearly 99% among nonhypotensive patients with acute symptomatic pulmonary embolism (PE), according to results of the large, registry-based study.

Similarly, using a 140-bpm cutoff increased the specificity of the Bova score for identifying intermediate-high–risk patients from about 93% to 98% in the study, which was recently published in the journal CHEST.

“Although standard dichotomization of HR [i.e., HR less than 110 vs. greater than 110 bpm] may be useful for guideline recommendations, our results will allow for more accuracy regarding clinical decision-making,” wrote lead author Ana Jaureguízar, MD, of the University of Alcalá in Madrid, on behalf of the RIETE (Registro Informatizado de la Enfermedad TromboEmbólica) investigators.
 

Intuitive findings inform future research

These observational findings are intuitive and do at least have the potential to inform the design of future randomized clinical trials, according to Albert J. Polito, MD, chief of the division of pulmonary medicine and medical director for the lung center at Mercy Medical Center in Baltimore.

“In medicine, there is a spectrum of risk,” Dr. Polito said in an interview. “While we love our cutoffs, which in this case has traditionally always been that 110 beats per minute for heart rate, it makes sense that there would be some range of risks of bad outcomes.”

Building on the observations of the present study, subsequent prospective randomized studies could potentially aim to determine, for example, when thrombolytic therapy should be considered in nonhypotensive patients with acute PE and higher heart rates.

“It would not be easy to design, but it’s a straightforward question to ask whether patients with the highest heart rates are the ones who potentially might benefit the most from thrombolytic therapy,” Dr. Polito said.
 

Value of alternative HR cutoffs

Heart rate is a simple and easily available vital sign that is clearly linked to prognosis in patients with pulmonary embolism, authors of the RIETE registry study say in their report. Accordingly, a heart rate threshold of 110 bpm has made its way into scoring systems that seek to identify low-risk patients, such as the sPESI, and those focused on identifying higher-risk patients, such as the Bova score.

However, it has not been clear whether alternative HR cutoffs would improve upon the 110-bpm threshold, they added. At the low-risk end, more accurate scoring systems could optimize the selection of patients for home treatment, while at the intermediate-high–risk end, they could better select patients for close monitoring or advanced PE treatments.
 

Better granularity on heart rate risks?

To better define the prognostic value of different heart rate thresholds, investigators analyzed data from RIETE, a large, ongoing, multinational prospective registry including patients with objectively confirmed acute venous thromboembolism.

For 44,331 consecutive nonhypotensive symptomatic PEs, the overall rate of 30-day all-cause mortality was 5.1%, and the 30-day PE-related mortality was 1.9%, the authors report.

Significantly poorer outcomes were seen in patients with higher heart rates as compared to patients in the 80-99 bpm range, they also found. As compared to that reference range, odds ratios for 30-day all-cause death ranged from 1.5 for heart rates of 100-109, up to 2.4 for those with heart rates of 140 bpm or greater.

Likewise, patients with higher heart rates had a 1.7- to 2.4-fold greater risk of 30-day PE-related death as compared to the 80- to 99-bpm reference range, while patients with lower heart rates had lesser risk, the data published in CHEST show.
 

Toward refinement of prognostic scoring

Next, investigators sought to refine the prognostic scoring systems for low-risk PE (sPESI) and intermediate-high–risk PE (Bova).

For sPESI, they found that dropping the cutoff value from 110 to 100 bpm increased the sensitivity of the score from 93.4% to 95.3%. Going down even further to 80 bpm increased sensitivity to 98.8%, according to the report.

By going down from 110 to 80 bpm, the proportion of patients defined as low-risk dropped from 35% to 12%, according to the investigators.

For the Bova score, increasing the cutoff value from 110 to 120 bpm likewise increased specificity from 93.2% to 95%, while going up even further to 140 bpm increased specificity to 98.0%, the report shows.

In sensitivity analyses, the findings were not impacted by excluding younger patients, those who received reperfusion therapies, or those with atrial fibrillation, according to the study findings.
 

Potential implications for clinical practice

Taken together, these findings could serve as a resource to inform discussions regarding PE management that include whether home therapy or use of thrombolytic therapy is appropriate, investigators said in their report.

“For instance, among low-risk sPESI patients, those with borderline tachycardia [i.e., a heart rate between 100-109 bpm] might benefit from initial hospital observation for trending,” they wrote.

Dr. Jaureguízar reported no disclosures. One coinvestigator reported funding support from the Institute of Health Carlos III (ISCIII) and the European Development Regional Fund (ERDF). One coinvestigator reported consulting in litigation involving two models of inferior vena cava filters.

Dr. Polito reported no disclosures.

Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.

In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.

“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.

The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said Dr. van der Steen.

He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
 

Trial stopped for safety

Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.

Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.

The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.

Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.

ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5,000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5,000 IU followed by 1,250 IU/h for 6 hours.

The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.

An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.

After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.

After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
 

Increased risk for sICH

In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.

The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.

The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR, 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs. 7.2%; aOR, 1.95).

Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.

The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs. 7.4%; aOR, 2.00).

Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.

The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).

There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
 

‘A unique trial’

“MR CLEAN-MED is a unique trial because it investigated a widely used treatment but until now without any proof of effectiveness,” said Dr. van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.

“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, said in an interview. “However, to make more definite statements, we will have to do more in-depth analyses.”

It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said Dr. van der Steen.

To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.

Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for this news organization.

At least three strategies are available: The use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.

“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Dr. Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”

The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Dr. van der Steen and Dr. Fisher have disclosed no relevant financial relationships.

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

Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.

In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.

“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.

The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said Dr. van der Steen.

He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
 

Trial stopped for safety

Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.

Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.

The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.

Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.

ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5,000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5,000 IU followed by 1,250 IU/h for 6 hours.

The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.

An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.

After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.

After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
 

Increased risk for sICH

In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.

The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.

The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR, 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs. 7.2%; aOR, 1.95).

Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.

The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs. 7.4%; aOR, 2.00).

Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.

The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).

There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
 

‘A unique trial’

“MR CLEAN-MED is a unique trial because it investigated a widely used treatment but until now without any proof of effectiveness,” said Dr. van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.

“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, said in an interview. “However, to make more definite statements, we will have to do more in-depth analyses.”

It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said Dr. van der Steen.

To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.

Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for this news organization.

At least three strategies are available: The use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.

“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Dr. Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”

The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Dr. van der Steen and Dr. Fisher have disclosed no relevant financial relationships.

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

Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.

In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.

“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.

The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said Dr. van der Steen.

He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
 

Trial stopped for safety

Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.

Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.

The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.

Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.

ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5,000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5,000 IU followed by 1,250 IU/h for 6 hours.

The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.

An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.

After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.

After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
 

Increased risk for sICH

In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.

The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.

The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR, 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs. 7.2%; aOR, 1.95).

Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.

The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs. 7.4%; aOR, 2.00).

Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.

The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).

There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
 

‘A unique trial’

“MR CLEAN-MED is a unique trial because it investigated a widely used treatment but until now without any proof of effectiveness,” said Dr. van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.

“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, said in an interview. “However, to make more definite statements, we will have to do more in-depth analyses.”

It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said Dr. van der Steen.

To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.

Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for this news organization.

At least three strategies are available: The use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.

“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Dr. Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”

The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Dr. van der Steen and Dr. Fisher have disclosed no relevant financial relationships.

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

A new study may help doctors assess the long-term risk for major bleeding if anticoagulation for unprovoked venous thromboembolisms (VTE) is continued beyond 3-6 months.

The meta-analysis of data from 27 studies with 17,202 patients was published in the Annals of Internal Medicine. According to two of the paper’s coauthors, Faizan Khan, MSc, and Marc A. Rodger, MD, it “provides best available estimates of long-term bleeding risk with different anticoagulants in patients with unprovoked VTE,” including subgroups at increased risk.

Patients at increased risk for major bleeding include those who are older; those using antiplatelet therapy; and patients with kidney disease, a history of bleeding, or anemia, noted the coauthors, who work for the Ottawa Hospital Research Institute.

The researchers focused on randomized controlled trials (RCTs) and prospective cohort studies that reported major bleeding among patients with a first unprovoked or weakly provoked VTE who received oral anticoagulation for at least 6 months beyond an initial anticoagulant treatment course of at least 3 months.

The investigators analyzed data from 14 RCTs and 13 cohort studies. In all, 9,982 patients received a vitamin K antagonist (VKA), and 7,220 received a direct oral anticoagulant (DOAC).

The incidence of major bleeding per 100 person-years was 1.7 events with VKAs, compared with 1.1 events with DOACs. The researchers estimated that the 5-year cumulative incidence of major bleeding with VKAs was 6.3%. The available data for DOACs were insufficient to estimate the incidence of major bleeding beyond 1 year.

“This information can help clinicians counsel patients and inform shared decision-making about extended therapy,” the researchers said.

Risks of serious bleeding ‘not trivial’

Margaret Fang, MD, with the University of California, San Francisco, agreed that the study can help clinicians and patients weigh the risks of extended anticoagulation for common types of VTE.

The study also “highlights that the risks of serious bleeding are not trivial” and points out gaps in the literature regarding the long-term use of DOACs for extended VTE therapy, Dr. Fang said.

Better ways to predict which patients will develop bleeding on anticoagulants are needed, Dr. Fang added. “It will also be important to establish which of the various therapies for preventing recurrent VTE – full dose versus lowered dose, or even aspirin – has the best balance of safety and efficacy,” she said.

‘Standardized approach’ for identifying high-risk patients lacking

Clinical practice guidelines recommend indefinite anticoagulation for an unprovoked VTE, except when patients are at high risk of bleeding, the authors noted. But clinicians lack a “standardized approach to identify patients at high risk of bleeding,” Mr. Khan and Dr. Rodger said. “Evidence from randomized trials on net long-term benefit of extended therapy is limited, and current guideline recommendations are largely based on expert consensus opinion. Major bleeding events are two to three times more likely to be fatal than recurrent VTE events, so extended therapy is not always associated with a net mortality benefit, particularly in patients at low risk of recurrent VTE or high risk of bleeding.”

The analysis indicates that there is “a clinically meaningful difference in long-term risk for anticoagulant-related major bleeding among patients with a first unprovoked VTE stratified according to presence or absence of the following risk factors: age older than 65 years, creatinine clearance less than 50 mL/min, history of bleeding, concomitant use of antiplatelet therapy, and hemoglobin level less than 100 g/L,” the authors said.

For example, the researchers found that the incidence of major bleeding was higher among those older than 65 years, compared with younger patients (incidence rate ratio, 1.84 with VKAs and 2.92 with DOACs), and among those with creatinine clearance less than 50 mL/min (IRR, 2.83 with VKAs and 3.71 with DOACs).

The case-fatality rate of major bleeding was 8.3% with VKAs and 9.7% with DOACs.

The study received funding from the Canadian Institutes of Health Research. Some of the coauthors are employees of or have financial ties to pharmaceutical companies. Mr. Khan, Dr. Rodger, and Dr. Fang had no relevant disclosures.

[email protected]

A new study may help doctors assess the long-term risk for major bleeding if anticoagulation for unprovoked venous thromboembolisms (VTE) is continued beyond 3-6 months.

The meta-analysis of data from 27 studies with 17,202 patients was published in the Annals of Internal Medicine. According to two of the paper’s coauthors, Faizan Khan, MSc, and Marc A. Rodger, MD, it “provides best available estimates of long-term bleeding risk with different anticoagulants in patients with unprovoked VTE,” including subgroups at increased risk.

Patients at increased risk for major bleeding include those who are older; those using antiplatelet therapy; and patients with kidney disease, a history of bleeding, or anemia, noted the coauthors, who work for the Ottawa Hospital Research Institute.

The researchers focused on randomized controlled trials (RCTs) and prospective cohort studies that reported major bleeding among patients with a first unprovoked or weakly provoked VTE who received oral anticoagulation for at least 6 months beyond an initial anticoagulant treatment course of at least 3 months.

The investigators analyzed data from 14 RCTs and 13 cohort studies. In all, 9,982 patients received a vitamin K antagonist (VKA), and 7,220 received a direct oral anticoagulant (DOAC).

The incidence of major bleeding per 100 person-years was 1.7 events with VKAs, compared with 1.1 events with DOACs. The researchers estimated that the 5-year cumulative incidence of major bleeding with VKAs was 6.3%. The available data for DOACs were insufficient to estimate the incidence of major bleeding beyond 1 year.

“This information can help clinicians counsel patients and inform shared decision-making about extended therapy,” the researchers said.

Risks of serious bleeding ‘not trivial’

Margaret Fang, MD, with the University of California, San Francisco, agreed that the study can help clinicians and patients weigh the risks of extended anticoagulation for common types of VTE.

The study also “highlights that the risks of serious bleeding are not trivial” and points out gaps in the literature regarding the long-term use of DOACs for extended VTE therapy, Dr. Fang said.

Better ways to predict which patients will develop bleeding on anticoagulants are needed, Dr. Fang added. “It will also be important to establish which of the various therapies for preventing recurrent VTE – full dose versus lowered dose, or even aspirin – has the best balance of safety and efficacy,” she said.

‘Standardized approach’ for identifying high-risk patients lacking

Clinical practice guidelines recommend indefinite anticoagulation for an unprovoked VTE, except when patients are at high risk of bleeding, the authors noted. But clinicians lack a “standardized approach to identify patients at high risk of bleeding,” Mr. Khan and Dr. Rodger said. “Evidence from randomized trials on net long-term benefit of extended therapy is limited, and current guideline recommendations are largely based on expert consensus opinion. Major bleeding events are two to three times more likely to be fatal than recurrent VTE events, so extended therapy is not always associated with a net mortality benefit, particularly in patients at low risk of recurrent VTE or high risk of bleeding.”

The analysis indicates that there is “a clinically meaningful difference in long-term risk for anticoagulant-related major bleeding among patients with a first unprovoked VTE stratified according to presence or absence of the following risk factors: age older than 65 years, creatinine clearance less than 50 mL/min, history of bleeding, concomitant use of antiplatelet therapy, and hemoglobin level less than 100 g/L,” the authors said.

For example, the researchers found that the incidence of major bleeding was higher among those older than 65 years, compared with younger patients (incidence rate ratio, 1.84 with VKAs and 2.92 with DOACs), and among those with creatinine clearance less than 50 mL/min (IRR, 2.83 with VKAs and 3.71 with DOACs).

The case-fatality rate of major bleeding was 8.3% with VKAs and 9.7% with DOACs.

The study received funding from the Canadian Institutes of Health Research. Some of the coauthors are employees of or have financial ties to pharmaceutical companies. Mr. Khan, Dr. Rodger, and Dr. Fang had no relevant disclosures.

[email protected]

A new study may help doctors assess the long-term risk for major bleeding if anticoagulation for unprovoked venous thromboembolisms (VTE) is continued beyond 3-6 months.

The meta-analysis of data from 27 studies with 17,202 patients was published in the Annals of Internal Medicine. According to two of the paper’s coauthors, Faizan Khan, MSc, and Marc A. Rodger, MD, it “provides best available estimates of long-term bleeding risk with different anticoagulants in patients with unprovoked VTE,” including subgroups at increased risk.

Patients at increased risk for major bleeding include those who are older; those using antiplatelet therapy; and patients with kidney disease, a history of bleeding, or anemia, noted the coauthors, who work for the Ottawa Hospital Research Institute.

The researchers focused on randomized controlled trials (RCTs) and prospective cohort studies that reported major bleeding among patients with a first unprovoked or weakly provoked VTE who received oral anticoagulation for at least 6 months beyond an initial anticoagulant treatment course of at least 3 months.

The investigators analyzed data from 14 RCTs and 13 cohort studies. In all, 9,982 patients received a vitamin K antagonist (VKA), and 7,220 received a direct oral anticoagulant (DOAC).

The incidence of major bleeding per 100 person-years was 1.7 events with VKAs, compared with 1.1 events with DOACs. The researchers estimated that the 5-year cumulative incidence of major bleeding with VKAs was 6.3%. The available data for DOACs were insufficient to estimate the incidence of major bleeding beyond 1 year.

“This information can help clinicians counsel patients and inform shared decision-making about extended therapy,” the researchers said.

Risks of serious bleeding ‘not trivial’

Margaret Fang, MD, with the University of California, San Francisco, agreed that the study can help clinicians and patients weigh the risks of extended anticoagulation for common types of VTE.

The study also “highlights that the risks of serious bleeding are not trivial” and points out gaps in the literature regarding the long-term use of DOACs for extended VTE therapy, Dr. Fang said.

Better ways to predict which patients will develop bleeding on anticoagulants are needed, Dr. Fang added. “It will also be important to establish which of the various therapies for preventing recurrent VTE – full dose versus lowered dose, or even aspirin – has the best balance of safety and efficacy,” she said.

‘Standardized approach’ for identifying high-risk patients lacking

Clinical practice guidelines recommend indefinite anticoagulation for an unprovoked VTE, except when patients are at high risk of bleeding, the authors noted. But clinicians lack a “standardized approach to identify patients at high risk of bleeding,” Mr. Khan and Dr. Rodger said. “Evidence from randomized trials on net long-term benefit of extended therapy is limited, and current guideline recommendations are largely based on expert consensus opinion. Major bleeding events are two to three times more likely to be fatal than recurrent VTE events, so extended therapy is not always associated with a net mortality benefit, particularly in patients at low risk of recurrent VTE or high risk of bleeding.”

The analysis indicates that there is “a clinically meaningful difference in long-term risk for anticoagulant-related major bleeding among patients with a first unprovoked VTE stratified according to presence or absence of the following risk factors: age older than 65 years, creatinine clearance less than 50 mL/min, history of bleeding, concomitant use of antiplatelet therapy, and hemoglobin level less than 100 g/L,” the authors said.

For example, the researchers found that the incidence of major bleeding was higher among those older than 65 years, compared with younger patients (incidence rate ratio, 1.84 with VKAs and 2.92 with DOACs), and among those with creatinine clearance less than 50 mL/min (IRR, 2.83 with VKAs and 3.71 with DOACs).

The case-fatality rate of major bleeding was 8.3% with VKAs and 9.7% with DOACs.

The study received funding from the Canadian Institutes of Health Research. Some of the coauthors are employees of or have financial ties to pharmaceutical companies. Mr. Khan, Dr. Rodger, and Dr. Fang had no relevant disclosures.

[email protected]

One month of dual antiplatelet therapy followed by 11 months of clopidogrel monotherapy failed to prove noninferiority to 12 unbroken months of DAPT for net clinical benefit in a multicenter Japanese trial that randomized more than 4,000 patients who underwent percutaneous coronary intervention (PCI) after a recent acute coronary syndrome episode.

© Astrid Gast/Thinkstock

The outcomes showed that while truncating DAPT duration could, as expected, cut major bleeding episodes roughly in half, it also led to a significant near doubling of myocardial infarction and showed a strong trend toward also increasing a composite tally of several types of ischemic events. These data were reported this week by Hirotoshi Watanabe, MD, PhD, at the virtual annual congress of the European Society of Cardiology. All study patients had undergone PCI with cobalt-chromium everolimus-eluting (CCEE) coronary stents (Xience).

These findings from the STOPDAPT-2 ACS trial highlighted the limits of minimizing DAPT after PCI in patients at high ischemic risk, such as after an acute coronary syndrome (ACS) event.

It also was a counterpoint to a somewhat similar study also reported at the congress, MASTER DAPT, which showed that 1 month of DAPT was noninferior to 3 or more months of DAPT for net clinical benefit in a distinctly different population of patients undergoing PCI (and using a different type of coronary stent) – those at high bleeding risk and with only about half the patients having had a recent ACS.

The results of STOPDAPT-2 ACS “do not support use of 1 month of DAPT followed by P2Y12 inhibitor monotherapy with clopidogrel compared with standard DAPT,” commented Robert A. Byrne, MBBCh, PhD, designated discussant for the report and professor at the RCSI University of Medicine and Health Sciences in Dublin.

“Although major bleeding was significantly reduced with this approach, there appeared to be a significant increase in adverse ischemic events, and there was a clear signal in relation to overall mortality, the ultimate arbiter of net clinical benefit,” added Dr. Byrne, who is also director of cardiology at Mater Private Hospital in Dublin.

