Thrombosis

Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.

The RAPID CABG trial found that early surgery 2-3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding, compared with waiting 5-7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.

Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.

The study was presented at the American Heart Association scientific sessions.

“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator Derek So, MD.

Dr. So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.

A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, Dr. So noted.

Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.

Dr. So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.

Dr. So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”

Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, said this was a “very important study,” being the only randomized trial to look at this issue to date.

Dr. Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”

However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.

 RAPID CABG

RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2-3 days after ticagrelor cessation, compared with a delay of 5-7 days among patients presenting with ACS who required nonemergency CABG surgery.

The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.   

Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.

The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.

Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs. 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12-inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.

The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1,000 mL in the first 12 hours, and reoperation for bleeding.

Results showed that 4.6% of the early-surgery group had a primary outcome bleeding event, compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).

Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.  

In terms of other bleeding outcomes, TIMI CABG bleeding occurred in two patients (3.1%) in the early-surgery group vs. no patients in the delayed group; BARC 4 bleeding occurred in two patients (3.1%) in the early group versus none in the delayed group, and there were no BARC 5 bleeding events in either group.

In the intention-to-treat analysis, ischemic events before surgery occurred in six patients (8.7%) in the delayed group (one myocardial infarction, four cases of recurrent ischemia, and one ventricular tachycardia) versus none in the early group.

Cumulative 6-month ischemic events occurred in nine patients (13.0%) in the delayed group vs. four patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.  

There were no cardiovascular deaths in either group and one all-cause death in both groups.

Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days versus 12 days in the delayed group.

Larger trial needed

Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the cardiac surgery department at Cedars-Sinai Medical Center, Los Angeles, said the results were in line with her practice.

“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.” 

Dr. Chikwe said her top-line message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”

However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.

“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Dr. Chikwe noted.  

She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”

The RAPID CABG study was funded by the Canadian Institutes of Health Research. Dr. So reports research support, consultancy, or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Dr. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).  

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

Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.

The RAPID CABG trial found that early surgery 2-3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding, compared with waiting 5-7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.

Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.

The study was presented at the American Heart Association scientific sessions.

“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator Derek So, MD.

Dr. So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.

A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, Dr. So noted.

Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.

Dr. So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.

Dr. So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”

Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, said this was a “very important study,” being the only randomized trial to look at this issue to date.

Dr. Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”

However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.

 RAPID CABG

RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2-3 days after ticagrelor cessation, compared with a delay of 5-7 days among patients presenting with ACS who required nonemergency CABG surgery.

The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.   

Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.

The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.

Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs. 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12-inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.

The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1,000 mL in the first 12 hours, and reoperation for bleeding.

Results showed that 4.6% of the early-surgery group had a primary outcome bleeding event, compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).

Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.  

In terms of other bleeding outcomes, TIMI CABG bleeding occurred in two patients (3.1%) in the early-surgery group vs. no patients in the delayed group; BARC 4 bleeding occurred in two patients (3.1%) in the early group versus none in the delayed group, and there were no BARC 5 bleeding events in either group.

In the intention-to-treat analysis, ischemic events before surgery occurred in six patients (8.7%) in the delayed group (one myocardial infarction, four cases of recurrent ischemia, and one ventricular tachycardia) versus none in the early group.

Cumulative 6-month ischemic events occurred in nine patients (13.0%) in the delayed group vs. four patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.  

There were no cardiovascular deaths in either group and one all-cause death in both groups.

Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days versus 12 days in the delayed group.

Larger trial needed

Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the cardiac surgery department at Cedars-Sinai Medical Center, Los Angeles, said the results were in line with her practice.

“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.” 

Dr. Chikwe said her top-line message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”

However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.

“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Dr. Chikwe noted.  

She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”

The RAPID CABG study was funded by the Canadian Institutes of Health Research. Dr. So reports research support, consultancy, or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Dr. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).  

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

Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.

The RAPID CABG trial found that early surgery 2-3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding, compared with waiting 5-7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.

Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.

The study was presented at the American Heart Association scientific sessions.

“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator Derek So, MD.

Dr. So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.

A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, Dr. So noted.

Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.

Dr. So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.

Dr. So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”

Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, said this was a “very important study,” being the only randomized trial to look at this issue to date.

Dr. Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”

However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.

 RAPID CABG

RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2-3 days after ticagrelor cessation, compared with a delay of 5-7 days among patients presenting with ACS who required nonemergency CABG surgery.

The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.   

Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.

The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.

Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs. 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12-inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.

The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1,000 mL in the first 12 hours, and reoperation for bleeding.

Results showed that 4.6% of the early-surgery group had a primary outcome bleeding event, compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).

Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.  

In terms of other bleeding outcomes, TIMI CABG bleeding occurred in two patients (3.1%) in the early-surgery group vs. no patients in the delayed group; BARC 4 bleeding occurred in two patients (3.1%) in the early group versus none in the delayed group, and there were no BARC 5 bleeding events in either group.

In the intention-to-treat analysis, ischemic events before surgery occurred in six patients (8.7%) in the delayed group (one myocardial infarction, four cases of recurrent ischemia, and one ventricular tachycardia) versus none in the early group.

Cumulative 6-month ischemic events occurred in nine patients (13.0%) in the delayed group vs. four patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.  

There were no cardiovascular deaths in either group and one all-cause death in both groups.

Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days versus 12 days in the delayed group.