He suggested that a mechanistic explanation for the signal of harm seem in STOPDAPT-2 ACS was the relatively low potency of clopidogrel (Plavix) as an antiplatelet agent, compared with other P2Y12 inhibitors such as prasugrel (Effient) and ticagrelor (Brilinta), as well as the genetically driven variability in response to clopidogrel that’s also absent with alternative agents.

These between-agent differences are of “particular clinical relevance in the early aftermath of an ACS event,” Dr. Byrne said.
 

12-month DAPT remains standard for PCI patients with recent ACS

The totality of clinical evidence “continues to support a standard 12-month duration of DAPT – using aspirin and either prasugrel or ticagrelor – as the preferred default approach,” Dr. Byrne concluded.

He acknowledged that an abbreviated duration of DAPT followed by P2Y12 inhibitor monotherapy “might be considered as an alternative.” In patients following an ACS event who do not have high risk for bleeding, he said, the minimum duration of DAPT should be at least 3 months and with preferential use of a more potent P2Y12 inhibitor.

Twelve months of DAPT treatment with aspirin and a P2Y12 inhibitor for patients following PCI “remains the standard of care in guidelines,” noted Marco Roffi, MD, a second discussant at the congress. But several questions remain, he added, such as which P2Y12 inhibitors work best and whether DAPT can be less than 12 months.

“The investigators [for STOPDAPT-2 ACS] pushed these questions to the limit with 1 month of DAPT and clopidogrel monotherapy,” said Dr. Roffi, professor and director of interventional cardiology at University Hospital, Geneva.

“This was a risky bet, and the investigators lost by not proving noninferiority and with excess ischemic events,” he commented.
 

First came STOPDAPT-2

Dr. Watanabe and colleagues designed STOPDAPT-2 ACS as a follow-up to their prior STOPDAPT-2 trial, which randomly assigned slightly more than 3000 patients at 90 Japanese centers to the identical two treatment options: 1 month of DAPT followed by 11 months of clopidogrel monotherapy or 12 months of DAPT, except the trial enrolled all types of patients undergoing PCI. This meant that a minority, 38%, had a recent ACS event, while the remaining patients had chronic coronary artery disease. As in STOPDAPT-2 ACS, all patients in STOPDAPT-2 had received a CCEE stent.

STOPDAPT-2 also used the same primary endpoint to tally net clinical benefit as STOPDAPT-2 ACS: cardiovascular death, MI, stroke of any type, definite stent thrombosis, or TIMI major or minor bleeding classification.

In STOPDAPT-2, using the mixed population with both recent ACS and chronic coronary disease, the regimen of 1 month of DAPT followed by 11 months of clopidogrel monotherapy was both noninferior to and superior to 12 months of DAPT, reducing the net adverse-event tally by 36% relative to 12-month DAPT and by an absolute reduction of 1.34%, as reported in 2019.

Despite this superiority, the results from STOPDAPT-2 had little impact on global practice, commented Kurt Huber, MD, professor and director of the cardiology ICU at the Medical University of Vienna.

“STOP-DAPT-2 did not give us a clear message with respect to reducing antiplatelet treatment after 1 month. I thought that for ACS patients 1 month might be too short,” Dr. Huber said during a press briefing.
 

Focusing on post-ACS

To directly address this issue, the investigators launched STOPDAPT-2 ACS, which used the same design as the preceding study but only enrolled patients soon after an ACS event. The trial included for its main analysis 3,008 newly enrolled patients with recent ACS, and 1,161 patients who had a recent ACS event and had been randomly assigned in STOPDAPT-2, creating a total study cohort for the new analysis of 4136 patients treated and followed for the study’s full 12 months.

The patients averaged 67 years old, 79% were men, and 30% had diabetes. About 56% had a recent ST-elevation MI, about 20% a recent non–ST-elevation MI, and the remaining 24% had unstable angina. For their unspecified P2Y12 inhibition, roughly half the patients received clopidogrel and the rest received prasugrel. Adherence to the two assigned treatment regimens was very good, with a very small number of patients not adhering to their assigned protocol.

The composite adverse event incidence over 12 months was 3.2% among those who received 1-month DAPT and 2.83% in those on DAPT for 12 months, a difference that failed to achieve the prespecified definition of noninferiority for 1-month DAPT, reported Dr. Watanabe, an interventional cardiologist at Kyoto University.

The ischemic event composite was 50% lower among those on 12-month DAPT, compared with 1 month of DAPT, a difference that just missed significance. The rate of MI was 91% higher with 1-month DAPT, compared with 12 months, a significant difference.

One-month DAPT also significantly reduced the primary measure of bleeding events – the combination of TIMI major and minor bleeds – by a significant 54%, compared with 12-month DAPT. A second metric of clinically meaningful bleeds, those that meet either the type 3 or 5 definition of the Bleeding Academic Research Consortium, were reduced by a significant 59% by 1-month DAPT, compared with 12 months of DAPT.

The new findings from STOPDAPT-2 ACS contrasted with those from MASTER DAPT, but in an explicable way that related to different patient types, different P2Y12 inhibitors, different treatment durations, and different stents.

“We’ve seen in MASTER DAPT that if you use the right stent and use ticagrelor for monotherapy there may be some ability to shorten DAPT, but we still do not know what would happen in patients with very high ischemic risk,” concluded Dr. Huber.

“A reduction in DAPT duration might work in patients without high bleeding risk, but I would exclude patients with very high ischemic risk,” he added. “I also can’t tell you whether 1 month or 3 months is the right approach, and I think clopidogrel is not the right drug to use for monotherapy after ACS.”

STOPDAPT-2 and STOPDAPT-2 ACS were both sponsored by Abbott Vascular, which markets the CCEE (Xience) stents used in both studies. Dr. Watanabe has received lecture fees from Abbott and from Daiichi-Sankyo. Dr. Byrne has received research funding from Abbott Vascular as well as from Biosensors, Biotronik, and Boston Scientific. Roffi has received research funding from Biotronik, Boston Scientific, GE Healthcare, Medtronic, and Terumo. Dr. Huber has received lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, Sanofi-Aventis, and The Medicines Company.

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

One month of dual antiplatelet therapy followed by 11 months of clopidogrel monotherapy failed to prove noninferiority to 12 unbroken months of DAPT for net clinical benefit in a multicenter Japanese trial that randomized more than 4,000 patients who underwent percutaneous coronary intervention (PCI) after a recent acute coronary syndrome episode.

© Astrid Gast/Thinkstock

The outcomes showed that while truncating DAPT duration could, as expected, cut major bleeding episodes roughly in half, it also led to a significant near doubling of myocardial infarction and showed a strong trend toward also increasing a composite tally of several types of ischemic events. These data were reported this week by Hirotoshi Watanabe, MD, PhD, at the virtual annual congress of the European Society of Cardiology. All study patients had undergone PCI with cobalt-chromium everolimus-eluting (CCEE) coronary stents (Xience).

These findings from the STOPDAPT-2 ACS trial highlighted the limits of minimizing DAPT after PCI in patients at high ischemic risk, such as after an acute coronary syndrome (ACS) event.

It also was a counterpoint to a somewhat similar study also reported at the congress, MASTER DAPT, which showed that 1 month of DAPT was noninferior to 3 or more months of DAPT for net clinical benefit in a distinctly different population of patients undergoing PCI (and using a different type of coronary stent) – those at high bleeding risk and with only about half the patients having had a recent ACS.

The results of STOPDAPT-2 ACS “do not support use of 1 month of DAPT followed by P2Y12 inhibitor monotherapy with clopidogrel compared with standard DAPT,” commented Robert A. Byrne, MBBCh, PhD, designated discussant for the report and professor at the RCSI University of Medicine and Health Sciences in Dublin.

“Although major bleeding was significantly reduced with this approach, there appeared to be a significant increase in adverse ischemic events, and there was a clear signal in relation to overall mortality, the ultimate arbiter of net clinical benefit,” added Dr. Byrne, who is also director of cardiology at Mater Private Hospital in Dublin.

He suggested that a mechanistic explanation for the signal of harm seem in STOPDAPT-2 ACS was the relatively low potency of clopidogrel (Plavix) as an antiplatelet agent, compared with other P2Y12 inhibitors such as prasugrel (Effient) and ticagrelor (Brilinta), as well as the genetically driven variability in response to clopidogrel that’s also absent with alternative agents.

These between-agent differences are of “particular clinical relevance in the early aftermath of an ACS event,” Dr. Byrne said.
 

12-month DAPT remains standard for PCI patients with recent ACS

The totality of clinical evidence “continues to support a standard 12-month duration of DAPT – using aspirin and either prasugrel or ticagrelor – as the preferred default approach,” Dr. Byrne concluded.

He acknowledged that an abbreviated duration of DAPT followed by P2Y12 inhibitor monotherapy “might be considered as an alternative.” In patients following an ACS event who do not have high risk for bleeding, he said, the minimum duration of DAPT should be at least 3 months and with preferential use of a more potent P2Y12 inhibitor.

Twelve months of DAPT treatment with aspirin and a P2Y12 inhibitor for patients following PCI “remains the standard of care in guidelines,” noted Marco Roffi, MD, a second discussant at the congress. But several questions remain, he added, such as which P2Y12 inhibitors work best and whether DAPT can be less than 12 months.

“The investigators [for STOPDAPT-2 ACS] pushed these questions to the limit with 1 month of DAPT and clopidogrel monotherapy,” said Dr. Roffi, professor and director of interventional cardiology at University Hospital, Geneva.

“This was a risky bet, and the investigators lost by not proving noninferiority and with excess ischemic events,” he commented.
 

First came STOPDAPT-2

Dr. Watanabe and colleagues designed STOPDAPT-2 ACS as a follow-up to their prior STOPDAPT-2 trial, which randomly assigned slightly more than 3000 patients at 90 Japanese centers to the identical two treatment options: 1 month of DAPT followed by 11 months of clopidogrel monotherapy or 12 months of DAPT, except the trial enrolled all types of patients undergoing PCI. This meant that a minority, 38%, had a recent ACS event, while the remaining patients had chronic coronary artery disease. As in STOPDAPT-2 ACS, all patients in STOPDAPT-2 had received a CCEE stent.

STOPDAPT-2 also used the same primary endpoint to tally net clinical benefit as STOPDAPT-2 ACS: cardiovascular death, MI, stroke of any type, definite stent thrombosis, or TIMI major or minor bleeding classification.

In STOPDAPT-2, using the mixed population with both recent ACS and chronic coronary disease, the regimen of 1 month of DAPT followed by 11 months of clopidogrel monotherapy was both noninferior to and superior to 12 months of DAPT, reducing the net adverse-event tally by 36% relative to 12-month DAPT and by an absolute reduction of 1.34%, as reported in 2019.

Despite this superiority, the results from STOPDAPT-2 had little impact on global practice, commented Kurt Huber, MD, professor and director of the cardiology ICU at the Medical University of Vienna.

“STOP-DAPT-2 did not give us a clear message with respect to reducing antiplatelet treatment after 1 month. I thought that for ACS patients 1 month might be too short,” Dr. Huber said during a press briefing.
 

Focusing on post-ACS

To directly address this issue, the investigators launched STOPDAPT-2 ACS, which used the same design as the preceding study but only enrolled patients soon after an ACS event. The trial included for its main analysis 3,008 newly enrolled patients with recent ACS, and 1,161 patients who had a recent ACS event and had been randomly assigned in STOPDAPT-2, creating a total study cohort for the new analysis of 4136 patients treated and followed for the study’s full 12 months.

The patients averaged 67 years old, 79% were men, and 30% had diabetes. About 56% had a recent ST-elevation MI, about 20% a recent non–ST-elevation MI, and the remaining 24% had unstable angina. For their unspecified P2Y12 inhibition, roughly half the patients received clopidogrel and the rest received prasugrel. Adherence to the two assigned treatment regimens was very good, with a very small number of patients not adhering to their assigned protocol.

The composite adverse event incidence over 12 months was 3.2% among those who received 1-month DAPT and 2.83% in those on DAPT for 12 months, a difference that failed to achieve the prespecified definition of noninferiority for 1-month DAPT, reported Dr. Watanabe, an interventional cardiologist at Kyoto University.

The ischemic event composite was 50% lower among those on 12-month DAPT, compared with 1 month of DAPT, a difference that just missed significance. The rate of MI was 91% higher with 1-month DAPT, compared with 12 months, a significant difference.

One-month DAPT also significantly reduced the primary measure of bleeding events – the combination of TIMI major and minor bleeds – by a significant 54%, compared with 12-month DAPT. A second metric of clinically meaningful bleeds, those that meet either the type 3 or 5 definition of the Bleeding Academic Research Consortium, were reduced by a significant 59% by 1-month DAPT, compared with 12 months of DAPT.

The new findings from STOPDAPT-2 ACS contrasted with those from MASTER DAPT, but in an explicable way that related to different patient types, different P2Y12 inhibitors, different treatment durations, and different stents.

“We’ve seen in MASTER DAPT that if you use the right stent and use ticagrelor for monotherapy there may be some ability to shorten DAPT, but we still do not know what would happen in patients with very high ischemic risk,” concluded Dr. Huber.

“A reduction in DAPT duration might work in patients without high bleeding risk, but I would exclude patients with very high ischemic risk,” he added. “I also can’t tell you whether 1 month or 3 months is the right approach, and I think clopidogrel is not the right drug to use for monotherapy after ACS.”

STOPDAPT-2 and STOPDAPT-2 ACS were both sponsored by Abbott Vascular, which markets the CCEE (Xience) stents used in both studies. Dr. Watanabe has received lecture fees from Abbott and from Daiichi-Sankyo. Dr. Byrne has received research funding from Abbott Vascular as well as from Biosensors, Biotronik, and Boston Scientific. Roffi has received research funding from Biotronik, Boston Scientific, GE Healthcare, Medtronic, and Terumo. Dr. Huber has received lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, Sanofi-Aventis, and The Medicines Company.

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

One month of dual antiplatelet therapy followed by 11 months of clopidogrel monotherapy failed to prove noninferiority to 12 unbroken months of DAPT for net clinical benefit in a multicenter Japanese trial that randomized more than 4,000 patients who underwent percutaneous coronary intervention (PCI) after a recent acute coronary syndrome episode.

© Astrid Gast/Thinkstock

The outcomes showed that while truncating DAPT duration could, as expected, cut major bleeding episodes roughly in half, it also led to a significant near doubling of myocardial infarction and showed a strong trend toward also increasing a composite tally of several types of ischemic events. These data were reported this week by Hirotoshi Watanabe, MD, PhD, at the virtual annual congress of the European Society of Cardiology. All study patients had undergone PCI with cobalt-chromium everolimus-eluting (CCEE) coronary stents (Xience).

These findings from the STOPDAPT-2 ACS trial highlighted the limits of minimizing DAPT after PCI in patients at high ischemic risk, such as after an acute coronary syndrome (ACS) event.

It also was a counterpoint to a somewhat similar study also reported at the congress, MASTER DAPT, which showed that 1 month of DAPT was noninferior to 3 or more months of DAPT for net clinical benefit in a distinctly different population of patients undergoing PCI (and using a different type of coronary stent) – those at high bleeding risk and with only about half the patients having had a recent ACS.

The results of STOPDAPT-2 ACS “do not support use of 1 month of DAPT followed by P2Y12 inhibitor monotherapy with clopidogrel compared with standard DAPT,” commented Robert A. Byrne, MBBCh, PhD, designated discussant for the report and professor at the RCSI University of Medicine and Health Sciences in Dublin.

“Although major bleeding was significantly reduced with this approach, there appeared to be a significant increase in adverse ischemic events, and there was a clear signal in relation to overall mortality, the ultimate arbiter of net clinical benefit,” added Dr. Byrne, who is also director of cardiology at Mater Private Hospital in Dublin.

He suggested that a mechanistic explanation for the signal of harm seem in STOPDAPT-2 ACS was the relatively low potency of clopidogrel (Plavix) as an antiplatelet agent, compared with other P2Y12 inhibitors such as prasugrel (Effient) and ticagrelor (Brilinta), as well as the genetically driven variability in response to clopidogrel that’s also absent with alternative agents.

These between-agent differences are of “particular clinical relevance in the early aftermath of an ACS event,” Dr. Byrne said.
 

12-month DAPT remains standard for PCI patients with recent ACS

The totality of clinical evidence “continues to support a standard 12-month duration of DAPT – using aspirin and either prasugrel or ticagrelor – as the preferred default approach,” Dr. Byrne concluded.

He acknowledged that an abbreviated duration of DAPT followed by P2Y12 inhibitor monotherapy “might be considered as an alternative.” In patients following an ACS event who do not have high risk for bleeding, he said, the minimum duration of DAPT should be at least 3 months and with preferential use of a more potent P2Y12 inhibitor.

Twelve months of DAPT treatment with aspirin and a P2Y12 inhibitor for patients following PCI “remains the standard of care in guidelines,” noted Marco Roffi, MD, a second discussant at the congress. But several questions remain, he added, such as which P2Y12 inhibitors work best and whether DAPT can be less than 12 months.

“The investigators [for STOPDAPT-2 ACS] pushed these questions to the limit with 1 month of DAPT and clopidogrel monotherapy,” said Dr. Roffi, professor and director of interventional cardiology at University Hospital, Geneva.

“This was a risky bet, and the investigators lost by not proving noninferiority and with excess ischemic events,” he commented.
 

First came STOPDAPT-2

Dr. Watanabe and colleagues designed STOPDAPT-2 ACS as a follow-up to their prior STOPDAPT-2 trial, which randomly assigned slightly more than 3000 patients at 90 Japanese centers to the identical two treatment options: 1 month of DAPT followed by 11 months of clopidogrel monotherapy or 12 months of DAPT, except the trial enrolled all types of patients undergoing PCI. This meant that a minority, 38%, had a recent ACS event, while the remaining patients had chronic coronary artery disease. As in STOPDAPT-2 ACS, all patients in STOPDAPT-2 had received a CCEE stent.

STOPDAPT-2 also used the same primary endpoint to tally net clinical benefit as STOPDAPT-2 ACS: cardiovascular death, MI, stroke of any type, definite stent thrombosis, or TIMI major or minor bleeding classification.

In STOPDAPT-2, using the mixed population with both recent ACS and chronic coronary disease, the regimen of 1 month of DAPT followed by 11 months of clopidogrel monotherapy was both noninferior to and superior to 12 months of DAPT, reducing the net adverse-event tally by 36% relative to 12-month DAPT and by an absolute reduction of 1.34%, as reported in 2019.

Despite this superiority, the results from STOPDAPT-2 had little impact on global practice, commented Kurt Huber, MD, professor and director of the cardiology ICU at the Medical University of Vienna.

“STOP-DAPT-2 did not give us a clear message with respect to reducing antiplatelet treatment after 1 month. I thought that for ACS patients 1 month might be too short,” Dr. Huber said during a press briefing.
 

Focusing on post-ACS

To directly address this issue, the investigators launched STOPDAPT-2 ACS, which used the same design as the preceding study but only enrolled patients soon after an ACS event. The trial included for its main analysis 3,008 newly enrolled patients with recent ACS, and 1,161 patients who had a recent ACS event and had been randomly assigned in STOPDAPT-2, creating a total study cohort for the new analysis of 4136 patients treated and followed for the study’s full 12 months.

The patients averaged 67 years old, 79% were men, and 30% had diabetes. About 56% had a recent ST-elevation MI, about 20% a recent non–ST-elevation MI, and the remaining 24% had unstable angina. For their unspecified P2Y12 inhibition, roughly half the patients received clopidogrel and the rest received prasugrel. Adherence to the two assigned treatment regimens was very good, with a very small number of patients not adhering to their assigned protocol.

The composite adverse event incidence over 12 months was 3.2% among those who received 1-month DAPT and 2.83% in those on DAPT for 12 months, a difference that failed to achieve the prespecified definition of noninferiority for 1-month DAPT, reported Dr. Watanabe, an interventional cardiologist at Kyoto University.

The ischemic event composite was 50% lower among those on 12-month DAPT, compared with 1 month of DAPT, a difference that just missed significance. The rate of MI was 91% higher with 1-month DAPT, compared with 12 months, a significant difference.

One-month DAPT also significantly reduced the primary measure of bleeding events – the combination of TIMI major and minor bleeds – by a significant 54%, compared with 12-month DAPT. A second metric of clinically meaningful bleeds, those that meet either the type 3 or 5 definition of the Bleeding Academic Research Consortium, were reduced by a significant 59% by 1-month DAPT, compared with 12 months of DAPT.

The new findings from STOPDAPT-2 ACS contrasted with those from MASTER DAPT, but in an explicable way that related to different patient types, different P2Y12 inhibitors, different treatment durations, and different stents.

“We’ve seen in MASTER DAPT that if you use the right stent and use ticagrelor for monotherapy there may be some ability to shorten DAPT, but we still do not know what would happen in patients with very high ischemic risk,” concluded Dr. Huber.

“A reduction in DAPT duration might work in patients without high bleeding risk, but I would exclude patients with very high ischemic risk,” he added. “I also can’t tell you whether 1 month or 3 months is the right approach, and I think clopidogrel is not the right drug to use for monotherapy after ACS.”

STOPDAPT-2 and STOPDAPT-2 ACS were both sponsored by Abbott Vascular, which markets the CCEE (Xience) stents used in both studies. Dr. Watanabe has received lecture fees from Abbott and from Daiichi-Sankyo. Dr. Byrne has received research funding from Abbott Vascular as well as from Biosensors, Biotronik, and Boston Scientific. Roffi has received research funding from Biotronik, Boston Scientific, GE Healthcare, Medtronic, and Terumo. Dr. Huber has received lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, Sanofi-Aventis, and The Medicines Company.

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

Carotid artery stenting (CAS) and carotid endarterectomy (CEA) provided comparable outcomes over time in asymptomatic patients receiving good medical therapy in the largest trial to date of what to do with severe carotid artery narrowing that is yet to cause a stroke.

aaM Photography, Ltd./iStock

Among more than 3,600 patients, stenting and surgery performed by experienced physicians involved a 1.0% risk for causing disabling stroke or death within 30 days.

The annual rate of fatal or disabling strokes was about 0.5% with either procedure over an average 5 years’ follow-up – essentially halving the annual stroke risk had neither procedure been performed, according to Alison Halliday, MD, principal investigator of the Asymptomatic Carotid Surgery Trial-2 (ACST-2).

The results were reported Aug. 29 in a Hot Line session at the virtual annual congress of the European Society of Cardiology and published simultaneously online in The Lancet.

Session chair Gilles Montalescot, MD, Sorbonne University, Paris, noted that ACST-2 doubled the number of randomly assigned patients with asymptomatic carotid stenosis studied in previous trials, “so, a huge contribution to the evidence base in this field and apparently good news for both revascularization techniques.”
 

Thirty-day and 5-year outcomes

The trial was conducted in 33 countries between January 2008 and December 2020, enrolling 3,625 patients (70% were male; mean age, 70 years) with carotid stenosis of at least 60% on ultrasonography, in whom stenting or surgery was suitable but both the doctor and patient were “substantially uncertain” which procedure to prefer.

Among the 1,811 patients assigned to stenting, 87% underwent the procedure at a median of 14 days; 6% crossed over to surgery, typically because of a highly calcified lesion or a more tortuous carotid than anticipated; and 6% had no intervention.

Among the 1,814 patients assigned to surgery, 92% had the procedure at a median of 14 days; 3% crossed over to stenting, typically because of patient or doctor preference or reluctance to undergo general anesthesia; and 4% had no intervention.

Patients without complications who had stenting stayed on average 1 day less than did those undergoing surgery.

During an earlier press briefing, Dr. Halliday highlighted the need for procedural competency and said doctors had to submit a record of their CEA or CAS experience and, consistent with current guidelines, had to demonstrate an independently verified stroke or death rate of 6% or less for symptomatic patients and 3% or lower for asymptomatic patients.

The results showed the 30-day risk for death, myocardial infarction (MI), or any stroke was 3.9% with carotid stenting and 3.2% with surgery (P = .26).

But with stenting, there was a slightly higher risk for procedural nondisabling strokes (48 vs. 29; P = .03), including 15 strokes vs. 5 strokes, respectively, that left patients with no residual symptoms. This is “consistent with large, recent nationally representative registry data,” observed Dr. Halliday, of the University of Oxford (England).

For those undergoing surgery, cranial nerve palsies were reported in 5.4% vs. no patients undergoing stenting.

At 5 years, the nonprocedural fatal or disabling stroke rate was 2.5% in each group (rate ratio [RR], 0.98; P = .91), with any nonprocedural stroke occurring in 5.3% of patients with stenting vs. 4.5% with surgery (RR, 1.16; P = .33).

The investigators performed a meta-analysis combining the ACST-2 results with those of eight prior trials (four in asymptomatic and four in symptomatic patients) that yielded a similar nonsignificant result for any nonprocedural stroke (RR, 1.11; P = .21).

Based on the results from ACST-2 plus the major trials, stenting and surgery involve “similar risks and similar benefits,” Dr. Halliday concluded.

Discussant Marco Roffi, MD, University Hospital of Geneva, said, “In centers with documented expertise, carotid artery stenting should be offered as an alternative to carotid endarterectomy in patients with asymptomatic stenosis and suitable anatomy.”

While the trial provides “good news” for patients, he pointed out that a reduction in the sample size from 5,000 to 3,625 limited the statistical power and that enrollment over a long period of time may have introduced confounders, such as changes in equipment technique, and medical therapy.

Also, many centers enrolled few patients, raising the concern over low-volume centers and operators, Dr. Roffi said. “We know that 8% of the centers enrolled 39% of the patients,” and “information on the credentialing and experience of the interventionalists was limited.”

Further, a lack of systematic MI assessment may have favored the surgery group, and more recent developments in stenting with the potential of reducing periprocedural stroke were rarely used, such as proximal emboli protection in only 15% and double-layer stents in 11%.

Friedhelm Beyersdorf, MD, University Hospital of Freiburg, Germany, said that, as a vascular surgeon, he finds it understandable that there might be a higher incidence of nonfatal strokes when treating carotid stenosis with stents, given the vulnerability of these lesions.

“Nevertheless, the main conclusion from the entire study is that carotid artery treatment is extremely safe, it has to be done in order to avoid strokes, and, obviously, there seems to be an advantage for surgery in terms of nondisabling stroke,” he said.

Session chair Dr. Montalescot, however, said that what the study cannot address – and what was the subject of many online audience comments – is whether either intervention should be performed in these patients. 

Unlike earlier trials comparing interventions to medical therapy, Dr. Halliday said ACST-2 enrolled patients for whom the decision had been made that revascularization was needed. In addition, 99%-100% were receiving antithrombotic therapy at baseline, 85%-90% were receiving antihypertensives, and about 85% were taking statins.

Longer-term follow-up should provide a better picture of the nonprocedural stroke risk, with patients asked annually about exactly what medications and doses they are taking, she said.

“We will have an enormous list of exactly what’s gone on and the intensity of that therapy, which is, of course, much more intense than when we carried out our first trial. But these were people in whom a procedure was thought to be necessary,” she noted.

When asked during the press conference which procedure she would choose, Dr. Halliday, a surgeon, observed that patient preference is important but that the nature of the lesion itself often determines the optimal choice.

“If you know the competence of the people doing it is equal, then the less invasive procedure – providing it has good long-term viability, and that’s why we’re following for 10 years – is the more important,” she added.

The study was funded by the UK Medical Research Council and Health Technology Assessment Programme. Dr. Halliday reports no relevant financial relationships.

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

Carotid artery stenting (CAS) and carotid endarterectomy (CEA) provided comparable outcomes over time in asymptomatic patients receiving good medical therapy in the largest trial to date of what to do with severe carotid artery narrowing that is yet to cause a stroke.

aaM Photography, Ltd./iStock

Among more than 3,600 patients, stenting and surgery performed by experienced physicians involved a 1.0% risk for causing disabling stroke or death within 30 days.

The annual rate of fatal or disabling strokes was about 0.5% with either procedure over an average 5 years’ follow-up – essentially halving the annual stroke risk had neither procedure been performed, according to Alison Halliday, MD, principal investigator of the Asymptomatic Carotid Surgery Trial-2 (ACST-2).

The results were reported Aug. 29 in a Hot Line session at the virtual annual congress of the European Society of Cardiology and published simultaneously online in The Lancet.

Session chair Gilles Montalescot, MD, Sorbonne University, Paris, noted that ACST-2 doubled the number of randomly assigned patients with asymptomatic carotid stenosis studied in previous trials, “so, a huge contribution to the evidence base in this field and apparently good news for both revascularization techniques.”
 

Thirty-day and 5-year outcomes

The trial was conducted in 33 countries between January 2008 and December 2020, enrolling 3,625 patients (70% were male; mean age, 70 years) with carotid stenosis of at least 60% on ultrasonography, in whom stenting or surgery was suitable but both the doctor and patient were “substantially uncertain” which procedure to prefer.

Among the 1,811 patients assigned to stenting, 87% underwent the procedure at a median of 14 days; 6% crossed over to surgery, typically because of a highly calcified lesion or a more tortuous carotid than anticipated; and 6% had no intervention.

Among the 1,814 patients assigned to surgery, 92% had the procedure at a median of 14 days; 3% crossed over to stenting, typically because of patient or doctor preference or reluctance to undergo general anesthesia; and 4% had no intervention.

Patients without complications who had stenting stayed on average 1 day less than did those undergoing surgery.

During an earlier press briefing, Dr. Halliday highlighted the need for procedural competency and said doctors had to submit a record of their CEA or CAS experience and, consistent with current guidelines, had to demonstrate an independently verified stroke or death rate of 6% or less for symptomatic patients and 3% or lower for asymptomatic patients.

The results showed the 30-day risk for death, myocardial infarction (MI), or any stroke was 3.9% with carotid stenting and 3.2% with surgery (P = .26).

But with stenting, there was a slightly higher risk for procedural nondisabling strokes (48 vs. 29; P = .03), including 15 strokes vs. 5 strokes, respectively, that left patients with no residual symptoms. This is “consistent with large, recent nationally representative registry data,” observed Dr. Halliday, of the University of Oxford (England).

For those undergoing surgery, cranial nerve palsies were reported in 5.4% vs. no patients undergoing stenting.

At 5 years, the nonprocedural fatal or disabling stroke rate was 2.5% in each group (rate ratio [RR], 0.98; P = .91), with any nonprocedural stroke occurring in 5.3% of patients with stenting vs. 4.5% with surgery (RR, 1.16; P = .33).

The investigators performed a meta-analysis combining the ACST-2 results with those of eight prior trials (four in asymptomatic and four in symptomatic patients) that yielded a similar nonsignificant result for any nonprocedural stroke (RR, 1.11; P = .21).

Based on the results from ACST-2 plus the major trials, stenting and surgery involve “similar risks and similar benefits,” Dr. Halliday concluded.

Discussant Marco Roffi, MD, University Hospital of Geneva, said, “In centers with documented expertise, carotid artery stenting should be offered as an alternative to carotid endarterectomy in patients with asymptomatic stenosis and suitable anatomy.”

While the trial provides “good news” for patients, he pointed out that a reduction in the sample size from 5,000 to 3,625 limited the statistical power and that enrollment over a long period of time may have introduced confounders, such as changes in equipment technique, and medical therapy.

Also, many centers enrolled few patients, raising the concern over low-volume centers and operators, Dr. Roffi said. “We know that 8% of the centers enrolled 39% of the patients,” and “information on the credentialing and experience of the interventionalists was limited.”

Further, a lack of systematic MI assessment may have favored the surgery group, and more recent developments in stenting with the potential of reducing periprocedural stroke were rarely used, such as proximal emboli protection in only 15% and double-layer stents in 11%.

Friedhelm Beyersdorf, MD, University Hospital of Freiburg, Germany, said that, as a vascular surgeon, he finds it understandable that there might be a higher incidence of nonfatal strokes when treating carotid stenosis with stents, given the vulnerability of these lesions.

“Nevertheless, the main conclusion from the entire study is that carotid artery treatment is extremely safe, it has to be done in order to avoid strokes, and, obviously, there seems to be an advantage for surgery in terms of nondisabling stroke,” he said.

Session chair Dr. Montalescot, however, said that what the study cannot address – and what was the subject of many online audience comments – is whether either intervention should be performed in these patients. 

Unlike earlier trials comparing interventions to medical therapy, Dr. Halliday said ACST-2 enrolled patients for whom the decision had been made that revascularization was needed. In addition, 99%-100% were receiving antithrombotic therapy at baseline, 85%-90% were receiving antihypertensives, and about 85% were taking statins.

Longer-term follow-up should provide a better picture of the nonprocedural stroke risk, with patients asked annually about exactly what medications and doses they are taking, she said.

“We will have an enormous list of exactly what’s gone on and the intensity of that therapy, which is, of course, much more intense than when we carried out our first trial. But these were people in whom a procedure was thought to be necessary,” she noted.

When asked during the press conference which procedure she would choose, Dr. Halliday, a surgeon, observed that patient preference is important but that the nature of the lesion itself often determines the optimal choice.

“If you know the competence of the people doing it is equal, then the less invasive procedure – providing it has good long-term viability, and that’s why we’re following for 10 years – is the more important,” she added.

The study was funded by the UK Medical Research Council and Health Technology Assessment Programme. Dr. Halliday reports no relevant financial relationships.

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

Carotid artery stenting (CAS) and carotid endarterectomy (CEA) provided comparable outcomes over time in asymptomatic patients receiving good medical therapy in the largest trial to date of what to do with severe carotid artery narrowing that is yet to cause a stroke.

aaM Photography, Ltd./iStock

Among more than 3,600 patients, stenting and surgery performed by experienced physicians involved a 1.0% risk for causing disabling stroke or death within 30 days.

The annual rate of fatal or disabling strokes was about 0.5% with either procedure over an average 5 years’ follow-up – essentially halving the annual stroke risk had neither procedure been performed, according to Alison Halliday, MD, principal investigator of the Asymptomatic Carotid Surgery Trial-2 (ACST-2).

The results were reported Aug. 29 in a Hot Line session at the virtual annual congress of the European Society of Cardiology and published simultaneously online in The Lancet.

Session chair Gilles Montalescot, MD, Sorbonne University, Paris, noted that ACST-2 doubled the number of randomly assigned patients with asymptomatic carotid stenosis studied in previous trials, “so, a huge contribution to the evidence base in this field and apparently good news for both revascularization techniques.”
 

Thirty-day and 5-year outcomes

The trial was conducted in 33 countries between January 2008 and December 2020, enrolling 3,625 patients (70% were male; mean age, 70 years) with carotid stenosis of at least 60% on ultrasonography, in whom stenting or surgery was suitable but both the doctor and patient were “substantially uncertain” which procedure to prefer.

Among the 1,811 patients assigned to stenting, 87% underwent the procedure at a median of 14 days; 6% crossed over to surgery, typically because of a highly calcified lesion or a more tortuous carotid than anticipated; and 6% had no intervention.

Among the 1,814 patients assigned to surgery, 92% had the procedure at a median of 14 days; 3% crossed over to stenting, typically because of patient or doctor preference or reluctance to undergo general anesthesia; and 4% had no intervention.

Patients without complications who had stenting stayed on average 1 day less than did those undergoing surgery.

During an earlier press briefing, Dr. Halliday highlighted the need for procedural competency and said doctors had to submit a record of their CEA or CAS experience and, consistent with current guidelines, had to demonstrate an independently verified stroke or death rate of 6% or less for symptomatic patients and 3% or lower for asymptomatic patients.

The results showed the 30-day risk for death, myocardial infarction (MI), or any stroke was 3.9% with carotid stenting and 3.2% with surgery (P = .26).

But with stenting, there was a slightly higher risk for procedural nondisabling strokes (48 vs. 29; P = .03), including 15 strokes vs. 5 strokes, respectively, that left patients with no residual symptoms. This is “consistent with large, recent nationally representative registry data,” observed Dr. Halliday, of the University of Oxford (England).

For those undergoing surgery, cranial nerve palsies were reported in 5.4% vs. no patients undergoing stenting.

At 5 years, the nonprocedural fatal or disabling stroke rate was 2.5% in each group (rate ratio [RR], 0.98; P = .91), with any nonprocedural stroke occurring in 5.3% of patients with stenting vs. 4.5% with surgery (RR, 1.16; P = .33).

The investigators performed a meta-analysis combining the ACST-2 results with those of eight prior trials (four in asymptomatic and four in symptomatic patients) that yielded a similar nonsignificant result for any nonprocedural stroke (RR, 1.11; P = .21).

Based on the results from ACST-2 plus the major trials, stenting and surgery involve “similar risks and similar benefits,” Dr. Halliday concluded.

Discussant Marco Roffi, MD, University Hospital of Geneva, said, “In centers with documented expertise, carotid artery stenting should be offered as an alternative to carotid endarterectomy in patients with asymptomatic stenosis and suitable anatomy.”

While the trial provides “good news” for patients, he pointed out that a reduction in the sample size from 5,000 to 3,625 limited the statistical power and that enrollment over a long period of time may have introduced confounders, such as changes in equipment technique, and medical therapy.

Also, many centers enrolled few patients, raising the concern over low-volume centers and operators, Dr. Roffi said. “We know that 8% of the centers enrolled 39% of the patients,” and “information on the credentialing and experience of the interventionalists was limited.”

Further, a lack of systematic MI assessment may have favored the surgery group, and more recent developments in stenting with the potential of reducing periprocedural stroke were rarely used, such as proximal emboli protection in only 15% and double-layer stents in 11%.

Friedhelm Beyersdorf, MD, University Hospital of Freiburg, Germany, said that, as a vascular surgeon, he finds it understandable that there might be a higher incidence of nonfatal strokes when treating carotid stenosis with stents, given the vulnerability of these lesions.

“Nevertheless, the main conclusion from the entire study is that carotid artery treatment is extremely safe, it has to be done in order to avoid strokes, and, obviously, there seems to be an advantage for surgery in terms of nondisabling stroke,” he said.

Session chair Dr. Montalescot, however, said that what the study cannot address – and what was the subject of many online audience comments – is whether either intervention should be performed in these patients. 

Unlike earlier trials comparing interventions to medical therapy, Dr. Halliday said ACST-2 enrolled patients for whom the decision had been made that revascularization was needed. In addition, 99%-100% were receiving antithrombotic therapy at baseline, 85%-90% were receiving antihypertensives, and about 85% were taking statins.

Longer-term follow-up should provide a better picture of the nonprocedural stroke risk, with patients asked annually about exactly what medications and doses they are taking, she said.

“We will have an enormous list of exactly what’s gone on and the intensity of that therapy, which is, of course, much more intense than when we carried out our first trial. But these were people in whom a procedure was thought to be necessary,” she noted.

When asked during the press conference which procedure she would choose, Dr. Halliday, a surgeon, observed that patient preference is important but that the nature of the lesion itself often determines the optimal choice.

“If you know the competence of the people doing it is equal, then the less invasive procedure – providing it has good long-term viability, and that’s why we’re following for 10 years – is the more important,” she added.

The study was funded by the UK Medical Research Council and Health Technology Assessment Programme. Dr. Halliday reports no relevant financial relationships.

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

Another trial has added to the movement toward shortening the duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI).

MDedge News

In the MASTER DAPT trial involving patients at high risk for bleeding who had undergone implantation of a biodegradable-polymer sirolimus-eluting stent, switching from DAPT to single antiplatelet therapy at a median of 34 days after PCI was noninferior to the continuation of DAPT treatment for a median duration of 193 days with regard to the incidence of major adverse cardiac or cerebral events, and was associated with a lower incidence of major or clinically relevant bleeding.

The results of the study were presented by Marco Valgimigli, MD, Cardiocentro Ticino Institute, Lugano, Switzerland, on Aug. 28 at the virtual European Society of Cardiology (ESC) Congress 2021. They were simultaneously published online in the New England Journal of Medicine.

“It has been suggested in previous studies that if patients are at high bleeding risk, then they do not seem to derive ischemic benefit from prolonging DAPT, they just get the increased bleeding risk,” Dr. Valgimigli said. “But this has never been prospectively tested until now.”