Larger trial needed

Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the cardiac surgery department at Cedars-Sinai Medical Center, Los Angeles, said the results were in line with her practice.

“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.” 

Dr. Chikwe said her top-line message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”

However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.

“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Dr. Chikwe noted.  

She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”

The RAPID CABG study was funded by the Canadian Institutes of Health Research. Dr. So reports research support, consultancy, or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Dr. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).  

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

On the basis of outcomes, there was no clear winner from a trial that directly compared two modern devices used in patients undergoing percutaneous left atrial appendage (LAA) closure.

But the devices were not interchangeable for rates of complications or leaks, according to results of the open-label SWISS APERO trial, which compared the Amplatzer Amulet to the Watchman FLX device at eight participating centers in Europe.

At 45 days, the overall rates of leaks and the clinical outcomes in the two randomized groups were not significantly different, but there were differences in secondary endpoints, such as rates of peridevice leak (PDL), which were lower in the Amulet device group, and procedural complications, which were higher, Roberto Galea, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

LAA closure devices were developed as an alternative to oral anticoagulation in patients with nonvalvular atrial fibrillation. Although a similar comparison of LAA closure devices, called Amulet IDE, was recently published, that trial compared Amulet to Watchman 2.5, an earlier generation device.

Started later, SWISS APERO was also a planned comparison of Amulet and the Watchman 2.5, but the comparison switched to the Watchman FLX, when it was released in March of 2019.
 

First randomized comparison with Watchman FLX

“This is the first multicenter randomized controlled trial to include the Watchman FLX,” said Dr. Galea, a clinical investigator in the department of cardiology, Bern (Switzerland) University Hospital. He noted that Watchman FLX included some adjustments in design with the potential to reduce leak rates.

After preprocedural transesophageal echocardiography confirmed that patients had suitable anatomy to receive either device, the 221 patients who qualified for SWISS APERO were randomized. The primary endpoint was a composite of a justified crossover to a device other than the one to which they were assigned or residual patency detected by coronary computed tomography angiography (CCTA) at 45 days.

The primary endpoint was reached by 67.6% of patients randomized to the Amulet device and 70% of those randomized to Watchman Flex, a statistically nonsignificant difference (P = .71).

Because only one patient in the Amulet group and none in the Watchman group had a justified crossover to a nonrandomized device, most of the differences in the 45-day CCTA involved patency, defined as LAA density of at least 100 Hounsfield units. While the proportion of patients with leaks was similar, the types of leaks, which were stratified by underlying leak mechanism into PDL, mixed leaks (including incomplete side sealing), intradevice leaks, and leaks of unclear origin, were different.
 

Peridevice leaks twofold greater with Watchman

Those randomized to the Watchman device were more than twice as likely to have PDL (27.5% vs. 13.7%; P = .02), although no visible leak exceeded 5 mm in size. They were also more likely to have mixed leaks (14% vs. 3.8%; P = .01) and patency with no visible leak (21.0% vs. 9.5%; P = .02). There were also more device-related thrombi in the Watchman group even though the difference did not reach statistical significance (9.9% vs. 3.7%; P = .08).

Intradevice leaks (44.8% vs. 23.0%; P = .001) were the only type of patency significantly more common among patients randomized to Amulet, but the difference was relatively large. In addition, procedural complications of any type (32.4% vs. 19.1%; P = .023) were higher in the Amulet group. Most of these involved non–clinically relevant pericardial effusions, Dr. Galea said at the meeting, sponsored by the Cardiovascular Research Foundation.

The proportion of patients with adverse outcomes by 45 days was similar, but the types of complications differed. Of the six deaths, two occurred in the Amulet group as a result of periprocedural complications (one stemming from an air embolism and the other from a series of events following pericardial effusion). Three of the four deaths in the Watchman group were due to fatal bleeding. The fourth was a sudden death that occurred 30 days after the procedure.
 

Amulet IDE trial generates similar data

The much larger Amulet IDE trial, which compared Amulet to the Watchman 2.5 device, produced generally similar results. Again, the proportion of patients reaching the composite primary endpoints was similar.

The primary safety endpoint, which included death and major bleeding within 12 months of randomization, occurred in 14.5% and 14.7% of the Amulet and Watchman patients, respectively (P < .001 for noninferiority). The primary efficacy endpoint, which included stroke or systemic embolism within 18 months of randomization, occurred in 2.8% of patients in both groups.

As in SWISS APERO, the 1,878-patient Amulet IDE trial showed that the devices are similarly effective and safe but not necessarily interchangeable. Ultimately, the rate of LAA occlusion was higher for Amulet than the older generation Watchman (98.9% vs. 96.8%; P = .003) but procedural complication occurred more frequently among those randomized to the Amulet device (4.5% vs. 2.5%).

“The closure mechanisms are not the same, which might explain why we see differences in some secondary outcomes even when they perform similarly on the primary outcomes,” said Dhanunjaya R. Lakkireddy, MD, executive medical director, Kansas City (Kansas) Heart Rhythm Institute.

The lead investigator of the Amulet IDE trial, Dr. Lakkireddy was referring to both the AMULET IDE and the SWISS APERO study when he said that the currently available data do not allow one device to be considered superior to the other. He did suggest that differences between devices might still be considered meaningful in specific clinical situations or to specific clinicians.

Without studies to show objective differences, Dr. Lakkireddy suggested that training and experience is probably the most important variable in achieving treatment goals. “Operator comfort is certainly important,” he said.

Dr. Galea reports no significant financial relationships. The investigator-initiated study received funding from Abbott, the manufacturer of the Amulet device. Dr. Lakkireddy has financial relationships with Abbott, AltaThera, Medtronic, Biotronik, and Boston Scientific, which makes the Watchman device.

On the basis of outcomes, there was no clear winner from a trial that directly compared two modern devices used in patients undergoing percutaneous left atrial appendage (LAA) closure.

But the devices were not interchangeable for rates of complications or leaks, according to results of the open-label SWISS APERO trial, which compared the Amplatzer Amulet to the Watchman FLX device at eight participating centers in Europe.

At 45 days, the overall rates of leaks and the clinical outcomes in the two randomized groups were not significantly different, but there were differences in secondary endpoints, such as rates of peridevice leak (PDL), which were lower in the Amulet device group, and procedural complications, which were higher, Roberto Galea, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

LAA closure devices were developed as an alternative to oral anticoagulation in patients with nonvalvular atrial fibrillation. Although a similar comparison of LAA closure devices, called Amulet IDE, was recently published, that trial compared Amulet to Watchman 2.5, an earlier generation device.

Started later, SWISS APERO was also a planned comparison of Amulet and the Watchman 2.5, but the comparison switched to the Watchman FLX, when it was released in March of 2019.
 

First randomized comparison with Watchman FLX

“This is the first multicenter randomized controlled trial to include the Watchman FLX,” said Dr. Galea, a clinical investigator in the department of cardiology, Bern (Switzerland) University Hospital. He noted that Watchman FLX included some adjustments in design with the potential to reduce leak rates.

After preprocedural transesophageal echocardiography confirmed that patients had suitable anatomy to receive either device, the 221 patients who qualified for SWISS APERO were randomized. The primary endpoint was a composite of a justified crossover to a device other than the one to which they were assigned or residual patency detected by coronary computed tomography angiography (CCTA) at 45 days.

The primary endpoint was reached by 67.6% of patients randomized to the Amulet device and 70% of those randomized to Watchman Flex, a statistically nonsignificant difference (P = .71).

Because only one patient in the Amulet group and none in the Watchman group had a justified crossover to a nonrandomized device, most of the differences in the 45-day CCTA involved patency, defined as LAA density of at least 100 Hounsfield units. While the proportion of patients with leaks was similar, the types of leaks, which were stratified by underlying leak mechanism into PDL, mixed leaks (including incomplete side sealing), intradevice leaks, and leaks of unclear origin, were different.
 

Peridevice leaks twofold greater with Watchman

Those randomized to the Watchman device were more than twice as likely to have PDL (27.5% vs. 13.7%; P = .02), although no visible leak exceeded 5 mm in size. They were also more likely to have mixed leaks (14% vs. 3.8%; P = .01) and patency with no visible leak (21.0% vs. 9.5%; P = .02). There were also more device-related thrombi in the Watchman group even though the difference did not reach statistical significance (9.9% vs. 3.7%; P = .08).

Intradevice leaks (44.8% vs. 23.0%; P = .001) were the only type of patency significantly more common among patients randomized to Amulet, but the difference was relatively large. In addition, procedural complications of any type (32.4% vs. 19.1%; P = .023) were higher in the Amulet group. Most of these involved non–clinically relevant pericardial effusions, Dr. Galea said at the meeting, sponsored by the Cardiovascular Research Foundation.

The proportion of patients with adverse outcomes by 45 days was similar, but the types of complications differed. Of the six deaths, two occurred in the Amulet group as a result of periprocedural complications (one stemming from an air embolism and the other from a series of events following pericardial effusion). Three of the four deaths in the Watchman group were due to fatal bleeding. The fourth was a sudden death that occurred 30 days after the procedure.
 

Amulet IDE trial generates similar data

The much larger Amulet IDE trial, which compared Amulet to the Watchman 2.5 device, produced generally similar results. Again, the proportion of patients reaching the composite primary endpoints was similar.

The primary safety endpoint, which included death and major bleeding within 12 months of randomization, occurred in 14.5% and 14.7% of the Amulet and Watchman patients, respectively (P < .001 for noninferiority). The primary efficacy endpoint, which included stroke or systemic embolism within 18 months of randomization, occurred in 2.8% of patients in both groups.

As in SWISS APERO, the 1,878-patient Amulet IDE trial showed that the devices are similarly effective and safe but not necessarily interchangeable. Ultimately, the rate of LAA occlusion was higher for Amulet than the older generation Watchman (98.9% vs. 96.8%; P = .003) but procedural complication occurred more frequently among those randomized to the Amulet device (4.5% vs. 2.5%).

“The closure mechanisms are not the same, which might explain why we see differences in some secondary outcomes even when they perform similarly on the primary outcomes,” said Dhanunjaya R. Lakkireddy, MD, executive medical director, Kansas City (Kansas) Heart Rhythm Institute.

The lead investigator of the Amulet IDE trial, Dr. Lakkireddy was referring to both the AMULET IDE and the SWISS APERO study when he said that the currently available data do not allow one device to be considered superior to the other. He did suggest that differences between devices might still be considered meaningful in specific clinical situations or to specific clinicians.

Without studies to show objective differences, Dr. Lakkireddy suggested that training and experience is probably the most important variable in achieving treatment goals. “Operator comfort is certainly important,” he said.