He pointed out that patients at high bleeding risk are a large group, representing up to 40% of patients undergoing PCI, and the MASTER DAPT trial included “all-comer” high-bleeding-risk patients with no selection based on ischemic risk.

M. Alexander Otto, MDedge News

The trial was very well received by commentators at the ESC Hot Line presentation.

Chair of the session, Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, described the trial as “practice-changing.”

And Robert Byrne, MD, Mater Private Hospital, Dublin, added: “This is a standout trial. We have become more comfortable with abbreviated DAPT in high-bleeding-risk patients, but definite evidence for this has been lacking until now. This study tells us that just 1 month of DAPT appears to be safe in that there was no increase in ischemic complications and there was a clear reduction in bleeding.”

The MASTER DAPT study involved 4,579 patients at high bleeding risk who had undergone implantation of a biodegradable-polymer sirolimus-eluting coronary stent (Ultimaster, Terumo). Around half the patients had PCI for acute coronary syndrome (ACS) and half had it electively. One month after PCI they were randomly assigned to discontinue DAPT immediately (abbreviated therapy) or to continue it for at least 2 additional months (standard therapy).

The three co-primary outcomes were net adverse clinical events (a composite of death from any cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (a composite of death from any cause, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding, all assessed cumulatively at 335 days. The first two outcomes were assessed for noninferiority in the per-protocol population, and the third outcome for superiority in the intention-to-treat population.

Dual antiplatelet therapy consisted of aspirin plus a P2Y12 inhibitor. The choices of the type of P2Y12 inhibitor for DAPT and the type of monotherapy after the discontinuation of DAPT were at the discretion of the investigator. Clopidogrel was the most popular choice, used as monotherapy in 54% of the patients in the abbreviated-therapy group and as part of DAPT in 79% of patients in the standard-therapy group.

Results showed that net adverse clinical events occurred in 7.5% of the abbreviated-therapy group and in 7.7% of the standard-therapy group (difference, –0.23 percentage points; 95% confidence interval, –1.80 to 1.33 percentage points; P < .001 for noninferiority).

Major adverse cardiac or cerebral events occurred in 6.1% of the abbreviated-therapy group and 5.9% of standard therapy group (difference, 0.11 percentage points; 95% CI, –1.29 to 1.51 percentage points; P = .001 for noninferiority).

Reduction in bleeding driven by BARC-2

Major bleeding or clinically relevant nonmajor bleeding occurred in 6.5% in the abbreviated-therapy group and in 9.4% in the standard-therapy group (difference, –2.82 percentage points; 95% CI, –4.40 to –1.24 percentage points; P < .001 for superiority).

“This is a highly statistically significant reduction in bleeding giving a number needed to treat of 35,” Dr. Valgimigli said.

The lower risk for bleeding in the abbreviated-therapy group was mainly due to the lower incidence of clinically relevant nonmajor bleeding events (BARC type 2) in this group than in the standard-therapy group (4.5% vs. 6.8%).

During the discussion, Dr. Byrne pointed out that the most serious type of bleeding (BARC type 3-5) was not reduced in the abbreviated DAPT group.

Dr. Valgimigli responded that the investigators were surprised about that because previous studies indicated that this most serious bleeding would be reduced, but he suggested that this may be explained by the standard group receiving 3-6 months of DAPT rather than a year or more in previous studies. “Having said that, BARC-2 bleeding is not a trivial event,” he added.
 

Can results be applied to other stents?

Dr. Byrne also questioned whether the results can be applied to patients receiving other types of stents – not just Ultimaster, which is not available everywhere. Dr. Valgimigli highlighted the low rate of stent thrombosis seen with the Ultimaster stent and said, “I would be scared to assume these results are reproducible with other stents.”

But Dr. Mehran challenged this view, saying, “I’m not so sure about that. I think we can probably extrapolate.”

In an interview, Dr. Mehran added: “I think this is one of the much-needed studies in our field. For the first time, we have a randomized trial on duration of DAPT in high-bleeding-risk patients. The study was inclusive, and enrolled truly high-bleeding-risk patients, including those on oral anticoagulants.  

“These results show that, although high-bleeding-risk patients are at high risk of ischemic events, just 1 month of DAPT works well for them regardless, by reducing bleeding, net adverse clinical events, and without increasing ischemic events,” she concluded.

In an editorial accompanying the publication, E. Magnus Ohman, MB, from Duke University, Durham, N.C., pointed out the wide CIs in the results, which he said introduced some uncertainly to the findings.

But he concluded that: “The findings of Dr. Valgimigli and colleagues are important and move us toward a shorter and simpler antithrombotic strategy after PCI.”

In an interview, Dr. Ohman pointed out that the Ultimaster stent is not available in the United States. “We have to think about whether this stent would perform differently to other third- or fourth-generation stents. I wouldn’t have thought so, but it is hard to say for sure.

“All in all, we are looking at shorter periods of DAPT now after PCI. Several trials have now suggested that is the way to go. The forthcoming U.S. PCI guidelines should put all the studies together and come up with recommendations on different patient groups,” he concluded.  

Several commentators said they would like to see the data on the patients receiving oral anticoagulants in the study before making firm conclusions on how to translate the results into clinical practice. “This is such an important group. It is difficult to interpret the results without this data,” Dr. Ohman noted.  Patients receiving oral anticoagulants, who made up 36% of the study population, will be the subject of a separate report to be presented at the ESC meeting.

The MASTER DAPT trial was supported by Terumo. Dr. Valgimigli reports research grants from Terumo, Abbott, and SMT and consulting or speaker fees from Terumo, Abbott, Daiichi Sankyo, Chiesi, Vesalio, Vifor, Avimedica, Medtronic, Boston Scientific, and AstraZeneca. Dr. Ohman reports grants from Abiomed, grants from Chiesi USA, personal fees from Cara Therapeutics, Genentech, Imbria, Impulse Dynamics, Milestone Pharmaceuticals, XyloCor, Cytokinetics, Dispersol, Otsuka, Pfizer, Cytosorbents, Neurocrine, and Paradigm, outside the submitted work.

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

Another trial has added to the movement toward shortening the duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI).

MDedge News

In the MASTER DAPT trial involving patients at high risk for bleeding who had undergone implantation of a biodegradable-polymer sirolimus-eluting stent, switching from DAPT to single antiplatelet therapy at a median of 34 days after PCI was noninferior to the continuation of DAPT treatment for a median duration of 193 days with regard to the incidence of major adverse cardiac or cerebral events, and was associated with a lower incidence of major or clinically relevant bleeding.

The results of the study were presented by Marco Valgimigli, MD, Cardiocentro Ticino Institute, Lugano, Switzerland, on Aug. 28 at the virtual European Society of Cardiology (ESC) Congress 2021. They were simultaneously published online in the New England Journal of Medicine.

“It has been suggested in previous studies that if patients are at high bleeding risk, then they do not seem to derive ischemic benefit from prolonging DAPT, they just get the increased bleeding risk,” Dr. Valgimigli said. “But this has never been prospectively tested until now.”

He pointed out that patients at high bleeding risk are a large group, representing up to 40% of patients undergoing PCI, and the MASTER DAPT trial included “all-comer” high-bleeding-risk patients with no selection based on ischemic risk.

M. Alexander Otto, MDedge News

The trial was very well received by commentators at the ESC Hot Line presentation.

Chair of the session, Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, described the trial as “practice-changing.”

And Robert Byrne, MD, Mater Private Hospital, Dublin, added: “This is a standout trial. We have become more comfortable with abbreviated DAPT in high-bleeding-risk patients, but definite evidence for this has been lacking until now. This study tells us that just 1 month of DAPT appears to be safe in that there was no increase in ischemic complications and there was a clear reduction in bleeding.”

The MASTER DAPT study involved 4,579 patients at high bleeding risk who had undergone implantation of a biodegradable-polymer sirolimus-eluting coronary stent (Ultimaster, Terumo). Around half the patients had PCI for acute coronary syndrome (ACS) and half had it electively. One month after PCI they were randomly assigned to discontinue DAPT immediately (abbreviated therapy) or to continue it for at least 2 additional months (standard therapy).

The three co-primary outcomes were net adverse clinical events (a composite of death from any cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (a composite of death from any cause, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding, all assessed cumulatively at 335 days. The first two outcomes were assessed for noninferiority in the per-protocol population, and the third outcome for superiority in the intention-to-treat population.

Dual antiplatelet therapy consisted of aspirin plus a P2Y12 inhibitor. The choices of the type of P2Y12 inhibitor for DAPT and the type of monotherapy after the discontinuation of DAPT were at the discretion of the investigator. Clopidogrel was the most popular choice, used as monotherapy in 54% of the patients in the abbreviated-therapy group and as part of DAPT in 79% of patients in the standard-therapy group.

Results showed that net adverse clinical events occurred in 7.5% of the abbreviated-therapy group and in 7.7% of the standard-therapy group (difference, –0.23 percentage points; 95% confidence interval, –1.80 to 1.33 percentage points; P < .001 for noninferiority).

Major adverse cardiac or cerebral events occurred in 6.1% of the abbreviated-therapy group and 5.9% of standard therapy group (difference, 0.11 percentage points; 95% CI, –1.29 to 1.51 percentage points; P = .001 for noninferiority).

Reduction in bleeding driven by BARC-2

Major bleeding or clinically relevant nonmajor bleeding occurred in 6.5% in the abbreviated-therapy group and in 9.4% in the standard-therapy group (difference, –2.82 percentage points; 95% CI, –4.40 to –1.24 percentage points; P < .001 for superiority).

“This is a highly statistically significant reduction in bleeding giving a number needed to treat of 35,” Dr. Valgimigli said.

The lower risk for bleeding in the abbreviated-therapy group was mainly due to the lower incidence of clinically relevant nonmajor bleeding events (BARC type 2) in this group than in the standard-therapy group (4.5% vs. 6.8%).

During the discussion, Dr. Byrne pointed out that the most serious type of bleeding (BARC type 3-5) was not reduced in the abbreviated DAPT group.

Dr. Valgimigli responded that the investigators were surprised about that because previous studies indicated that this most serious bleeding would be reduced, but he suggested that this may be explained by the standard group receiving 3-6 months of DAPT rather than a year or more in previous studies. “Having said that, BARC-2 bleeding is not a trivial event,” he added.
 

Can results be applied to other stents?

Dr. Byrne also questioned whether the results can be applied to patients receiving other types of stents – not just Ultimaster, which is not available everywhere. Dr. Valgimigli highlighted the low rate of stent thrombosis seen with the Ultimaster stent and said, “I would be scared to assume these results are reproducible with other stents.”

But Dr. Mehran challenged this view, saying, “I’m not so sure about that. I think we can probably extrapolate.”

In an interview, Dr. Mehran added: “I think this is one of the much-needed studies in our field. For the first time, we have a randomized trial on duration of DAPT in high-bleeding-risk patients. The study was inclusive, and enrolled truly high-bleeding-risk patients, including those on oral anticoagulants.  

“These results show that, although high-bleeding-risk patients are at high risk of ischemic events, just 1 month of DAPT works well for them regardless, by reducing bleeding, net adverse clinical events, and without increasing ischemic events,” she concluded.

In an editorial accompanying the publication, E. Magnus Ohman, MB, from Duke University, Durham, N.C., pointed out the wide CIs in the results, which he said introduced some uncertainly to the findings.

But he concluded that: “The findings of Dr. Valgimigli and colleagues are important and move us toward a shorter and simpler antithrombotic strategy after PCI.”

In an interview, Dr. Ohman pointed out that the Ultimaster stent is not available in the United States. “We have to think about whether this stent would perform differently to other third- or fourth-generation stents. I wouldn’t have thought so, but it is hard to say for sure.

“All in all, we are looking at shorter periods of DAPT now after PCI. Several trials have now suggested that is the way to go. The forthcoming U.S. PCI guidelines should put all the studies together and come up with recommendations on different patient groups,” he concluded.  

Several commentators said they would like to see the data on the patients receiving oral anticoagulants in the study before making firm conclusions on how to translate the results into clinical practice. “This is such an important group. It is difficult to interpret the results without this data,” Dr. Ohman noted.  Patients receiving oral anticoagulants, who made up 36% of the study population, will be the subject of a separate report to be presented at the ESC meeting.

The MASTER DAPT trial was supported by Terumo. Dr. Valgimigli reports research grants from Terumo, Abbott, and SMT and consulting or speaker fees from Terumo, Abbott, Daiichi Sankyo, Chiesi, Vesalio, Vifor, Avimedica, Medtronic, Boston Scientific, and AstraZeneca. Dr. Ohman reports grants from Abiomed, grants from Chiesi USA, personal fees from Cara Therapeutics, Genentech, Imbria, Impulse Dynamics, Milestone Pharmaceuticals, XyloCor, Cytokinetics, Dispersol, Otsuka, Pfizer, Cytosorbents, Neurocrine, and Paradigm, outside the submitted work.

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

Another trial has added to the movement toward shortening the duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI).

MDedge News

In the MASTER DAPT trial involving patients at high risk for bleeding who had undergone implantation of a biodegradable-polymer sirolimus-eluting stent, switching from DAPT to single antiplatelet therapy at a median of 34 days after PCI was noninferior to the continuation of DAPT treatment for a median duration of 193 days with regard to the incidence of major adverse cardiac or cerebral events, and was associated with a lower incidence of major or clinically relevant bleeding.

The results of the study were presented by Marco Valgimigli, MD, Cardiocentro Ticino Institute, Lugano, Switzerland, on Aug. 28 at the virtual European Society of Cardiology (ESC) Congress 2021. They were simultaneously published online in the New England Journal of Medicine.

“It has been suggested in previous studies that if patients are at high bleeding risk, then they do not seem to derive ischemic benefit from prolonging DAPT, they just get the increased bleeding risk,” Dr. Valgimigli said. “But this has never been prospectively tested until now.”

He pointed out that patients at high bleeding risk are a large group, representing up to 40% of patients undergoing PCI, and the MASTER DAPT trial included “all-comer” high-bleeding-risk patients with no selection based on ischemic risk.

M. Alexander Otto, MDedge News

The trial was very well received by commentators at the ESC Hot Line presentation.

Chair of the session, Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, described the trial as “practice-changing.”

And Robert Byrne, MD, Mater Private Hospital, Dublin, added: “This is a standout trial. We have become more comfortable with abbreviated DAPT in high-bleeding-risk patients, but definite evidence for this has been lacking until now. This study tells us that just 1 month of DAPT appears to be safe in that there was no increase in ischemic complications and there was a clear reduction in bleeding.”

The MASTER DAPT study involved 4,579 patients at high bleeding risk who had undergone implantation of a biodegradable-polymer sirolimus-eluting coronary stent (Ultimaster, Terumo). Around half the patients had PCI for acute coronary syndrome (ACS) and half had it electively. One month after PCI they were randomly assigned to discontinue DAPT immediately (abbreviated therapy) or to continue it for at least 2 additional months (standard therapy).

The three co-primary outcomes were net adverse clinical events (a composite of death from any cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (a composite of death from any cause, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding, all assessed cumulatively at 335 days. The first two outcomes were assessed for noninferiority in the per-protocol population, and the third outcome for superiority in the intention-to-treat population.

Dual antiplatelet therapy consisted of aspirin plus a P2Y12 inhibitor. The choices of the type of P2Y12 inhibitor for DAPT and the type of monotherapy after the discontinuation of DAPT were at the discretion of the investigator. Clopidogrel was the most popular choice, used as monotherapy in 54% of the patients in the abbreviated-therapy group and as part of DAPT in 79% of patients in the standard-therapy group.

Results showed that net adverse clinical events occurred in 7.5% of the abbreviated-therapy group and in 7.7% of the standard-therapy group (difference, –0.23 percentage points; 95% confidence interval, –1.80 to 1.33 percentage points; P < .001 for noninferiority).

Major adverse cardiac or cerebral events occurred in 6.1% of the abbreviated-therapy group and 5.9% of standard therapy group (difference, 0.11 percentage points; 95% CI, –1.29 to 1.51 percentage points; P = .001 for noninferiority).

Reduction in bleeding driven by BARC-2

Major bleeding or clinically relevant nonmajor bleeding occurred in 6.5% in the abbreviated-therapy group and in 9.4% in the standard-therapy group (difference, –2.82 percentage points; 95% CI, –4.40 to –1.24 percentage points; P < .001 for superiority).

“This is a highly statistically significant reduction in bleeding giving a number needed to treat of 35,” Dr. Valgimigli said.

The lower risk for bleeding in the abbreviated-therapy group was mainly due to the lower incidence of clinically relevant nonmajor bleeding events (BARC type 2) in this group than in the standard-therapy group (4.5% vs. 6.8%).

During the discussion, Dr. Byrne pointed out that the most serious type of bleeding (BARC type 3-5) was not reduced in the abbreviated DAPT group.

Dr. Valgimigli responded that the investigators were surprised about that because previous studies indicated that this most serious bleeding would be reduced, but he suggested that this may be explained by the standard group receiving 3-6 months of DAPT rather than a year or more in previous studies. “Having said that, BARC-2 bleeding is not a trivial event,” he added.
 

Can results be applied to other stents?

Dr. Byrne also questioned whether the results can be applied to patients receiving other types of stents – not just Ultimaster, which is not available everywhere. Dr. Valgimigli highlighted the low rate of stent thrombosis seen with the Ultimaster stent and said, “I would be scared to assume these results are reproducible with other stents.”

But Dr. Mehran challenged this view, saying, “I’m not so sure about that. I think we can probably extrapolate.”

In an interview, Dr. Mehran added: “I think this is one of the much-needed studies in our field. For the first time, we have a randomized trial on duration of DAPT in high-bleeding-risk patients. The study was inclusive, and enrolled truly high-bleeding-risk patients, including those on oral anticoagulants.  

“These results show that, although high-bleeding-risk patients are at high risk of ischemic events, just 1 month of DAPT works well for them regardless, by reducing bleeding, net adverse clinical events, and without increasing ischemic events,” she concluded.

In an editorial accompanying the publication, E. Magnus Ohman, MB, from Duke University, Durham, N.C., pointed out the wide CIs in the results, which he said introduced some uncertainly to the findings.

But he concluded that: “The findings of Dr. Valgimigli and colleagues are important and move us toward a shorter and simpler antithrombotic strategy after PCI.”

In an interview, Dr. Ohman pointed out that the Ultimaster stent is not available in the United States. “We have to think about whether this stent would perform differently to other third- or fourth-generation stents. I wouldn’t have thought so, but it is hard to say for sure.

“All in all, we are looking at shorter periods of DAPT now after PCI. Several trials have now suggested that is the way to go. The forthcoming U.S. PCI guidelines should put all the studies together and come up with recommendations on different patient groups,” he concluded.  

Several commentators said they would like to see the data on the patients receiving oral anticoagulants in the study before making firm conclusions on how to translate the results into clinical practice. “This is such an important group. It is difficult to interpret the results without this data,” Dr. Ohman noted.  Patients receiving oral anticoagulants, who made up 36% of the study population, will be the subject of a separate report to be presented at the ESC meeting.

The MASTER DAPT trial was supported by Terumo. Dr. Valgimigli reports research grants from Terumo, Abbott, and SMT and consulting or speaker fees from Terumo, Abbott, Daiichi Sankyo, Chiesi, Vesalio, Vifor, Avimedica, Medtronic, Boston Scientific, and AstraZeneca. Dr. Ohman reports grants from Abiomed, grants from Chiesi USA, personal fees from Cara Therapeutics, Genentech, Imbria, Impulse Dynamics, Milestone Pharmaceuticals, XyloCor, Cytokinetics, Dispersol, Otsuka, Pfizer, Cytosorbents, Neurocrine, and Paradigm, outside the submitted work.

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

There will be so much more to the annual congress of the European Society of Cardiology, which begins Aug. 27 with an all-virtual format, than detailed primary results of EMPEROR-Preserved, a trial that could mark a turning point for heart failure (HF) medical therapy.