Dr. Galea reports no significant financial relationships. The investigator-initiated study received funding from Abbott, the manufacturer of the Amulet device. Dr. Lakkireddy has financial relationships with Abbott, AltaThera, Medtronic, Biotronik, and Boston Scientific, which makes the Watchman device.

On the basis of outcomes, there was no clear winner from a trial that directly compared two modern devices used in patients undergoing percutaneous left atrial appendage (LAA) closure.

But the devices were not interchangeable for rates of complications or leaks, according to results of the open-label SWISS APERO trial, which compared the Amplatzer Amulet to the Watchman FLX device at eight participating centers in Europe.

At 45 days, the overall rates of leaks and the clinical outcomes in the two randomized groups were not significantly different, but there were differences in secondary endpoints, such as rates of peridevice leak (PDL), which were lower in the Amulet device group, and procedural complications, which were higher, Roberto Galea, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

LAA closure devices were developed as an alternative to oral anticoagulation in patients with nonvalvular atrial fibrillation. Although a similar comparison of LAA closure devices, called Amulet IDE, was recently published, that trial compared Amulet to Watchman 2.5, an earlier generation device.

Started later, SWISS APERO was also a planned comparison of Amulet and the Watchman 2.5, but the comparison switched to the Watchman FLX, when it was released in March of 2019.
 

First randomized comparison with Watchman FLX

“This is the first multicenter randomized controlled trial to include the Watchman FLX,” said Dr. Galea, a clinical investigator in the department of cardiology, Bern (Switzerland) University Hospital. He noted that Watchman FLX included some adjustments in design with the potential to reduce leak rates.

After preprocedural transesophageal echocardiography confirmed that patients had suitable anatomy to receive either device, the 221 patients who qualified for SWISS APERO were randomized. The primary endpoint was a composite of a justified crossover to a device other than the one to which they were assigned or residual patency detected by coronary computed tomography angiography (CCTA) at 45 days.

The primary endpoint was reached by 67.6% of patients randomized to the Amulet device and 70% of those randomized to Watchman Flex, a statistically nonsignificant difference (P = .71).

Because only one patient in the Amulet group and none in the Watchman group had a justified crossover to a nonrandomized device, most of the differences in the 45-day CCTA involved patency, defined as LAA density of at least 100 Hounsfield units. While the proportion of patients with leaks was similar, the types of leaks, which were stratified by underlying leak mechanism into PDL, mixed leaks (including incomplete side sealing), intradevice leaks, and leaks of unclear origin, were different.
 

Peridevice leaks twofold greater with Watchman

Those randomized to the Watchman device were more than twice as likely to have PDL (27.5% vs. 13.7%; P = .02), although no visible leak exceeded 5 mm in size. They were also more likely to have mixed leaks (14% vs. 3.8%; P = .01) and patency with no visible leak (21.0% vs. 9.5%; P = .02). There were also more device-related thrombi in the Watchman group even though the difference did not reach statistical significance (9.9% vs. 3.7%; P = .08).

Intradevice leaks (44.8% vs. 23.0%; P = .001) were the only type of patency significantly more common among patients randomized to Amulet, but the difference was relatively large. In addition, procedural complications of any type (32.4% vs. 19.1%; P = .023) were higher in the Amulet group. Most of these involved non–clinically relevant pericardial effusions, Dr. Galea said at the meeting, sponsored by the Cardiovascular Research Foundation.

The proportion of patients with adverse outcomes by 45 days was similar, but the types of complications differed. Of the six deaths, two occurred in the Amulet group as a result of periprocedural complications (one stemming from an air embolism and the other from a series of events following pericardial effusion). Three of the four deaths in the Watchman group were due to fatal bleeding. The fourth was a sudden death that occurred 30 days after the procedure.
 

Amulet IDE trial generates similar data

The much larger Amulet IDE trial, which compared Amulet to the Watchman 2.5 device, produced generally similar results. Again, the proportion of patients reaching the composite primary endpoints was similar.

The primary safety endpoint, which included death and major bleeding within 12 months of randomization, occurred in 14.5% and 14.7% of the Amulet and Watchman patients, respectively (P < .001 for noninferiority). The primary efficacy endpoint, which included stroke or systemic embolism within 18 months of randomization, occurred in 2.8% of patients in both groups.

As in SWISS APERO, the 1,878-patient Amulet IDE trial showed that the devices are similarly effective and safe but not necessarily interchangeable. Ultimately, the rate of LAA occlusion was higher for Amulet than the older generation Watchman (98.9% vs. 96.8%; P = .003) but procedural complication occurred more frequently among those randomized to the Amulet device (4.5% vs. 2.5%).

“The closure mechanisms are not the same, which might explain why we see differences in some secondary outcomes even when they perform similarly on the primary outcomes,” said Dhanunjaya R. Lakkireddy, MD, executive medical director, Kansas City (Kansas) Heart Rhythm Institute.

The lead investigator of the Amulet IDE trial, Dr. Lakkireddy was referring to both the AMULET IDE and the SWISS APERO study when he said that the currently available data do not allow one device to be considered superior to the other. He did suggest that differences between devices might still be considered meaningful in specific clinical situations or to specific clinicians.

Without studies to show objective differences, Dr. Lakkireddy suggested that training and experience is probably the most important variable in achieving treatment goals. “Operator comfort is certainly important,” he said.

Dr. Galea reports no significant financial relationships. The investigator-initiated study received funding from Abbott, the manufacturer of the Amulet device. Dr. Lakkireddy has financial relationships with Abbott, AltaThera, Medtronic, Biotronik, and Boston Scientific, which makes the Watchman device.

Just months after the MASTER DAPT trial showed that abbreviated dual-antiplatelet therapy (DAPT) lowers the risk of bleeding after stent placement in patients at high bleeding risk, a new analysis showed the favorable benefit-to-risk ratio was about the same in the subgroup who also had an acute or recent myocardial infarction.

In the new prespecified MASTER DAPT analysis, the data show that the subgroup with both an increased bleeding risk and an increased risk of ischemic events benefited much like the entire study population from a shorter DAPT duration, reported Pieter C. Smits, MD, PhD, at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

“There was no signal towards increased ischemic risk in the abbreviated DAPT population presenting with recent acute MI,” said Dr. Smits, emphasizing the consistency of results in this “bi-risk” subgroup with objective criteria for increased risks of bleeding and ischemic events.

MASTER DAPT main results published

The main results of the MASTER DAPT trial were presented at the 2021 annual meeting of the European Society of Cardiology and published recently in the New England Journal of Medicine. The trial randomized 4,434 patients who met one or more criteria for high bleeding risk. These included age of at least 75 years, documented anemia, a clinical indication for oral anticoagulants, and previous bleeding episodes requiring hospitalization.

In the trial, all patients were maintained on DAPT for 1 month after implantation of a biodegradable-polymer, sirolimus-eluting coronary stent (Ultimaster, Terumo). At the end of the month, those randomized to abbreviated DAPT started immediately on single-agent antiplatelet therapy, while those in the standard DAPT group remained on DAPT for at least 2 additional months.

Over 1 year of follow-up, the bleeding event rate was lower in the abbreviated DAPT group (6.5% vs. 9.4%; P < .0001 for superiority). The slight increase in major ischemic events among those in the abbreviated DAPT group (6.1% vs. 5.9%) was not significantly different (P = .001 for noninferiority).

When compared on the basis of net adverse clinical events (NACE), which comprised all-case death, MI, stroke, or Bleeding Academic Research Consortium (BARC) level 3 or 5 bleeding, there was a slight advantage for abbreviated DAPT (7.5% vs. 7.7%). This did not reach significance, but it was similar (P < .001 for noninferiority), favoring the abbreviated course of DAPT because of the bleeding advantage.

Recent MI vs. no MI

In the new analysis, patients in both the abbreviated and standard DAPT group were stratified into those with no major cardiovascular event within the past 12 months and those with an acute MI or acute coronary syndrome within this time. There were somewhat more patients without a history of MI within the previous 12 months in both the abbreviated DAPT (1,381 vs. 914 patients) and standard DAPT (1,418 vs. 866) groups.

In those without a recent MI, NACE rates were nearly identical over 1-year follow-up for those who received abbreviated versus standard DAPT. In both, slightly more than 6% had a NACE event, producing a hazard ratio of 1.03 for abbreviated versus standard DAPT (P = 0.85).

For those with a recent MI, event rates began to separate within 30 days. By 1 year, NACE rates exceeded 10% in those on standard DAPT, but remained below 9% for those on abbreviated DAPT. The lower hazard ratio in the abbreviated DAPT group (HR, 0.83; P = .22) did not reach statistical significance, but it did echo the larger MASTER DAPT conclusion.

“An abbreviated DAPT strategy significantly reduced clinically relevant bleeding risk in these bi-risk patients without increasing risk of ischemic events,” reported Dr. Smits, director of interventional cardiology at Maasstad Hospital, Rotterdam, the Netherlands.
 

No difference in NACE components

In fact, when the components of NACE were evaluated individually in the subgroup of patients with prior MI, both stroke (HR, 0.47; P = .16) and all-cause death (HR, 0.78; P = .28), although not significant, numerically favored abbreviated DAPT.

There was no difference between abbreviated and standard DAPT for risk of MI at 1 year (HR, 1.03; P = .92).

As in the overall MASTER DAPT results, bleeding risk (BARC 2, 3, or 5 bleeding) was significantly reduced in the substudy among those with a recent prior MI (P = .013) or those with no MI in the prior 12 months (P = .01).

In MASTER DAPT, which was an open-label study that randomized participants in 30 countries, all patients received one type of drug-eluting stent. While Dr. Smits conceded that it is not clear whether the conclusions about abbreviated DAPT can be extrapolated to other stents, he noted that recent long-term outcomes for modern drug-eluting coronary stents have been similar, suggesting these results might be more broadly applicable.

According to Dr. Smit, the consistency of this subgroup analysis with the previously published MASTER DAPT study is mutually reinforcing for a role of abbreviated DAPT in patients at high bleeding risk. Other experts agreed.

“One of the concerns that people have had is exactly what has been addressed here in this subgroup analysis. These are the patients that are not only bleeding-risk high but ischemic-risk high. The question was whether the benefit of reducing bleeding risk is offset by increasing stent thrombosis or other ischemic event outcomes, and the answer from the analysis is really clearly no,” said Philippe Gabriel Steg, MD, chief, department of cardiology, Hôpital Bichat, Paris, at the meeting, sponsored by the Cardiovascular Research Foundation.

Dr. Smits reports financial relationships with Abiomed, Abbott Vascular, Daiichi-Sankyo, Microport, Opsense, and Terumo Medical. Dr. Steg reports financial relationships with Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Idorsia, Merck, Novartis, Regeneron, and Sanofi-Aventis.