Also among the featured Hot Line and Late-Breaking Science sessions are – along with many other studies – explorations of arrhythmia management (ablation or guided by loop recorder); secondary prevention, including by vaccination; oral anticoagulation, notably after transcatheter valve procedures; and colchicine or thrombosis prophylaxis in hospitalized patients with COVID-19.

There will even be a head-to-head comparison of two long-familiar left atrial appendage (LAA) occluders, and a population-based, randomized trial of sodium restriction through wide-scale use of a potassium-based salt substitute.

The congress will also introduce four guideline documents at sessions throughout the Congress, one on each day. They cover new and modified recommendations for heart failure; pacing, including cardiac resynchronization therapy (CRT); cardiovascular (CV) disease prevention; and, with cosponsorship from the European Association for Cardio-Thoracic Surgery, valvular heart disease.
 

The virtues of virtual

That next year’s Congress is slated for Aug. 27-30 in Barcelona should be welcome news for anyone whose “what if” curiosity about all-virtual conferences has already been satisfied. But with experience comes wisdom, as the medical societies have learned that online scientific meetings have some winning qualities that may be worth keeping, as least for a while.

“I think there is no doubt that the digital format will continue, for several reasons. One is that this pandemic is not over,” ESC Congress program committee chair Stephan Windecker, MD, Bern (Switzerland) University Hospital, , told this news organization. “As long as it is not over, the digital format is here to stay.”

But it also appears that people who haven’t been able to attend the congress in person are keen to log in and engage online, Dr. Windecker said. The 2020 all-virtual conference drew a much younger pool of registrants, on average, than did the live conferences before the pandemic.

“I think that’s an indication of people that may be in training, in early stages of their career, or they don’t have the support from departments or from their practice, or other financial means.” But they are able to participate via computer, tablet, or smartphone, he said.

“Another advantage is that the recorded content can be replayed at the convenience of whoever wants to consume it at a later point in time,” he added. “Those are just some examples why the digital format is likely to stay,” on its own or in a new age of hybrid meetings.  
 

New and updated guidelines

Leading off the guideline series is the document on diagnosis and treatment of acute and chronic HF, which leveraged the past few busy years of HF clinical trials to arrive at a number of new recommendations and strengthened level-of-evidence ratings. It covers both drug and device therapy of HF with reduced ejection fraction (HFrEF) and acute decompensated HF, and tweaks and further enshrines the concept of HF with mildly reduced ejection fraction (HFmrEF).

Several updated recommendations for both long-used and novel medications, notably the sodium-glucose cotransporter 2 inhibitors, will be included because of the recently appreciated evidence-based impact in HFrEF, Dr. Windecker noted.

“I think it will be particularly interesting to look for the SGLT2 inhibitors as not a completely new class of drugs, but certainly one where there has been a lot of new evidence, to look at how those drugs will be integrated in the overall care pathway.”

A top-line preview of the new HF guideline limited to drug therapy, presented at July’s Heart Failure Association of the European Society of Cardiology (ESC-HFA), provided a simple answer to a common question in the new, bountiful age of HFrEF medications: Which meds, initiated in what order?

As it happens, the new recommendation for first-line HFrEF drug therapy is not a silver bullet, but a shotgun – prompt initiation of at least four meds, one from each of four drug classes: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2 inhibitors. Each class, as described in the document, is to be started as soon as safely feasible, in a sequence deemed appropriate for each individual patient.
 

Spotlight on EMPEROR-Preserved

The world already knows that the trial, which tested the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on top of standard therapy, “met” its primary endpoint in almost 6,000 patients with HF with preserved ejection fraction (HFpEF), who included some with HFmrEF by more contemporary definitions.

That means patients in EMPEROR-Preserved assigned to take empagliflozin showed significantly fewer events that made up the study’s primary endpoint, a composite of CV death or HF hospitalization. It appears to be the first clearly significant overall medical therapy benefit for a clinical primary endpoint in a major randomized HFpEF drug trial.

And that, pending fuller presentation of trial results at the Congress on Aug. 27, could be a huge deal for the half of HF patients with left ventricular ejection fractions (LVEF) higher than the HFrEF range.

Those early top-line results weren’t a decisive bombshell for a field now filled with hope for a practice-changing empagliflozin outcome in EMPEROR-Preserved, which isn’t a certainty. They were more like the “boom” of a mortar launching a rocket of fireworks that may explode into a chrysanthemum or green comet or, sometimes, turn out to be no more than a dud. The promise of the early cursory results critically depends on further details.

“Provided there is a compelling benefit, this is what everyone has been waiting for in this condition for decades,” Mikhail N. Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said.

“Already knowing that the trial met the primary endpoint is obviously very intriguing and encouraging,” he added. “But there are things we don’t know, such as: What is the magnitude of benefit? And whether that benefit, whatever the magnitude, is driven by reductions in both heart failure hospitalizations and cardiovascular death, or only one of the two.”

For example: “If we see an impressive benefit for reduction of hospitalizations, but not a significant reduction in death, that would still be a huge advance. That’s because, to date, we don’t have any drug for HFpEF that has convincingly demonstrated a compelling reduction in heart failure hospitalization or improvement in symptoms, function, or quality of life,” observed Dr. Kosiborod, who wasn’t part of EMPEROR-Preserved.

There have been “suggestions” from HFrEF trials that empagliflozin and dapagliflozin (Farxiga, AstraZeneca) “have very comparable effects on at least the endpoint of cardiovascular death or hospitalization for heart failure,” he said. “So, my expectation would be that whatever is observed in EMPEROR-Preserved is likely a class effect, as well.”

Following EMPEROR-Preserved on the agenda is EMPEROR-Pooled, a patient-level combined analysis of the EMPEROR series of trials that spans the range of HF, regardless of ejection fraction or diabetes status, primarily exploring the effects of empagliflozin on renal function.
 

Other offerings, Friday, Aug. 27

Scheduled immediately after EMPEROR-Preserved is a presentation on the SMART-MI trial, which should clarify whether management guided by continuous ambulatory monitoring is effective in patients considered at especially high arrhythmic risk. Entry called for recent myocardial infarction and an LVEF of 36%-50% with evidence of cardiac autonomic dysfunction.

The trial randomly assigned 400 such patients to be or not be implanted with a Reveal LINQ (Medtronic) loop recorder and followed them for up to 18 months, primarily for detection of potentially serious arrhythmic events. Endpoints that involved mortality, hospitalization or other clinical events were secondary.

In a time slot preceding both SMART-MI and EMPEROR-Preserved, the GUIDE-HF trial is following a projected 3,600 patients with HF implanted with a CardioMEMS HF System (Abbott) pulmonary artery (PA) pressure sensor to explore the its value for guiding management.

The trial’s three cohorts, followed for at least 12 months, include randomized sensor-monitored and control groups of patients with New York Heart Association class 2-4 symptoms, as well as a third observational set of patients in NYHA class 3. That’s the indication for which the CardioMEMS monitor gained approval in the United States in 2014 based on the 2011 CHAMPION trial, and which fared just as well in the 2017 CHAMPION Post-Approval Study.

The Friday Hot Lines also include Dal-GenE, which has entered about 6,000 patients with recent MI to test the once-abandoned cholesterol ester transfer protein (CETP) inhibitor dalcetrapib (DalCor) for any secondary-prevention benefits when used selectively. The trial’s hook: All its patients are confirmed to have the AA genotype of the rs1967309 variant in the ADCY9 gene, which has been associated with a pronounced clinical response to CETP inhibition.

Saturday, Aug. 28

The direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in patients with nonvalvular atrial fibrillation (AFib). But whether DOACs are similarly preferable in the growing world population of people who have undergone transcatheter aortic valve replacement (TAVR or TAVI), an issue explored with variable results in the ATLANTIS and GALILEO trials, is far from settled.

The ENVISAGE-TAVI AF trial explored the question for the factor X inhibitor edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) in 1,400 patients with AFib and a transfemoral TAVR in the previous 5 days, who were randomly assigned to the DOAC or standard management along with discretionary antiplatelet therapy. They’ve been followed for up to 3 years for a composite endpoint of clinical events – including death, MI, and stroke – and for major bleeding.

The day will also feature MASTER DAPT, a comparison of two dual-antiplatelet therapy (DAPT) regimens in an estimated 4,300 patients considered to be high-risk for bleeding who had received the sirolimus-eluting Ultimaster (Terumo) coronary stent, which has a bioresorbable polymer coating.

Investigators have randomly assigned patients to receive either very-short-duration DAPT, for about a month after stenting, followed by a P2Y12 inhibitor alone for up to a year after the procedure; or a more conventional regimen of a P2Y12 inhibitor for 6-12 months with aspirin maintained for a total of 12 months.

Later that day, investigators from the FIGARO-DKD trial will present their results based on 7,437 patients with type 2 diabetes and chronic kidney disease (CKD), a much fuller version than the top-line findings announced by sponsor Bayer 3 months ago.

Those top-line results suggested that patients assigned to receive the nonsteroidal nonselective mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) on top of standard care benefited with a drop in risk for the primary endpoint of CV death or nonfatal CV events.

Finerenone was recently approved in the United States for treating patients with both type 2 diabetes and CKD based on the published FIDELIO-DKD trial, which had seen less CKD progression and fewer CV events in such patients who took the novel MRA.

Although similar in design to FIGARO-DKD, FIDELIO-DKD had entered fewer patients with early-stage diabetic kidney disease (DKD). That led researchers to pool the two trials’ populations to create a cohort that spans the spectrum of DKD severity. An analysis of the pooled cohort, dubbed FIDELITY, is on the schedule after FIGARO-DKD.

After FIDELITY is the prospective APAF-CRT trial that is following a projected 1,830 patients with permanent, symptomatic AFib and a recent hospitalization for AFib or HF and who were not good candidates for standard ablation. They were assigned to receive either atrioventricular junctional ablation followed by CRT, with or without a defibrillation, on top of optimal meds – a so-called “ablate-and-pace” strategy – or an implantable cardioverter defibrillator with rate-control drug therapy.

The new analysis represents the trial’s second phase in which mortality was followed for 4 years as the primary endpoint, in contrast to the previously reported initial phase that followed the first 102 patients for 2 years for the composite primary endpoint of death, worsening HF, and HF hospitalization. The first phase had halted enrollment before reaching its planned target of 280 patients after an interim analysis showed a significant benefit for ablate and pace. 

Next up: DECAAF 2, a randomized assessment of whether catheter ablation for AFib guided by delayed gadolinium enhancement on MRI, a proxy for scar tissue, can be more effective than standard AFib ablation by pulmonary vein isolation alone. An estimated 900 patients with persistent AFib who had never before undergone ablation for the arrhythmia were randomly assigned to one strategy or the other and followed for AFib recurrence over 18 months.
 

Sunday, Aug. 29

The TOMAHAWK trial aimed to clarify the optimal timing of invasive coronary angiography for resuscitated patients with non–ST-segment elevation out-of-hospital cardiac arrest, a broad population in a setting for which there is little randomized-trial guidance. Investigators randomly assigned 558 such patients to undergo immediate invasive angiography or to direct intensive care unit admission for initial standard care with discretionary delayed angiography. Patients were followed for all-cause mortality, with other clinical events and neurologic outcomes as secondary endpoints.

Next on the schedule, the RIPCORD-2 trial randomly assigned 1,100 patients with stable known or suspected coronary artery disease (CAD) to undergo conventional angiography alone or with added direct pressure-wire measurement of fractional flow reserve to guide management decisions. Primary outcomes include health care costs and patient-reported quality of life at 1 year.

Slated for later that day, the Asymptomatic Carotid Surgery Trial-2 (ACST-2) has entered an estimated 3600 patients with a substantial carotid artery narrowing not associated with symptoms but for which either carotid endarterectomy (CEA) or carotid artery stenting (CAS) was considered anatomically feasible. There also must have been “substantial uncertainty” regarding the optimal procedure choice.

The trial, conducted in 40 countries primarily in Europe and North America and launched in 2008, randomly assigned the patients to undergo either CEA or CAS, in both cases with appropriate medical therapy, and followed them for periprocedural events and up to 10 years for strokes and stroke-related events.

The LOOP study, which is to directly follow ACST-2, has explored whether screening for AFib using the Medtronic Reveal LINQ monitor in older patients with non-AFib stroke risk factors – with oral anticoagulation prescribed for those who test positive – can lower their risk for stroke or systemic embolism. It randomly assigned 6,000 such patients to care guided by the loop recorder or to standard care.

On a somewhat larger scale, the Salt Substitute and Stroke Study (SSaSS) randomly assigned a total of 20,996 people in about 600 villages across northern China and Tibet to sodium-restriction intervention and control groups by village. All participants had a history of stroke or were aged at least 60 years with uncontrolled hypertension.

As described by the trial’s online portal, participants in villages assigned to the intervention group were given a supply of a low-sodium, potassium-supplementing salt substitute to replace their own salt supplies, along with education on the health benefits of sodium restriction. Participants in control villages continued their normal diets and, at the trial’s beginning, received “advice to reduce their salt intake.” All were required to own a telephone.

Clinical events, including strokes and hospitalizations throughout a 5-year follow-up, were tracked by phone calls made to all participants every 6 months and were documented at follow-up home visits.

Sunday is also to feature a Late-Breaking Trials session with a focus on COVID-19, which leads off with COLCOVID, a test of colchicine in patients hospitalized for suspected SARS-CoV-2 infection and in acute respiratory distress.

The 1,279 participants in Argentina were randomly assigned to receive or not receive the potent anti-inflammatory agent on top of antivirals and other standard management and followed for death or new need for mechanical ventilation. A successful outcome would contrast with the RECOVERY trial, which terminated a colchicine group of patients hospitalized with COVID-19 because of a lack of efficacy earlier this year.

COLCOVID is to be followed by the MICHELLE trial of rivaroxaban (Xarelto, Bayer/Janssen) prophylaxis, compared with no preventive oral anticoagulant, in 320 patients who, when hospitalized with COVID-19, had been on parenteral anticoagulants because of an elevated risk for venous thromboembolism. The trial, conducted in Brazil, called for postdischarge rivaroxaban at a once-daily dosage of 10 mg for about 1 month.

The session also includes a presentation called “Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial,” the primary outcomes of which will be reported on the first day of the Congress.

Following is a presentation on the PREPARE-IT study of icosapent ethyl (Vascepa, Amarin), given at high dosages intended to be anti-inflammatory, compared with placebo, in an estimated 4,000 adults. The trial has two groups: A prevention group of adults living and circulating in the community; and a treatment group of patients aged at least 40 years with confirmed symptomatic SARS-CoV-2 infection for whom the need for hospitalization isn’t clear.
 

Monday, Aug. 30

The final day of the Congress features a trial called Influenza Vaccination after Myocardial Infarction (IAMI), which has tested the secondary preventive effect of influenza vaccination by randomly assigning 2,571 patients to receive a standard vaccine or a saline placebo injection on one occasion.

Entry to the international trial called for a diagnosis of MI with or without ST-segment elevation, or stable CAD and age at least 75 years with other risk factors. The patients were followed for death, MI, stent thrombosis, and a slew of secondary endpoints over 12 months.

Monday offerings continue later in a time block leading off with the STEP trial, which has randomly assigned an estimated 8,000 patients at 40 centers in China who are 60 to 80 years of age with a systolic blood pressure of 140 to <190 mm Hg to be on standard guideline-based therapy or an intensive drug-management strategy.

The systolic BP goals are 130 to <150 mm Hg for standard care and 110 to <130 mm Hg for the intensive regimen. The composite primary endpoint includes death and clinical events related to acute coronary syndromes, HF, revascularization, and stroke.

Following on heels of STEP, the Amulet IDE trial – the first major randomized comparison of two transcatheter LAA closure devices – entered 1,878 patients with nonvalvular AFib who were considered high-risk for bleeding and stroke or systemic embolism.

They were randomly assigned in the noninferiority trial to receive either the AMPLATZER Amulet (Abbott Medical Devices) or the WATCHMAN (Boston Scientific) closure devices and were followed for safety and efficacy for up to 5 years.

Both LAA closure devices, intended to make patients with AFib less reliant on oral anticoagulation, are now available on both sides of the Atlantic – as well as many other countries – after the Amulet’s United States market approval on Aug. 16, based largely on the Amulet IDE trial.

Rounding out the final Hot Line set is one of the latest efforts to show the efficacy and safety of a very short DAPT period after coronary stenting in patients with acute coronary syndromes, the STOPDAPT-2 ACS trial.

The study assigned 3,008 patients in Japan to receive aspirin and clopidogrel for either 1 month or 1 year after implantation with an everolimus-eluting cobalt-chromium stent and followed them for up to 5 years for a composite of MI, CV death, stent thrombosis, stroke, and bleeding.

The trial follows the published STOPDAPT-2 trial that showed superiority for the 1-month DAPT regimen in a predominantly stable-CAD population treated with the same kind of stent.
 

Program structure and format

A total of 15 online channels are to be available in the morning, European time, their schedules running in parallel. Presentations often are prerecorded, but also include live sessions at 8:00 a.m. Central time and 12 p.m. CET (2:00 a.m. and 6:00 a.m. Eastern time) to liven up the channel offerings, Dr. Windecker observed, and to make them more immediate and potentially interactive.

Many of the parallel channels are devoted throughout the Congress to particular silos of cardiology; for example, arrhythmias and device therapy is on channel 3; CAD and acute care is on 5; HF is on 6; and preventive cardiology is on 9.

Other channels swing across different topics from day to day, such as channel 1, which covers COVID-19 topics on the first and third day of the meeting, “advances in science” on day 2, and “digital health, public health, health economics” on day 4.

The focus each day, starting at 2:00 p.m. CET (8:00 a.m. ET) and continuing into the evening in Europe, shifts over to the Prime Time live program, which features the Hot Line and guideline presentations and many of the live abstract presentations.

Dr. Kosiborod, not a researcher with the EMPEROR trials, is chair of the Dapagliflozin in Preserved Ejection Fraction Heart Failure ( PRESERVED-HF ) trial, which is scheduled for presentation at the September 2021 Heart Failure Society of American meeting.

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

There will be so much more to the annual congress of the European Society of Cardiology, which begins Aug. 27 with an all-virtual format, than detailed primary results of EMPEROR-Preserved, a trial that could mark a turning point for heart failure (HF) medical therapy.

Also among the featured Hot Line and Late-Breaking Science sessions are – along with many other studies – explorations of arrhythmia management (ablation or guided by loop recorder); secondary prevention, including by vaccination; oral anticoagulation, notably after transcatheter valve procedures; and colchicine or thrombosis prophylaxis in hospitalized patients with COVID-19.

There will even be a head-to-head comparison of two long-familiar left atrial appendage (LAA) occluders, and a population-based, randomized trial of sodium restriction through wide-scale use of a potassium-based salt substitute.

The congress will also introduce four guideline documents at sessions throughout the Congress, one on each day. They cover new and modified recommendations for heart failure; pacing, including cardiac resynchronization therapy (CRT); cardiovascular (CV) disease prevention; and, with cosponsorship from the European Association for Cardio-Thoracic Surgery, valvular heart disease.
 

The virtues of virtual

That next year’s Congress is slated for Aug. 27-30 in Barcelona should be welcome news for anyone whose “what if” curiosity about all-virtual conferences has already been satisfied. But with experience comes wisdom, as the medical societies have learned that online scientific meetings have some winning qualities that may be worth keeping, as least for a while.

“I think there is no doubt that the digital format will continue, for several reasons. One is that this pandemic is not over,” ESC Congress program committee chair Stephan Windecker, MD, Bern (Switzerland) University Hospital, , told this news organization. “As long as it is not over, the digital format is here to stay.”

But it also appears that people who haven’t been able to attend the congress in person are keen to log in and engage online, Dr. Windecker said. The 2020 all-virtual conference drew a much younger pool of registrants, on average, than did the live conferences before the pandemic.

“I think that’s an indication of people that may be in training, in early stages of their career, or they don’t have the support from departments or from their practice, or other financial means.” But they are able to participate via computer, tablet, or smartphone, he said.

“Another advantage is that the recorded content can be replayed at the convenience of whoever wants to consume it at a later point in time,” he added. “Those are just some examples why the digital format is likely to stay,” on its own or in a new age of hybrid meetings.  
 