Just months after the MASTER DAPT trial showed that abbreviated dual-antiplatelet therapy (DAPT) lowers the risk of bleeding after stent placement in patients at high bleeding risk, a new analysis showed the favorable benefit-to-risk ratio was about the same in the subgroup who also had an acute or recent myocardial infarction.

In the new prespecified MASTER DAPT analysis, the data show that the subgroup with both an increased bleeding risk and an increased risk of ischemic events benefited much like the entire study population from a shorter DAPT duration, reported Pieter C. Smits, MD, PhD, at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

“There was no signal towards increased ischemic risk in the abbreviated DAPT population presenting with recent acute MI,” said Dr. Smits, emphasizing the consistency of results in this “bi-risk” subgroup with objective criteria for increased risks of bleeding and ischemic events.

MASTER DAPT main results published

The main results of the MASTER DAPT trial were presented at the 2021 annual meeting of the European Society of Cardiology and published recently in the New England Journal of Medicine. The trial randomized 4,434 patients who met one or more criteria for high bleeding risk. These included age of at least 75 years, documented anemia, a clinical indication for oral anticoagulants, and previous bleeding episodes requiring hospitalization.

In the trial, all patients were maintained on DAPT for 1 month after implantation of a biodegradable-polymer, sirolimus-eluting coronary stent (Ultimaster, Terumo). At the end of the month, those randomized to abbreviated DAPT started immediately on single-agent antiplatelet therapy, while those in the standard DAPT group remained on DAPT for at least 2 additional months.

Over 1 year of follow-up, the bleeding event rate was lower in the abbreviated DAPT group (6.5% vs. 9.4%; P < .0001 for superiority). The slight increase in major ischemic events among those in the abbreviated DAPT group (6.1% vs. 5.9%) was not significantly different (P = .001 for noninferiority).

When compared on the basis of net adverse clinical events (NACE), which comprised all-case death, MI, stroke, or Bleeding Academic Research Consortium (BARC) level 3 or 5 bleeding, there was a slight advantage for abbreviated DAPT (7.5% vs. 7.7%). This did not reach significance, but it was similar (P < .001 for noninferiority), favoring the abbreviated course of DAPT because of the bleeding advantage.

Recent MI vs. no MI

In the new analysis, patients in both the abbreviated and standard DAPT group were stratified into those with no major cardiovascular event within the past 12 months and those with an acute MI or acute coronary syndrome within this time. There were somewhat more patients without a history of MI within the previous 12 months in both the abbreviated DAPT (1,381 vs. 914 patients) and standard DAPT (1,418 vs. 866) groups.

In those without a recent MI, NACE rates were nearly identical over 1-year follow-up for those who received abbreviated versus standard DAPT. In both, slightly more than 6% had a NACE event, producing a hazard ratio of 1.03 for abbreviated versus standard DAPT (P = 0.85).

For those with a recent MI, event rates began to separate within 30 days. By 1 year, NACE rates exceeded 10% in those on standard DAPT, but remained below 9% for those on abbreviated DAPT. The lower hazard ratio in the abbreviated DAPT group (HR, 0.83; P = .22) did not reach statistical significance, but it did echo the larger MASTER DAPT conclusion.

“An abbreviated DAPT strategy significantly reduced clinically relevant bleeding risk in these bi-risk patients without increasing risk of ischemic events,” reported Dr. Smits, director of interventional cardiology at Maasstad Hospital, Rotterdam, the Netherlands.
 

No difference in NACE components

In fact, when the components of NACE were evaluated individually in the subgroup of patients with prior MI, both stroke (HR, 0.47; P = .16) and all-cause death (HR, 0.78; P = .28), although not significant, numerically favored abbreviated DAPT.

There was no difference between abbreviated and standard DAPT for risk of MI at 1 year (HR, 1.03; P = .92).

As in the overall MASTER DAPT results, bleeding risk (BARC 2, 3, or 5 bleeding) was significantly reduced in the substudy among those with a recent prior MI (P = .013) or those with no MI in the prior 12 months (P = .01).

In MASTER DAPT, which was an open-label study that randomized participants in 30 countries, all patients received one type of drug-eluting stent. While Dr. Smits conceded that it is not clear whether the conclusions about abbreviated DAPT can be extrapolated to other stents, he noted that recent long-term outcomes for modern drug-eluting coronary stents have been similar, suggesting these results might be more broadly applicable.

According to Dr. Smit, the consistency of this subgroup analysis with the previously published MASTER DAPT study is mutually reinforcing for a role of abbreviated DAPT in patients at high bleeding risk. Other experts agreed.

“One of the concerns that people have had is exactly what has been addressed here in this subgroup analysis. These are the patients that are not only bleeding-risk high but ischemic-risk high. The question was whether the benefit of reducing bleeding risk is offset by increasing stent thrombosis or other ischemic event outcomes, and the answer from the analysis is really clearly no,” said Philippe Gabriel Steg, MD, chief, department of cardiology, Hôpital Bichat, Paris, at the meeting, sponsored by the Cardiovascular Research Foundation.

Dr. Smits reports financial relationships with Abiomed, Abbott Vascular, Daiichi-Sankyo, Microport, Opsense, and Terumo Medical. Dr. Steg reports financial relationships with Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Idorsia, Merck, Novartis, Regeneron, and Sanofi-Aventis.