New and updated guidelines

Leading off the guideline series is the document on diagnosis and treatment of acute and chronic HF, which leveraged the past few busy years of HF clinical trials to arrive at a number of new recommendations and strengthened level-of-evidence ratings. It covers both drug and device therapy of HF with reduced ejection fraction (HFrEF) and acute decompensated HF, and tweaks and further enshrines the concept of HF with mildly reduced ejection fraction (HFmrEF).

Several updated recommendations for both long-used and novel medications, notably the sodium-glucose cotransporter 2 inhibitors, will be included because of the recently appreciated evidence-based impact in HFrEF, Dr. Windecker noted.

“I think it will be particularly interesting to look for the SGLT2 inhibitors as not a completely new class of drugs, but certainly one where there has been a lot of new evidence, to look at how those drugs will be integrated in the overall care pathway.”

A top-line preview of the new HF guideline limited to drug therapy, presented at July’s Heart Failure Association of the European Society of Cardiology (ESC-HFA), provided a simple answer to a common question in the new, bountiful age of HFrEF medications: Which meds, initiated in what order?

As it happens, the new recommendation for first-line HFrEF drug therapy is not a silver bullet, but a shotgun – prompt initiation of at least four meds, one from each of four drug classes: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2 inhibitors. Each class, as described in the document, is to be started as soon as safely feasible, in a sequence deemed appropriate for each individual patient.
 

Spotlight on EMPEROR-Preserved

The world already knows that the trial, which tested the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on top of standard therapy, “met” its primary endpoint in almost 6,000 patients with HF with preserved ejection fraction (HFpEF), who included some with HFmrEF by more contemporary definitions.

That means patients in EMPEROR-Preserved assigned to take empagliflozin showed significantly fewer events that made up the study’s primary endpoint, a composite of CV death or HF hospitalization. It appears to be the first clearly significant overall medical therapy benefit for a clinical primary endpoint in a major randomized HFpEF drug trial.

And that, pending fuller presentation of trial results at the Congress on Aug. 27, could be a huge deal for the half of HF patients with left ventricular ejection fractions (LVEF) higher than the HFrEF range.

Those early top-line results weren’t a decisive bombshell for a field now filled with hope for a practice-changing empagliflozin outcome in EMPEROR-Preserved, which isn’t a certainty. They were more like the “boom” of a mortar launching a rocket of fireworks that may explode into a chrysanthemum or green comet or, sometimes, turn out to be no more than a dud. The promise of the early cursory results critically depends on further details.

“Provided there is a compelling benefit, this is what everyone has been waiting for in this condition for decades,” Mikhail N. Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said.

“Already knowing that the trial met the primary endpoint is obviously very intriguing and encouraging,” he added. “But there are things we don’t know, such as: What is the magnitude of benefit? And whether that benefit, whatever the magnitude, is driven by reductions in both heart failure hospitalizations and cardiovascular death, or only one of the two.”

For example: “If we see an impressive benefit for reduction of hospitalizations, but not a significant reduction in death, that would still be a huge advance. That’s because, to date, we don’t have any drug for HFpEF that has convincingly demonstrated a compelling reduction in heart failure hospitalization or improvement in symptoms, function, or quality of life,” observed Dr. Kosiborod, who wasn’t part of EMPEROR-Preserved.

There have been “suggestions” from HFrEF trials that empagliflozin and dapagliflozin (Farxiga, AstraZeneca) “have very comparable effects on at least the endpoint of cardiovascular death or hospitalization for heart failure,” he said. “So, my expectation would be that whatever is observed in EMPEROR-Preserved is likely a class effect, as well.”

Following EMPEROR-Preserved on the agenda is EMPEROR-Pooled, a patient-level combined analysis of the EMPEROR series of trials that spans the range of HF, regardless of ejection fraction or diabetes status, primarily exploring the effects of empagliflozin on renal function.
 

Other offerings, Friday, Aug. 27

Scheduled immediately after EMPEROR-Preserved is a presentation on the SMART-MI trial, which should clarify whether management guided by continuous ambulatory monitoring is effective in patients considered at especially high arrhythmic risk. Entry called for recent myocardial infarction and an LVEF of 36%-50% with evidence of cardiac autonomic dysfunction.

The trial randomly assigned 400 such patients to be or not be implanted with a Reveal LINQ (Medtronic) loop recorder and followed them for up to 18 months, primarily for detection of potentially serious arrhythmic events. Endpoints that involved mortality, hospitalization or other clinical events were secondary.

In a time slot preceding both SMART-MI and EMPEROR-Preserved, the GUIDE-HF trial is following a projected 3,600 patients with HF implanted with a CardioMEMS HF System (Abbott) pulmonary artery (PA) pressure sensor to explore the its value for guiding management.

The trial’s three cohorts, followed for at least 12 months, include randomized sensor-monitored and control groups of patients with New York Heart Association class 2-4 symptoms, as well as a third observational set of patients in NYHA class 3. That’s the indication for which the CardioMEMS monitor gained approval in the United States in 2014 based on the 2011 CHAMPION trial, and which fared just as well in the 2017 CHAMPION Post-Approval Study.

The Friday Hot Lines also include Dal-GenE, which has entered about 6,000 patients with recent MI to test the once-abandoned cholesterol ester transfer protein (CETP) inhibitor dalcetrapib (DalCor) for any secondary-prevention benefits when used selectively. The trial’s hook: All its patients are confirmed to have the AA genotype of the rs1967309 variant in the ADCY9 gene, which has been associated with a pronounced clinical response to CETP inhibition.

Saturday, Aug. 28

The direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in patients with nonvalvular atrial fibrillation (AFib). But whether DOACs are similarly preferable in the growing world population of people who have undergone transcatheter aortic valve replacement (TAVR or TAVI), an issue explored with variable results in the ATLANTIS and GALILEO trials, is far from settled.

The ENVISAGE-TAVI AF trial explored the question for the factor X inhibitor edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) in 1,400 patients with AFib and a transfemoral TAVR in the previous 5 days, who were randomly assigned to the DOAC or standard management along with discretionary antiplatelet therapy. They’ve been followed for up to 3 years for a composite endpoint of clinical events – including death, MI, and stroke – and for major bleeding.

The day will also feature MASTER DAPT, a comparison of two dual-antiplatelet therapy (DAPT) regimens in an estimated 4,300 patients considered to be high-risk for bleeding who had received the sirolimus-eluting Ultimaster (Terumo) coronary stent, which has a bioresorbable polymer coating.

Investigators have randomly assigned patients to receive either very-short-duration DAPT, for about a month after stenting, followed by a P2Y12 inhibitor alone for up to a year after the procedure; or a more conventional regimen of a P2Y12 inhibitor for 6-12 months with aspirin maintained for a total of 12 months.

Later that day, investigators from the FIGARO-DKD trial will present their results based on 7,437 patients with type 2 diabetes and chronic kidney disease (CKD), a much fuller version than the top-line findings announced by sponsor Bayer 3 months ago.

Those top-line results suggested that patients assigned to receive the nonsteroidal nonselective mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) on top of standard care benefited with a drop in risk for the primary endpoint of CV death or nonfatal CV events.

Finerenone was recently approved in the United States for treating patients with both type 2 diabetes and CKD based on the published FIDELIO-DKD trial, which had seen less CKD progression and fewer CV events in such patients who took the novel MRA.

Although similar in design to FIGARO-DKD, FIDELIO-DKD had entered fewer patients with early-stage diabetic kidney disease (DKD). That led researchers to pool the two trials’ populations to create a cohort that spans the spectrum of DKD severity. An analysis of the pooled cohort, dubbed FIDELITY, is on the schedule after FIGARO-DKD.

After FIDELITY is the prospective APAF-CRT trial that is following a projected 1,830 patients with permanent, symptomatic AFib and a recent hospitalization for AFib or HF and who were not good candidates for standard ablation. They were assigned to receive either atrioventricular junctional ablation followed by CRT, with or without a defibrillation, on top of optimal meds – a so-called “ablate-and-pace” strategy – or an implantable cardioverter defibrillator with rate-control drug therapy.

The new analysis represents the trial’s second phase in which mortality was followed for 4 years as the primary endpoint, in contrast to the previously reported initial phase that followed the first 102 patients for 2 years for the composite primary endpoint of death, worsening HF, and HF hospitalization. The first phase had halted enrollment before reaching its planned target of 280 patients after an interim analysis showed a significant benefit for ablate and pace. 

Next up: DECAAF 2, a randomized assessment of whether catheter ablation for AFib guided by delayed gadolinium enhancement on MRI, a proxy for scar tissue, can be more effective than standard AFib ablation by pulmonary vein isolation alone. An estimated 900 patients with persistent AFib who had never before undergone ablation for the arrhythmia were randomly assigned to one strategy or the other and followed for AFib recurrence over 18 months.
 

Sunday, Aug. 29

The TOMAHAWK trial aimed to clarify the optimal timing of invasive coronary angiography for resuscitated patients with non–ST-segment elevation out-of-hospital cardiac arrest, a broad population in a setting for which there is little randomized-trial guidance. Investigators randomly assigned 558 such patients to undergo immediate invasive angiography or to direct intensive care unit admission for initial standard care with discretionary delayed angiography. Patients were followed for all-cause mortality, with other clinical events and neurologic outcomes as secondary endpoints.

Next on the schedule, the RIPCORD-2 trial randomly assigned 1,100 patients with stable known or suspected coronary artery disease (CAD) to undergo conventional angiography alone or with added direct pressure-wire measurement of fractional flow reserve to guide management decisions. Primary outcomes include health care costs and patient-reported quality of life at 1 year.

Slated for later that day, the Asymptomatic Carotid Surgery Trial-2 (ACST-2) has entered an estimated 3600 patients with a substantial carotid artery narrowing not associated with symptoms but for which either carotid endarterectomy (CEA) or carotid artery stenting (CAS) was considered anatomically feasible. There also must have been “substantial uncertainty” regarding the optimal procedure choice.

The trial, conducted in 40 countries primarily in Europe and North America and launched in 2008, randomly assigned the patients to undergo either CEA or CAS, in both cases with appropriate medical therapy, and followed them for periprocedural events and up to 10 years for strokes and stroke-related events.

The LOOP study, which is to directly follow ACST-2, has explored whether screening for AFib using the Medtronic Reveal LINQ monitor in older patients with non-AFib stroke risk factors – with oral anticoagulation prescribed for those who test positive – can lower their risk for stroke or systemic embolism. It randomly assigned 6,000 such patients to care guided by the loop recorder or to standard care.

On a somewhat larger scale, the Salt Substitute and Stroke Study (SSaSS) randomly assigned a total of 20,996 people in about 600 villages across northern China and Tibet to sodium-restriction intervention and control groups by village. All participants had a history of stroke or were aged at least 60 years with uncontrolled hypertension.

As described by the trial’s online portal, participants in villages assigned to the intervention group were given a supply of a low-sodium, potassium-supplementing salt substitute to replace their own salt supplies, along with education on the health benefits of sodium restriction. Participants in control villages continued their normal diets and, at the trial’s beginning, received “advice to reduce their salt intake.” All were required to own a telephone.

Clinical events, including strokes and hospitalizations throughout a 5-year follow-up, were tracked by phone calls made to all participants every 6 months and were documented at follow-up home visits.

Sunday is also to feature a Late-Breaking Trials session with a focus on COVID-19, which leads off with COLCOVID, a test of colchicine in patients hospitalized for suspected SARS-CoV-2 infection and in acute respiratory distress.

The 1,279 participants in Argentina were randomly assigned to receive or not receive the potent anti-inflammatory agent on top of antivirals and other standard management and followed for death or new need for mechanical ventilation. A successful outcome would contrast with the RECOVERY trial, which terminated a colchicine group of patients hospitalized with COVID-19 because of a lack of efficacy earlier this year.

COLCOVID is to be followed by the MICHELLE trial of rivaroxaban (Xarelto, Bayer/Janssen) prophylaxis, compared with no preventive oral anticoagulant, in 320 patients who, when hospitalized with COVID-19, had been on parenteral anticoagulants because of an elevated risk for venous thromboembolism. The trial, conducted in Brazil, called for postdischarge rivaroxaban at a once-daily dosage of 10 mg for about 1 month.

The session also includes a presentation called “Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial,” the primary outcomes of which will be reported on the first day of the Congress.

Following is a presentation on the PREPARE-IT study of icosapent ethyl (Vascepa, Amarin), given at high dosages intended to be anti-inflammatory, compared with placebo, in an estimated 4,000 adults. The trial has two groups: A prevention group of adults living and circulating in the community; and a treatment group of patients aged at least 40 years with confirmed symptomatic SARS-CoV-2 infection for whom the need for hospitalization isn’t clear.
 

Monday, Aug. 30

The final day of the Congress features a trial called Influenza Vaccination after Myocardial Infarction (IAMI), which has tested the secondary preventive effect of influenza vaccination by randomly assigning 2,571 patients to receive a standard vaccine or a saline placebo injection on one occasion.

Entry to the international trial called for a diagnosis of MI with or without ST-segment elevation, or stable CAD and age at least 75 years with other risk factors. The patients were followed for death, MI, stent thrombosis, and a slew of secondary endpoints over 12 months.

Monday offerings continue later in a time block leading off with the STEP trial, which has randomly assigned an estimated 8,000 patients at 40 centers in China who are 60 to 80 years of age with a systolic blood pressure of 140 to <190 mm Hg to be on standard guideline-based therapy or an intensive drug-management strategy.

The systolic BP goals are 130 to <150 mm Hg for standard care and 110 to <130 mm Hg for the intensive regimen. The composite primary endpoint includes death and clinical events related to acute coronary syndromes, HF, revascularization, and stroke.

Following on heels of STEP, the Amulet IDE trial – the first major randomized comparison of two transcatheter LAA closure devices – entered 1,878 patients with nonvalvular AFib who were considered high-risk for bleeding and stroke or systemic embolism.

They were randomly assigned in the noninferiority trial to receive either the AMPLATZER Amulet (Abbott Medical Devices) or the WATCHMAN (Boston Scientific) closure devices and were followed for safety and efficacy for up to 5 years.

Both LAA closure devices, intended to make patients with AFib less reliant on oral anticoagulation, are now available on both sides of the Atlantic – as well as many other countries – after the Amulet’s United States market approval on Aug. 16, based largely on the Amulet IDE trial.

Rounding out the final Hot Line set is one of the latest efforts to show the efficacy and safety of a very short DAPT period after coronary stenting in patients with acute coronary syndromes, the STOPDAPT-2 ACS trial.

The study assigned 3,008 patients in Japan to receive aspirin and clopidogrel for either 1 month or 1 year after implantation with an everolimus-eluting cobalt-chromium stent and followed them for up to 5 years for a composite of MI, CV death, stent thrombosis, stroke, and bleeding.

The trial follows the published STOPDAPT-2 trial that showed superiority for the 1-month DAPT regimen in a predominantly stable-CAD population treated with the same kind of stent.
 

Program structure and format

A total of 15 online channels are to be available in the morning, European time, their schedules running in parallel. Presentations often are prerecorded, but also include live sessions at 8:00 a.m. Central time and 12 p.m. CET (2:00 a.m. and 6:00 a.m. Eastern time) to liven up the channel offerings, Dr. Windecker observed, and to make them more immediate and potentially interactive.

Many of the parallel channels are devoted throughout the Congress to particular silos of cardiology; for example, arrhythmias and device therapy is on channel 3; CAD and acute care is on 5; HF is on 6; and preventive cardiology is on 9.

Other channels swing across different topics from day to day, such as channel 1, which covers COVID-19 topics on the first and third day of the meeting, “advances in science” on day 2, and “digital health, public health, health economics” on day 4.

The focus each day, starting at 2:00 p.m. CET (8:00 a.m. ET) and continuing into the evening in Europe, shifts over to the Prime Time live program, which features the Hot Line and guideline presentations and many of the live abstract presentations.

Dr. Kosiborod, not a researcher with the EMPEROR trials, is chair of the Dapagliflozin in Preserved Ejection Fraction Heart Failure ( PRESERVED-HF ) trial, which is scheduled for presentation at the September 2021 Heart Failure Society of American meeting.

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

There will be so much more to the annual congress of the European Society of Cardiology, which begins Aug. 27 with an all-virtual format, than detailed primary results of EMPEROR-Preserved, a trial that could mark a turning point for heart failure (HF) medical therapy.

Also among the featured Hot Line and Late-Breaking Science sessions are – along with many other studies – explorations of arrhythmia management (ablation or guided by loop recorder); secondary prevention, including by vaccination; oral anticoagulation, notably after transcatheter valve procedures; and colchicine or thrombosis prophylaxis in hospitalized patients with COVID-19.

There will even be a head-to-head comparison of two long-familiar left atrial appendage (LAA) occluders, and a population-based, randomized trial of sodium restriction through wide-scale use of a potassium-based salt substitute.

The congress will also introduce four guideline documents at sessions throughout the Congress, one on each day. They cover new and modified recommendations for heart failure; pacing, including cardiac resynchronization therapy (CRT); cardiovascular (CV) disease prevention; and, with cosponsorship from the European Association for Cardio-Thoracic Surgery, valvular heart disease.
 

The virtues of virtual

That next year’s Congress is slated for Aug. 27-30 in Barcelona should be welcome news for anyone whose “what if” curiosity about all-virtual conferences has already been satisfied. But with experience comes wisdom, as the medical societies have learned that online scientific meetings have some winning qualities that may be worth keeping, as least for a while.

“I think there is no doubt that the digital format will continue, for several reasons. One is that this pandemic is not over,” ESC Congress program committee chair Stephan Windecker, MD, Bern (Switzerland) University Hospital, , told this news organization. “As long as it is not over, the digital format is here to stay.”

But it also appears that people who haven’t been able to attend the congress in person are keen to log in and engage online, Dr. Windecker said. The 2020 all-virtual conference drew a much younger pool of registrants, on average, than did the live conferences before the pandemic.

“I think that’s an indication of people that may be in training, in early stages of their career, or they don’t have the support from departments or from their practice, or other financial means.” But they are able to participate via computer, tablet, or smartphone, he said.

“Another advantage is that the recorded content can be replayed at the convenience of whoever wants to consume it at a later point in time,” he added. “Those are just some examples why the digital format is likely to stay,” on its own or in a new age of hybrid meetings.  
 

New and updated guidelines

Leading off the guideline series is the document on diagnosis and treatment of acute and chronic HF, which leveraged the past few busy years of HF clinical trials to arrive at a number of new recommendations and strengthened level-of-evidence ratings. It covers both drug and device therapy of HF with reduced ejection fraction (HFrEF) and acute decompensated HF, and tweaks and further enshrines the concept of HF with mildly reduced ejection fraction (HFmrEF).

Several updated recommendations for both long-used and novel medications, notably the sodium-glucose cotransporter 2 inhibitors, will be included because of the recently appreciated evidence-based impact in HFrEF, Dr. Windecker noted.

“I think it will be particularly interesting to look for the SGLT2 inhibitors as not a completely new class of drugs, but certainly one where there has been a lot of new evidence, to look at how those drugs will be integrated in the overall care pathway.”

A top-line preview of the new HF guideline limited to drug therapy, presented at July’s Heart Failure Association of the European Society of Cardiology (ESC-HFA), provided a simple answer to a common question in the new, bountiful age of HFrEF medications: Which meds, initiated in what order?

As it happens, the new recommendation for first-line HFrEF drug therapy is not a silver bullet, but a shotgun – prompt initiation of at least four meds, one from each of four drug classes: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2 inhibitors. Each class, as described in the document, is to be started as soon as safely feasible, in a sequence deemed appropriate for each individual patient.
 

Spotlight on EMPEROR-Preserved

The world already knows that the trial, which tested the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on top of standard therapy, “met” its primary endpoint in almost 6,000 patients with HF with preserved ejection fraction (HFpEF), who included some with HFmrEF by more contemporary definitions.

That means patients in EMPEROR-Preserved assigned to take empagliflozin showed significantly fewer events that made up the study’s primary endpoint, a composite of CV death or HF hospitalization. It appears to be the first clearly significant overall medical therapy benefit for a clinical primary endpoint in a major randomized HFpEF drug trial.