Just months after the MASTER DAPT trial showed that abbreviated dual-antiplatelet therapy (DAPT) lowers the risk of bleeding after stent placement in patients at high bleeding risk, a new analysis showed the favorable benefit-to-risk ratio was about the same in the subgroup who also had an acute or recent myocardial infarction.

In the new prespecified MASTER DAPT analysis, the data show that the subgroup with both an increased bleeding risk and an increased risk of ischemic events benefited much like the entire study population from a shorter DAPT duration, reported Pieter C. Smits, MD, PhD, at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

“There was no signal towards increased ischemic risk in the abbreviated DAPT population presenting with recent acute MI,” said Dr. Smits, emphasizing the consistency of results in this “bi-risk” subgroup with objective criteria for increased risks of bleeding and ischemic events.

MASTER DAPT main results published

The main results of the MASTER DAPT trial were presented at the 2021 annual meeting of the European Society of Cardiology and published recently in the New England Journal of Medicine. The trial randomized 4,434 patients who met one or more criteria for high bleeding risk. These included age of at least 75 years, documented anemia, a clinical indication for oral anticoagulants, and previous bleeding episodes requiring hospitalization.

In the trial, all patients were maintained on DAPT for 1 month after implantation of a biodegradable-polymer, sirolimus-eluting coronary stent (Ultimaster, Terumo). At the end of the month, those randomized to abbreviated DAPT started immediately on single-agent antiplatelet therapy, while those in the standard DAPT group remained on DAPT for at least 2 additional months.

Over 1 year of follow-up, the bleeding event rate was lower in the abbreviated DAPT group (6.5% vs. 9.4%; P < .0001 for superiority). The slight increase in major ischemic events among those in the abbreviated DAPT group (6.1% vs. 5.9%) was not significantly different (P = .001 for noninferiority).

When compared on the basis of net adverse clinical events (NACE), which comprised all-case death, MI, stroke, or Bleeding Academic Research Consortium (BARC) level 3 or 5 bleeding, there was a slight advantage for abbreviated DAPT (7.5% vs. 7.7%). This did not reach significance, but it was similar (P < .001 for noninferiority), favoring the abbreviated course of DAPT because of the bleeding advantage.

Recent MI vs. no MI

In the new analysis, patients in both the abbreviated and standard DAPT group were stratified into those with no major cardiovascular event within the past 12 months and those with an acute MI or acute coronary syndrome within this time. There were somewhat more patients without a history of MI within the previous 12 months in both the abbreviated DAPT (1,381 vs. 914 patients) and standard DAPT (1,418 vs. 866) groups.

In those without a recent MI, NACE rates were nearly identical over 1-year follow-up for those who received abbreviated versus standard DAPT. In both, slightly more than 6% had a NACE event, producing a hazard ratio of 1.03 for abbreviated versus standard DAPT (P = 0.85).

For those with a recent MI, event rates began to separate within 30 days. By 1 year, NACE rates exceeded 10% in those on standard DAPT, but remained below 9% for those on abbreviated DAPT. The lower hazard ratio in the abbreviated DAPT group (HR, 0.83; P = .22) did not reach statistical significance, but it did echo the larger MASTER DAPT conclusion.

“An abbreviated DAPT strategy significantly reduced clinically relevant bleeding risk in these bi-risk patients without increasing risk of ischemic events,” reported Dr. Smits, director of interventional cardiology at Maasstad Hospital, Rotterdam, the Netherlands.
 

No difference in NACE components

In fact, when the components of NACE were evaluated individually in the subgroup of patients with prior MI, both stroke (HR, 0.47; P = .16) and all-cause death (HR, 0.78; P = .28), although not significant, numerically favored abbreviated DAPT.

There was no difference between abbreviated and standard DAPT for risk of MI at 1 year (HR, 1.03; P = .92).

As in the overall MASTER DAPT results, bleeding risk (BARC 2, 3, or 5 bleeding) was significantly reduced in the substudy among those with a recent prior MI (P = .013) or those with no MI in the prior 12 months (P = .01).

In MASTER DAPT, which was an open-label study that randomized participants in 30 countries, all patients received one type of drug-eluting stent. While Dr. Smits conceded that it is not clear whether the conclusions about abbreviated DAPT can be extrapolated to other stents, he noted that recent long-term outcomes for modern drug-eluting coronary stents have been similar, suggesting these results might be more broadly applicable.

According to Dr. Smit, the consistency of this subgroup analysis with the previously published MASTER DAPT study is mutually reinforcing for a role of abbreviated DAPT in patients at high bleeding risk. Other experts agreed.

“One of the concerns that people have had is exactly what has been addressed here in this subgroup analysis. These are the patients that are not only bleeding-risk high but ischemic-risk high. The question was whether the benefit of reducing bleeding risk is offset by increasing stent thrombosis or other ischemic event outcomes, and the answer from the analysis is really clearly no,” said Philippe Gabriel Steg, MD, chief, department of cardiology, Hôpital Bichat, Paris, at the meeting, sponsored by the Cardiovascular Research Foundation.

Dr. Smits reports financial relationships with Abiomed, Abbott Vascular, Daiichi-Sankyo, Microport, Opsense, and Terumo Medical. Dr. Steg reports financial relationships with Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Idorsia, Merck, Novartis, Regeneron, and Sanofi-Aventis.