And that, pending fuller presentation of trial results at the Congress on Aug. 27, could be a huge deal for the half of HF patients with left ventricular ejection fractions (LVEF) higher than the HFrEF range.

Those early top-line results weren’t a decisive bombshell for a field now filled with hope for a practice-changing empagliflozin outcome in EMPEROR-Preserved, which isn’t a certainty. They were more like the “boom” of a mortar launching a rocket of fireworks that may explode into a chrysanthemum or green comet or, sometimes, turn out to be no more than a dud. The promise of the early cursory results critically depends on further details.

“Provided there is a compelling benefit, this is what everyone has been waiting for in this condition for decades,” Mikhail N. Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said.

“Already knowing that the trial met the primary endpoint is obviously very intriguing and encouraging,” he added. “But there are things we don’t know, such as: What is the magnitude of benefit? And whether that benefit, whatever the magnitude, is driven by reductions in both heart failure hospitalizations and cardiovascular death, or only one of the two.”

For example: “If we see an impressive benefit for reduction of hospitalizations, but not a significant reduction in death, that would still be a huge advance. That’s because, to date, we don’t have any drug for HFpEF that has convincingly demonstrated a compelling reduction in heart failure hospitalization or improvement in symptoms, function, or quality of life,” observed Dr. Kosiborod, who wasn’t part of EMPEROR-Preserved.

There have been “suggestions” from HFrEF trials that empagliflozin and dapagliflozin (Farxiga, AstraZeneca) “have very comparable effects on at least the endpoint of cardiovascular death or hospitalization for heart failure,” he said. “So, my expectation would be that whatever is observed in EMPEROR-Preserved is likely a class effect, as well.”

Following EMPEROR-Preserved on the agenda is EMPEROR-Pooled, a patient-level combined analysis of the EMPEROR series of trials that spans the range of HF, regardless of ejection fraction or diabetes status, primarily exploring the effects of empagliflozin on renal function.
 

Other offerings, Friday, Aug. 27

Scheduled immediately after EMPEROR-Preserved is a presentation on the SMART-MI trial, which should clarify whether management guided by continuous ambulatory monitoring is effective in patients considered at especially high arrhythmic risk. Entry called for recent myocardial infarction and an LVEF of 36%-50% with evidence of cardiac autonomic dysfunction.

The trial randomly assigned 400 such patients to be or not be implanted with a Reveal LINQ (Medtronic) loop recorder and followed them for up to 18 months, primarily for detection of potentially serious arrhythmic events. Endpoints that involved mortality, hospitalization or other clinical events were secondary.

In a time slot preceding both SMART-MI and EMPEROR-Preserved, the GUIDE-HF trial is following a projected 3,600 patients with HF implanted with a CardioMEMS HF System (Abbott) pulmonary artery (PA) pressure sensor to explore the its value for guiding management.

The trial’s three cohorts, followed for at least 12 months, include randomized sensor-monitored and control groups of patients with New York Heart Association class 2-4 symptoms, as well as a third observational set of patients in NYHA class 3. That’s the indication for which the CardioMEMS monitor gained approval in the United States in 2014 based on the 2011 CHAMPION trial, and which fared just as well in the 2017 CHAMPION Post-Approval Study.

The Friday Hot Lines also include Dal-GenE, which has entered about 6,000 patients with recent MI to test the once-abandoned cholesterol ester transfer protein (CETP) inhibitor dalcetrapib (DalCor) for any secondary-prevention benefits when used selectively. The trial’s hook: All its patients are confirmed to have the AA genotype of the rs1967309 variant in the ADCY9 gene, which has been associated with a pronounced clinical response to CETP inhibition.

Saturday, Aug. 28

The direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in patients with nonvalvular atrial fibrillation (AFib). But whether DOACs are similarly preferable in the growing world population of people who have undergone transcatheter aortic valve replacement (TAVR or TAVI), an issue explored with variable results in the ATLANTIS and GALILEO trials, is far from settled.

The ENVISAGE-TAVI AF trial explored the question for the factor X inhibitor edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) in 1,400 patients with AFib and a transfemoral TAVR in the previous 5 days, who were randomly assigned to the DOAC or standard management along with discretionary antiplatelet therapy. They’ve been followed for up to 3 years for a composite endpoint of clinical events – including death, MI, and stroke – and for major bleeding.

The day will also feature MASTER DAPT, a comparison of two dual-antiplatelet therapy (DAPT) regimens in an estimated 4,300 patients considered to be high-risk for bleeding who had received the sirolimus-eluting Ultimaster (Terumo) coronary stent, which has a bioresorbable polymer coating.

Investigators have randomly assigned patients to receive either very-short-duration DAPT, for about a month after stenting, followed by a P2Y12 inhibitor alone for up to a year after the procedure; or a more conventional regimen of a P2Y12 inhibitor for 6-12 months with aspirin maintained for a total of 12 months.

Later that day, investigators from the FIGARO-DKD trial will present their results based on 7,437 patients with type 2 diabetes and chronic kidney disease (CKD), a much fuller version than the top-line findings announced by sponsor Bayer 3 months ago.

Those top-line results suggested that patients assigned to receive the nonsteroidal nonselective mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) on top of standard care benefited with a drop in risk for the primary endpoint of CV death or nonfatal CV events.

Finerenone was recently approved in the United States for treating patients with both type 2 diabetes and CKD based on the published FIDELIO-DKD trial, which had seen less CKD progression and fewer CV events in such patients who took the novel MRA.

Although similar in design to FIGARO-DKD, FIDELIO-DKD had entered fewer patients with early-stage diabetic kidney disease (DKD). That led researchers to pool the two trials’ populations to create a cohort that spans the spectrum of DKD severity. An analysis of the pooled cohort, dubbed FIDELITY, is on the schedule after FIGARO-DKD.

After FIDELITY is the prospective APAF-CRT trial that is following a projected 1,830 patients with permanent, symptomatic AFib and a recent hospitalization for AFib or HF and who were not good candidates for standard ablation. They were assigned to receive either atrioventricular junctional ablation followed by CRT, with or without a defibrillation, on top of optimal meds – a so-called “ablate-and-pace” strategy – or an implantable cardioverter defibrillator with rate-control drug therapy.

The new analysis represents the trial’s second phase in which mortality was followed for 4 years as the primary endpoint, in contrast to the previously reported initial phase that followed the first 102 patients for 2 years for the composite primary endpoint of death, worsening HF, and HF hospitalization. The first phase had halted enrollment before reaching its planned target of 280 patients after an interim analysis showed a significant benefit for ablate and pace. 

Next up: DECAAF 2, a randomized assessment of whether catheter ablation for AFib guided by delayed gadolinium enhancement on MRI, a proxy for scar tissue, can be more effective than standard AFib ablation by pulmonary vein isolation alone. An estimated 900 patients with persistent AFib who had never before undergone ablation for the arrhythmia were randomly assigned to one strategy or the other and followed for AFib recurrence over 18 months.
 

Sunday, Aug. 29

The TOMAHAWK trial aimed to clarify the optimal timing of invasive coronary angiography for resuscitated patients with non–ST-segment elevation out-of-hospital cardiac arrest, a broad population in a setting for which there is little randomized-trial guidance. Investigators randomly assigned 558 such patients to undergo immediate invasive angiography or to direct intensive care unit admission for initial standard care with discretionary delayed angiography. Patients were followed for all-cause mortality, with other clinical events and neurologic outcomes as secondary endpoints.

Next on the schedule, the RIPCORD-2 trial randomly assigned 1,100 patients with stable known or suspected coronary artery disease (CAD) to undergo conventional angiography alone or with added direct pressure-wire measurement of fractional flow reserve to guide management decisions. Primary outcomes include health care costs and patient-reported quality of life at 1 year.

Slated for later that day, the Asymptomatic Carotid Surgery Trial-2 (ACST-2) has entered an estimated 3600 patients with a substantial carotid artery narrowing not associated with symptoms but for which either carotid endarterectomy (CEA) or carotid artery stenting (CAS) was considered anatomically feasible. There also must have been “substantial uncertainty” regarding the optimal procedure choice.

The trial, conducted in 40 countries primarily in Europe and North America and launched in 2008, randomly assigned the patients to undergo either CEA or CAS, in both cases with appropriate medical therapy, and followed them for periprocedural events and up to 10 years for strokes and stroke-related events.

The LOOP study, which is to directly follow ACST-2, has explored whether screening for AFib using the Medtronic Reveal LINQ monitor in older patients with non-AFib stroke risk factors – with oral anticoagulation prescribed for those who test positive – can lower their risk for stroke or systemic embolism. It randomly assigned 6,000 such patients to care guided by the loop recorder or to standard care.

On a somewhat larger scale, the Salt Substitute and Stroke Study (SSaSS) randomly assigned a total of 20,996 people in about 600 villages across northern China and Tibet to sodium-restriction intervention and control groups by village. All participants had a history of stroke or were aged at least 60 years with uncontrolled hypertension.

As described by the trial’s online portal, participants in villages assigned to the intervention group were given a supply of a low-sodium, potassium-supplementing salt substitute to replace their own salt supplies, along with education on the health benefits of sodium restriction. Participants in control villages continued their normal diets and, at the trial’s beginning, received “advice to reduce their salt intake.” All were required to own a telephone.

Clinical events, including strokes and hospitalizations throughout a 5-year follow-up, were tracked by phone calls made to all participants every 6 months and were documented at follow-up home visits.

Sunday is also to feature a Late-Breaking Trials session with a focus on COVID-19, which leads off with COLCOVID, a test of colchicine in patients hospitalized for suspected SARS-CoV-2 infection and in acute respiratory distress.

The 1,279 participants in Argentina were randomly assigned to receive or not receive the potent anti-inflammatory agent on top of antivirals and other standard management and followed for death or new need for mechanical ventilation. A successful outcome would contrast with the RECOVERY trial, which terminated a colchicine group of patients hospitalized with COVID-19 because of a lack of efficacy earlier this year.

COLCOVID is to be followed by the MICHELLE trial of rivaroxaban (Xarelto, Bayer/Janssen) prophylaxis, compared with no preventive oral anticoagulant, in 320 patients who, when hospitalized with COVID-19, had been on parenteral anticoagulants because of an elevated risk for venous thromboembolism. The trial, conducted in Brazil, called for postdischarge rivaroxaban at a once-daily dosage of 10 mg for about 1 month.

The session also includes a presentation called “Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial,” the primary outcomes of which will be reported on the first day of the Congress.

Following is a presentation on the PREPARE-IT study of icosapent ethyl (Vascepa, Amarin), given at high dosages intended to be anti-inflammatory, compared with placebo, in an estimated 4,000 adults. The trial has two groups: A prevention group of adults living and circulating in the community; and a treatment group of patients aged at least 40 years with confirmed symptomatic SARS-CoV-2 infection for whom the need for hospitalization isn’t clear.
 

Monday, Aug. 30

The final day of the Congress features a trial called Influenza Vaccination after Myocardial Infarction (IAMI), which has tested the secondary preventive effect of influenza vaccination by randomly assigning 2,571 patients to receive a standard vaccine or a saline placebo injection on one occasion.

Entry to the international trial called for a diagnosis of MI with or without ST-segment elevation, or stable CAD and age at least 75 years with other risk factors. The patients were followed for death, MI, stent thrombosis, and a slew of secondary endpoints over 12 months.

Monday offerings continue later in a time block leading off with the STEP trial, which has randomly assigned an estimated 8,000 patients at 40 centers in China who are 60 to 80 years of age with a systolic blood pressure of 140 to <190 mm Hg to be on standard guideline-based therapy or an intensive drug-management strategy.

The systolic BP goals are 130 to <150 mm Hg for standard care and 110 to <130 mm Hg for the intensive regimen. The composite primary endpoint includes death and clinical events related to acute coronary syndromes, HF, revascularization, and stroke.

Following on heels of STEP, the Amulet IDE trial – the first major randomized comparison of two transcatheter LAA closure devices – entered 1,878 patients with nonvalvular AFib who were considered high-risk for bleeding and stroke or systemic embolism.

They were randomly assigned in the noninferiority trial to receive either the AMPLATZER Amulet (Abbott Medical Devices) or the WATCHMAN (Boston Scientific) closure devices and were followed for safety and efficacy for up to 5 years.

Both LAA closure devices, intended to make patients with AFib less reliant on oral anticoagulation, are now available on both sides of the Atlantic – as well as many other countries – after the Amulet’s United States market approval on Aug. 16, based largely on the Amulet IDE trial.

Rounding out the final Hot Line set is one of the latest efforts to show the efficacy and safety of a very short DAPT period after coronary stenting in patients with acute coronary syndromes, the STOPDAPT-2 ACS trial.

The study assigned 3,008 patients in Japan to receive aspirin and clopidogrel for either 1 month or 1 year after implantation with an everolimus-eluting cobalt-chromium stent and followed them for up to 5 years for a composite of MI, CV death, stent thrombosis, stroke, and bleeding.

The trial follows the published STOPDAPT-2 trial that showed superiority for the 1-month DAPT regimen in a predominantly stable-CAD population treated with the same kind of stent.
 

Program structure and format

A total of 15 online channels are to be available in the morning, European time, their schedules running in parallel. Presentations often are prerecorded, but also include live sessions at 8:00 a.m. Central time and 12 p.m. CET (2:00 a.m. and 6:00 a.m. Eastern time) to liven up the channel offerings, Dr. Windecker observed, and to make them more immediate and potentially interactive.

Many of the parallel channels are devoted throughout the Congress to particular silos of cardiology; for example, arrhythmias and device therapy is on channel 3; CAD and acute care is on 5; HF is on 6; and preventive cardiology is on 9.

Other channels swing across different topics from day to day, such as channel 1, which covers COVID-19 topics on the first and third day of the meeting, “advances in science” on day 2, and “digital health, public health, health economics” on day 4.

The focus each day, starting at 2:00 p.m. CET (8:00 a.m. ET) and continuing into the evening in Europe, shifts over to the Prime Time live program, which features the Hot Line and guideline presentations and many of the live abstract presentations.

Dr. Kosiborod, not a researcher with the EMPEROR trials, is chair of the Dapagliflozin in Preserved Ejection Fraction Heart Failure ( PRESERVED-HF ) trial, which is scheduled for presentation at the September 2021 Heart Failure Society of American meeting.

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

Background: Direct oral anticoagulants have proven to be more efficacious, safe, and easy to use, compared with warfarin, in patients with atrial fibrillation (Afib). An indirect comparison showed apixaban to be more effective and safer than rivaroxaban. But randomized controlled trials and head-to-head comparison data regarding the same have been lacking until now.

This observational study has several limitations including an inability to balance unmeasured confounding factors, both ICD-9 and ICD-10 codes being used for defined outcomes, an inability to account for time-varying confounders for stroke or bleeding, an inability to capture patients from locations other than primary internist and cardiologists, and a shorter follow-up period, compared with that of clinical trials.

Bottom line: In routine practice, apixaban is more effective and safer than rivaroxaban with a lower rate of strokes, systemic embolism, and major bleeding.

Citation: Fralick M et al. Effectiveness and safety of apixaban compared with rivaroxaban for patients with atrial fibrillation in routine practice: a cohort study. Ann Intern Med. 2020 Apr 7. doi: 10.7326/M19-2522.

Dr. Almagdub is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: Direct oral anticoagulants have proven to be more efficacious, safe, and easy to use, compared with warfarin, in patients with atrial fibrillation (Afib). An indirect comparison showed apixaban to be more effective and safer than rivaroxaban. But randomized controlled trials and head-to-head comparison data regarding the same have been lacking until now.

This observational study has several limitations including an inability to balance unmeasured confounding factors, both ICD-9 and ICD-10 codes being used for defined outcomes, an inability to account for time-varying confounders for stroke or bleeding, an inability to capture patients from locations other than primary internist and cardiologists, and a shorter follow-up period, compared with that of clinical trials.

Bottom line: In routine practice, apixaban is more effective and safer than rivaroxaban with a lower rate of strokes, systemic embolism, and major bleeding.

Citation: Fralick M et al. Effectiveness and safety of apixaban compared with rivaroxaban for patients with atrial fibrillation in routine practice: a cohort study. Ann Intern Med. 2020 Apr 7. doi: 10.7326/M19-2522.

Dr. Almagdub is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: Direct oral anticoagulants have proven to be more efficacious, safe, and easy to use, compared with warfarin, in patients with atrial fibrillation (Afib). An indirect comparison showed apixaban to be more effective and safer than rivaroxaban. But randomized controlled trials and head-to-head comparison data regarding the same have been lacking until now.

This observational study has several limitations including an inability to balance unmeasured confounding factors, both ICD-9 and ICD-10 codes being used for defined outcomes, an inability to account for time-varying confounders for stroke or bleeding, an inability to capture patients from locations other than primary internist and cardiologists, and a shorter follow-up period, compared with that of clinical trials.

Bottom line: In routine practice, apixaban is more effective and safer than rivaroxaban with a lower rate of strokes, systemic embolism, and major bleeding.

Citation: Fralick M et al. Effectiveness and safety of apixaban compared with rivaroxaban for patients with atrial fibrillation in routine practice: a cohort study. Ann Intern Med. 2020 Apr 7. doi: 10.7326/M19-2522.

Dr. Almagdub is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

The Food and Drug Administration has approved the Amplatzer Amulet left atrial appendage occluder (Abbott) to treat people with nonvalvular atrial fibrillation who are at increased risk for stroke and systemic embolism.

The Amulet and its competitor, Boston Scientific’s Watchman, are minimally invasive devices used to close off the left atrial appendage (LAA), an area where blood clots tend to form in people with atrial fibrillation.

Amulet uses dual-seal technology to completely and immediately seal the LAA, the company says, whereas the other minimally invasive solution uses a single component to seal the LAA that requires blood-thinning drugs to heal and additional patient monitoring. The Amulet also has the widest range of occluder sizes on the market and is recapturable and repositionable to ensure optimal placement.

“As the world’s population continues to age, we’re seeing a surge in atrial fibrillation cases, and with that comes increased risk of stroke. The approval of Abbott’s Amulet device provides physicians with a treatment option that reduces the risk of stroke and eliminates the need for blood-thinning medication immediately after the procedure, which is incredibly valuable given the bleeding risks associated with these medicines,” Dhanunjaya Lakkireddy, MD, Kansas City Heart Rhythm Institute at HCA Midwest Health, Overland Park, Kan., and principal investigator for the study that led to FDA approval, said in a news release from Abbott.

The FDA approval is supported by findings from the global Amulet IDE trial, a head-to-head comparison of the Amulet and Watchman devices in 1,878 participants with nonvalvular atrial fibrillation. The results will be presented virtually on Aug. 30 at the 2021 annual congress of the European Society of Cardiology.

The Amplatzer Amulet received CE Mark designation in 2013 and is approved for use in more than 80 countries, including in Australia, Canada, and European countries.

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

The Food and Drug Administration has approved the Amplatzer Amulet left atrial appendage occluder (Abbott) to treat people with nonvalvular atrial fibrillation who are at increased risk for stroke and systemic embolism.

The Amulet and its competitor, Boston Scientific’s Watchman, are minimally invasive devices used to close off the left atrial appendage (LAA), an area where blood clots tend to form in people with atrial fibrillation.

Amulet uses dual-seal technology to completely and immediately seal the LAA, the company says, whereas the other minimally invasive solution uses a single component to seal the LAA that requires blood-thinning drugs to heal and additional patient monitoring. The Amulet also has the widest range of occluder sizes on the market and is recapturable and repositionable to ensure optimal placement.

“As the world’s population continues to age, we’re seeing a surge in atrial fibrillation cases, and with that comes increased risk of stroke. The approval of Abbott’s Amulet device provides physicians with a treatment option that reduces the risk of stroke and eliminates the need for blood-thinning medication immediately after the procedure, which is incredibly valuable given the bleeding risks associated with these medicines,” Dhanunjaya Lakkireddy, MD, Kansas City Heart Rhythm Institute at HCA Midwest Health, Overland Park, Kan., and principal investigator for the study that led to FDA approval, said in a news release from Abbott.

The FDA approval is supported by findings from the global Amulet IDE trial, a head-to-head comparison of the Amulet and Watchman devices in 1,878 participants with nonvalvular atrial fibrillation. The results will be presented virtually on Aug. 30 at the 2021 annual congress of the European Society of Cardiology.

The Amplatzer Amulet received CE Mark designation in 2013 and is approved for use in more than 80 countries, including in Australia, Canada, and European countries.

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

The Food and Drug Administration has approved the Amplatzer Amulet left atrial appendage occluder (Abbott) to treat people with nonvalvular atrial fibrillation who are at increased risk for stroke and systemic embolism.

The Amulet and its competitor, Boston Scientific’s Watchman, are minimally invasive devices used to close off the left atrial appendage (LAA), an area where blood clots tend to form in people with atrial fibrillation.

Amulet uses dual-seal technology to completely and immediately seal the LAA, the company says, whereas the other minimally invasive solution uses a single component to seal the LAA that requires blood-thinning drugs to heal and additional patient monitoring. The Amulet also has the widest range of occluder sizes on the market and is recapturable and repositionable to ensure optimal placement.

“As the world’s population continues to age, we’re seeing a surge in atrial fibrillation cases, and with that comes increased risk of stroke. The approval of Abbott’s Amulet device provides physicians with a treatment option that reduces the risk of stroke and eliminates the need for blood-thinning medication immediately after the procedure, which is incredibly valuable given the bleeding risks associated with these medicines,” Dhanunjaya Lakkireddy, MD, Kansas City Heart Rhythm Institute at HCA Midwest Health, Overland Park, Kan., and principal investigator for the study that led to FDA approval, said in a news release from Abbott.

The FDA approval is supported by findings from the global Amulet IDE trial, a head-to-head comparison of the Amulet and Watchman devices in 1,878 participants with nonvalvular atrial fibrillation. The results will be presented virtually on Aug. 30 at the 2021 annual congress of the European Society of Cardiology.

The Amplatzer Amulet received CE Mark designation in 2013 and is approved for use in more than 80 countries, including in Australia, Canada, and European countries.

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

Women have more in-hospital complications than men and double the risk for major adverse events after left atrial appendage occlusion (LAAO) with the Watchman device, according to new National Cardiovascular Data Registry (NCDR) LAAO Registry data.

In-hospital mortality was also twofold higher among women than men and hospital stay was longer. Even after adjustment for potential confounders, these relationships still exist, Douglas Darden, MD, University of California, San Diego, and colleagues reported online in JAMA Cardiology.

“I think this article certainly highlights – specific to a procedure that has gained more popularity and will become more commonplace in cardiovascular practice – that operators and patients need to pay more attention [to the fact] that women may be at more risk for adverse events and mortality,” senior author Jonathan Hsu, MD, also from UCSD, told this news organization.

Possible explanations for the disparities include anatomic differences between the sexes, such as smaller vessel diameter, thinner myocardial wall, and a more friable LLA in women; increased frailty; and clinician inexperience, the authors suggest.

“It could be something as simple or as specific as thinness of tissue or friability of tissue that may predispose women more than men to perforation or other risks that may put them at risk for adverse events specifically,” Dr. Hsu said.

Commenting further, he said, “I think we would be remiss not to mention the fact that part of this association may unfortunately be a disparity in care that women as a specific sex may receive,” he said.

Indeed, postimplantation women had higher adjusted odds of receiving a direct oral anticoagulant only (odds ratio, 1.07, P = .02) and warfarin only (OR, 1.12; P < .001), and lower odds of receiving clinical trial-recommended combined oral anticoagulants plus single antiplatelet therapy (OR, 0.91; P < .001).

“This article highlights the fact that in all aspects we need to pay attention that women receive as high-level, guideline-driven care as men,” Dr. Hsu said.

First author Dr. Darden pointed out in an email that women suffer disproportionately from atrial fibrillation (AFib), compared with men, with worse quality of life and higher risk for stroke. So “it’s only natural to seek further treatment in order to decrease that risk, specifically LAAO with Watchman.”

Despite the fact that women are known to be at greater risk for adverse events after invasive procedures, including AFib ablation and TAVR, little is known about sex differences with LAAO, as the LAAO clinical trials only included about 30% women, he said.

Two 2021 papers zeroing in on these sex differences produced mixed results. An American report in roughly 9,200 patients reported a higher risk for major in-hospital events in women after receipt of Watchman implants, whereas a German report found similar safety and efficacy among 387 consecutive patients, regardless of sex.

The present study involved 20,388 women and 28,969 men implanted with the Watchman device between January 2016 and June 2019 in the NCDR registry, the largest LAAO registry with adjudicated events with participation mandated for Medicare coverage.

The women were older (mean age, 76.5 vs. 75.8 years), had a higher mean CHA2DS2-VASc score (5.3 vs. 4.5), and were more likely to have a high fall risk as an indication for LAAO (39.8% vs. 33.5%).

Furthermore, women were more likely than men to have paroxysmal atrial fibrillation and uncontrolled hypertension, but less likely to have congestive heart failure, diabetes, and coronary artery disease.

After multivariable adjustment, all but one of the primary outcomes was significantly worse in women versus men:

• Aborted or canceled procedure: 3.0% vs. 2.9% (OR, 1.01; P = .87)
• Any adverse event: 6.3% vs. 3.9% (OR, 1.63; P < .001)
• Major adverse event: 4.1% vs. 2.0% (OR, 2.06; P < .001)
• Hospital stay more than 1 day: 16.0% vs. 11.6% (OR, 1.46; P < .001)
• Death: 58/0.3% vs. 37/0.1% (OR, 2.01; P = .001).

The authors point out that device-related adverse events are lower than in the PROTECT-AF and PREVAIL clinical trials of the Watchman, with 0.8% of patients developing a pericardial effusion requiring drainage and 1.2% having major bleeding, down from highs of 4.8% and 3.5%, respectively, in PROTECT-AF.

Although promising overall, adverse events among women were driven by higher rates of both pericardial effusion requiring draining (1.2% vs. 0.5%; P < .001) and major bleeding (1.7% vs. 0.8%; P < .001).

Commenting for this news organization John Mandrola, MD, Baptist Health, Louisville, Kentucky, expressed concern that despite its increasing popularity, the rate of serious complications appears to be increasing for the preventive procedure. “That’s peculiar because you’d expect increased experience and device iterations to decrease complications. And the NCDR data surely undercounts the real rate of adverse events because it only includes in-hospital complications.”

Based on the current data, he observed that there’s a 3% chance for a major complication overall, with the typical female Watchman patient facing a 6% chance of any adverse event and 4% risk for a major adverse event during her hospital stay alone.

“The striking difference in complications in women is a super important observation because higher upfront risk has an even more negative effect on the harm-benefit calculus of this procedure,” Dr. Mandrola said.

“Some of the increased harm in women may have been due to the slightly higher rate of comorbid conditions, but that is real-life,” he said. “Registry data like this is extremely valuable because, unlike the carefully selected randomized trial, registries reflect what is actually being done in practice.”

Dr. Hsu agreed that the absolute numbers are concerning. Nevertheless, “it doesn’t necessarily sound an alarm that our adverse events are worse in contemporary practice or that adverse events continue to increase. But, in general, it just points to the fact that there is this inherent larger risk in women, compared with men, and that we need to, first, figure out why, and second, we need to figure out how to improve.”

Strategies to mitigate procedural risk included ultrasound-guided venous access, preprocedural imaging, improved proficiency with LAAO devices, and continued development of safer devices, they note.

Despite the more generalizable nature of registry data, “the results of this study should not result in differing sex-based thresholds for LAAO implant,” the authors conclude.

The study was supported by the American College of Cardiology Foundation’s NCDR. Dr. Hsu reports financial relationships with Medtronic, Boston Scientific, Abbott, Biotronik, Janssen Pharmaceutical, Bristol Myers Squibb, Pfizer, Biosense Webster, Altathera Pharmaceuticals, and Zoll Medical and holding equity interest in Acutus Medical and Vektor Medical outside the submitted work. Dr. Darden reports no relevant financial relationships. Dr. Mandrola is a regular contributor to Medscape Cardiology.

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

Women have more in-hospital complications than men and double the risk for major adverse events after left atrial appendage occlusion (LAAO) with the Watchman device, according to new National Cardiovascular Data Registry (NCDR) LAAO Registry data.

In-hospital mortality was also twofold higher among women than men and hospital stay was longer. Even after adjustment for potential confounders, these relationships still exist, Douglas Darden, MD, University of California, San Diego, and colleagues reported online in JAMA Cardiology.

“I think this article certainly highlights – specific to a procedure that has gained more popularity and will become more commonplace in cardiovascular practice – that operators and patients need to pay more attention [to the fact] that women may be at more risk for adverse events and mortality,” senior author Jonathan Hsu, MD, also from UCSD, told this news organization.

Possible explanations for the disparities include anatomic differences between the sexes, such as smaller vessel diameter, thinner myocardial wall, and a more friable LLA in women; increased frailty; and clinician inexperience, the authors suggest.

“It could be something as simple or as specific as thinness of tissue or friability of tissue that may predispose women more than men to perforation or other risks that may put them at risk for adverse events specifically,” Dr. Hsu said.

Commenting further, he said, “I think we would be remiss not to mention the fact that part of this association may unfortunately be a disparity in care that women as a specific sex may receive,” he said.

Indeed, postimplantation women had higher adjusted odds of receiving a direct oral anticoagulant only (odds ratio, 1.07, P = .02) and warfarin only (OR, 1.12; P < .001), and lower odds of receiving clinical trial-recommended combined oral anticoagulants plus single antiplatelet therapy (OR, 0.91; P < .001).

“This article highlights the fact that in all aspects we need to pay attention that women receive as high-level, guideline-driven care as men,” Dr. Hsu said.

First author Dr. Darden pointed out in an email that women suffer disproportionately from atrial fibrillation (AFib), compared with men, with worse quality of life and higher risk for stroke. So “it’s only natural to seek further treatment in order to decrease that risk, specifically LAAO with Watchman.”

Despite the fact that women are known to be at greater risk for adverse events after invasive procedures, including AFib ablation and TAVR, little is known about sex differences with LAAO, as the LAAO clinical trials only included about 30% women, he said.

Two 2021 papers zeroing in on these sex differences produced mixed results. An American report in roughly 9,200 patients reported a higher risk for major in-hospital events in women after receipt of Watchman implants, whereas a German report found similar safety and efficacy among 387 consecutive patients, regardless of sex.

The present study involved 20,388 women and 28,969 men implanted with the Watchman device between January 2016 and June 2019 in the NCDR registry, the largest LAAO registry with adjudicated events with participation mandated for Medicare coverage.

The women were older (mean age, 76.5 vs. 75.8 years), had a higher mean CHA2DS2-VASc score (5.3 vs. 4.5), and were more likely to have a high fall risk as an indication for LAAO (39.8% vs. 33.5%).

Furthermore, women were more likely than men to have paroxysmal atrial fibrillation and uncontrolled hypertension, but less likely to have congestive heart failure, diabetes, and coronary artery disease.

After multivariable adjustment, all but one of the primary outcomes was significantly worse in women versus men:

• Aborted or canceled procedure: 3.0% vs. 2.9% (OR, 1.01; P = .87)
• Any adverse event: 6.3% vs. 3.9% (OR, 1.63; P < .001)
• Major adverse event: 4.1% vs. 2.0% (OR, 2.06; P < .001)
• Hospital stay more than 1 day: 16.0% vs. 11.6% (OR, 1.46; P < .001)
• Death: 58/0.3% vs. 37/0.1% (OR, 2.01; P = .001).

The authors point out that device-related adverse events are lower than in the PROTECT-AF and PREVAIL clinical trials of the Watchman, with 0.8% of patients developing a pericardial effusion requiring drainage and 1.2% having major bleeding, down from highs of 4.8% and 3.5%, respectively, in PROTECT-AF.

Although promising overall, adverse events among women were driven by higher rates of both pericardial effusion requiring draining (1.2% vs. 0.5%; P < .001) and major bleeding (1.7% vs. 0.8%; P < .001).

Commenting for this news organization John Mandrola, MD, Baptist Health, Louisville, Kentucky, expressed concern that despite its increasing popularity, the rate of serious complications appears to be increasing for the preventive procedure. “That’s peculiar because you’d expect increased experience and device iterations to decrease complications. And the NCDR data surely undercounts the real rate of adverse events because it only includes in-hospital complications.”

Based on the current data, he observed that there’s a 3% chance for a major complication overall, with the typical female Watchman patient facing a 6% chance of any adverse event and 4% risk for a major adverse event during her hospital stay alone.

“The striking difference in complications in women is a super important observation because higher upfront risk has an even more negative effect on the harm-benefit calculus of this procedure,” Dr. Mandrola said.

“Some of the increased harm in women may have been due to the slightly higher rate of comorbid conditions, but that is real-life,” he said. “Registry data like this is extremely valuable because, unlike the carefully selected randomized trial, registries reflect what is actually being done in practice.”

Dr. Hsu agreed that the absolute numbers are concerning. Nevertheless, “it doesn’t necessarily sound an alarm that our adverse events are worse in contemporary practice or that adverse events continue to increase. But, in general, it just points to the fact that there is this inherent larger risk in women, compared with men, and that we need to, first, figure out why, and second, we need to figure out how to improve.”

Strategies to mitigate procedural risk included ultrasound-guided venous access, preprocedural imaging, improved proficiency with LAAO devices, and continued development of safer devices, they note.

Despite the more generalizable nature of registry data, “the results of this study should not result in differing sex-based thresholds for LAAO implant,” the authors conclude.

The study was supported by the American College of Cardiology Foundation’s NCDR. Dr. Hsu reports financial relationships with Medtronic, Boston Scientific, Abbott, Biotronik, Janssen Pharmaceutical, Bristol Myers Squibb, Pfizer, Biosense Webster, Altathera Pharmaceuticals, and Zoll Medical and holding equity interest in Acutus Medical and Vektor Medical outside the submitted work. Dr. Darden reports no relevant financial relationships. Dr. Mandrola is a regular contributor to Medscape Cardiology.

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

Women have more in-hospital complications than men and double the risk for major adverse events after left atrial appendage occlusion (LAAO) with the Watchman device, according to new National Cardiovascular Data Registry (NCDR) LAAO Registry data.

In-hospital mortality was also twofold higher among women than men and hospital stay was longer. Even after adjustment for potential confounders, these relationships still exist, Douglas Darden, MD, University of California, San Diego, and colleagues reported online in JAMA Cardiology.

“I think this article certainly highlights – specific to a procedure that has gained more popularity and will become more commonplace in cardiovascular practice – that operators and patients need to pay more attention [to the fact] that women may be at more risk for adverse events and mortality,” senior author Jonathan Hsu, MD, also from UCSD, told this news organization.

Possible explanations for the disparities include anatomic differences between the sexes, such as smaller vessel diameter, thinner myocardial wall, and a more friable LLA in women; increased frailty; and clinician inexperience, the authors suggest.

“It could be something as simple or as specific as thinness of tissue or friability of tissue that may predispose women more than men to perforation or other risks that may put them at risk for adverse events specifically,” Dr. Hsu said.

Commenting further, he said, “I think we would be remiss not to mention the fact that part of this association may unfortunately be a disparity in care that women as a specific sex may receive,” he said.

Indeed, postimplantation women had higher adjusted odds of receiving a direct oral anticoagulant only (odds ratio, 1.07, P = .02) and warfarin only (OR, 1.12; P < .001), and lower odds of receiving clinical trial-recommended combined oral anticoagulants plus single antiplatelet therapy (OR, 0.91; P < .001).

“This article highlights the fact that in all aspects we need to pay attention that women receive as high-level, guideline-driven care as men,” Dr. Hsu said.

First author Dr. Darden pointed out in an email that women suffer disproportionately from atrial fibrillation (AFib), compared with men, with worse quality of life and higher risk for stroke. So “it’s only natural to seek further treatment in order to decrease that risk, specifically LAAO with Watchman.”

Despite the fact that women are known to be at greater risk for adverse events after invasive procedures, including AFib ablation and TAVR, little is known about sex differences with LAAO, as the LAAO clinical trials only included about 30% women, he said.

Two 2021 papers zeroing in on these sex differences produced mixed results. An American report in roughly 9,200 patients reported a higher risk for major in-hospital events in women after receipt of Watchman implants, whereas a German report found similar safety and efficacy among 387 consecutive patients, regardless of sex.

The present study involved 20,388 women and 28,969 men implanted with the Watchman device between January 2016 and June 2019 in the NCDR registry, the largest LAAO registry with adjudicated events with participation mandated for Medicare coverage.

The women were older (mean age, 76.5 vs. 75.8 years), had a higher mean CHA2DS2-VASc score (5.3 vs. 4.5), and were more likely to have a high fall risk as an indication for LAAO (39.8% vs. 33.5%).

Furthermore, women were more likely than men to have paroxysmal atrial fibrillation and uncontrolled hypertension, but less likely to have congestive heart failure, diabetes, and coronary artery disease.

After multivariable adjustment, all but one of the primary outcomes was significantly worse in women versus men:

• Aborted or canceled procedure: 3.0% vs. 2.9% (OR, 1.01; P = .87)
• Any adverse event: 6.3% vs. 3.9% (OR, 1.63; P < .001)
• Major adverse event: 4.1% vs. 2.0% (OR, 2.06; P < .001)
• Hospital stay more than 1 day: 16.0% vs. 11.6% (OR, 1.46; P < .001)
• Death: 58/0.3% vs. 37/0.1% (OR, 2.01; P = .001).

The authors point out that device-related adverse events are lower than in the PROTECT-AF and PREVAIL clinical trials of the Watchman, with 0.8% of patients developing a pericardial effusion requiring drainage and 1.2% having major bleeding, down from highs of 4.8% and 3.5%, respectively, in PROTECT-AF.

Although promising overall, adverse events among women were driven by higher rates of both pericardial effusion requiring draining (1.2% vs. 0.5%; P < .001) and major bleeding (1.7% vs. 0.8%; P < .001).

Commenting for this news organization John Mandrola, MD, Baptist Health, Louisville, Kentucky, expressed concern that despite its increasing popularity, the rate of serious complications appears to be increasing for the preventive procedure. “That’s peculiar because you’d expect increased experience and device iterations to decrease complications. And the NCDR data surely undercounts the real rate of adverse events because it only includes in-hospital complications.”

Based on the current data, he observed that there’s a 3% chance for a major complication overall, with the typical female Watchman patient facing a 6% chance of any adverse event and 4% risk for a major adverse event during her hospital stay alone.

“The striking difference in complications in women is a super important observation because higher upfront risk has an even more negative effect on the harm-benefit calculus of this procedure,” Dr. Mandrola said.

“Some of the increased harm in women may have been due to the slightly higher rate of comorbid conditions, but that is real-life,” he said. “Registry data like this is extremely valuable because, unlike the carefully selected randomized trial, registries reflect what is actually being done in practice.”

Dr. Hsu agreed that the absolute numbers are concerning. Nevertheless, “it doesn’t necessarily sound an alarm that our adverse events are worse in contemporary practice or that adverse events continue to increase. But, in general, it just points to the fact that there is this inherent larger risk in women, compared with men, and that we need to, first, figure out why, and second, we need to figure out how to improve.”

Strategies to mitigate procedural risk included ultrasound-guided venous access, preprocedural imaging, improved proficiency with LAAO devices, and continued development of safer devices, they note.

Despite the more generalizable nature of registry data, “the results of this study should not result in differing sex-based thresholds for LAAO implant,” the authors conclude.

The study was supported by the American College of Cardiology Foundation’s NCDR. Dr. Hsu reports financial relationships with Medtronic, Boston Scientific, Abbott, Biotronik, Janssen Pharmaceutical, Bristol Myers Squibb, Pfizer, Biosense Webster, Altathera Pharmaceuticals, and Zoll Medical and holding equity interest in Acutus Medical and Vektor Medical outside the submitted work. Dr. Darden reports no relevant financial relationships. Dr. Mandrola is a regular contributor to Medscape Cardiology.

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