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

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

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

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

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

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

Calculating the estimated glucose disposal rate (eGDR) as a proxy for the level of insulin resistance may be useful way to determine if someone with type 2 diabetes (T2D) is at risk for having a first stroke, Swedish researchers have found.

purestock/Thinkstock

In a large population-based study, the lower the eGDR score went, the higher the risk for having a first stroke became.

The eGDR score was also predictive of the chance of dying from any or a cardiovascular cause, Alexander Zabala, MD, reported at the annual meeting of the European Association for the Study of Diabetes (Abstract OP 01-4).

The link between insulin resistance and an increased risk for stroke has been known for some time, and not just in people with T2D. However, the current way of determining insulin resistance is not suitable for widespread practice.

“The goal standard technique for measuring insulin resistance is the euglycemic clamp method,” said Dr. Zabala, an internal medical resident at Södersjukhuset hospital and researcher at the Karolinska Institutet in Stockholm.

“For that reason, [the eGDR], a method based on readily available clinical factors – waist circumference, hypertension, and glycosylated hemoglobin was developed,” he explained. Body mass index can also be used in place of waist circumference, he qualified.

The eGDR has already been proven to be very precise in people with type 1 diabetes, said Dr. Zabala, and could be an “excellent tool to measure insulin resistance in a large patient population.”
 

Investigating the link between eGDR and first stroke risk

The aim of the study he presented was to see if changes in the eGDR were associated with changes in the risk of someone with T2D experiencing a first stroke, or dying from a cardiovascular or other cause.

An observational cohort was formed by first considering data on all adult patients with T2D who were logged in the Swedish National Diabetes Registry (NDR) during 2004-2016. Then anyone with a history of stroke, or with any missing data on the clinical variables needed to calculate the eGDR, were excluded.

This resulted in an overall population of 104,697 individuals, aged a mean of 63 years, who had developed T2D at around the age of 59 years. About 44% of the study population were women. The mean eGDR for the whole population was 5.6 mg/kg per min.

The study subjects were grouped according to four eGDR levels: 24,706 were in the lowest quartile of eGDR (less than 4 mg/kg per min), signifying the highest level of insulin resistance, and 18,762 were in the upper quartile of eGDR (greater than 8 mg/kg per min), signifying the lowest level of insulin resistance. The middle two groups had an eGDR between 4 and 6 mg/kg per min (40,187), and 6 and 8 mg/kg/min (21,042).

Data from the NDR were then combined with the Swedish Cause of Death register, the Swedish In-patient Care Diagnoses registry, and the Longitudinal Database for Health Insurance and Labour Market Studies (LISA) to determine the rates of stroke, ischemic stroke, hemorrhagic stroke, all-cause mortality, and cardiovascular mortality.
 

Increasing insulin resistance ups risk for stroke, death

After a median follow-up of 5.6 years, 4% (4,201) of the study population had had a stroke.

“We clearly see an increased occurrence of first-time stroke in the group with the lowest eGDR, indicating worst insulin resistance, in comparison with the group with the highest eGDR, indicating less insulin resistance,” Dr. Zabala reported.

After adjustment for potential confounding factors, including age at baseline, gender, diabetes duration, among other variables, the risk for stroke was lowest in those with a high eGDR value and highest for those with a low eGDR value.

Using individuals with the lowest eGDR (less than 4 mg/kg per min) and thus greatest risk of stroke as the reference, adjusted hazard ratios (aHR) for first-time stroke were: 0.60, 0.68, and 0.77 for those with an eGDR of greater than 8, 6-8, and 4-6 mg/kg per min, respectively.

The corresponding values for risk of ischemic stroke were 0.55, 0.68, and 0.75. Regarding hemorrhagic stroke, there was no statistically significant correlation between eGDR levels and stroke occurrence. This was due to the small number of cases recorded.

As for all-cause and cardiovascular mortality, a similar pattern was seen, with higher rates of death linked to increasing insulin resistance. Adjusted hazard ratios according to increasing insulin resistance (decreasing eGDR scores) for all-cause death were 0.68, 0.75, and 0.82 and for cardiovascular mortality were 0.65, 0.75, and 0.82.

A sensitivity analysis, using BMI instead of waist circumference to calculate the eGDR, showed a similar pattern, and “interestingly, a correlation between eGDR levels and risk of hemorrhagic stroke.” Dr. Zabala said.
 

Limitations and take-homes

Of course, this is an observational cohort study, so no conclusions on causality can be made and there are no data on the use of anti-diabetic treatments specifically. But there are strengths such as covering almost all adults with T2D in Sweden and a relatively long-follow-up time.

The findings suggest that “eGDR, which may reflect insulin resistance may be a useful risk marker for stroke and death in people with type 2 diabetes,” said Dr. Zabala.

“You had a very large cohort, and that certainly makes your results very valid,” observed Peter Novodvorsky, MUDr. (Hons), PhD, MRCP, a consultant diabetologist in Trenčín, Slovakia.

Dr. Novodvorsky, who chaired the session, picked up on the lack of information about how many people were taking newer diabetes drugs, such as the glucagon-like peptide 1 receptor antagonists and sodium glucose-lowering transport 2 inhibitors.

“As we all know, these might have protective effects which are not necessarily related to the glucose lowering or insulin resistance-lowering” effects, so could have influenced the results. In terms of how practical the eGDR is for clinical practice, Dr. Zabala observed in a press release: “eGDR could be used to help T2D patients better understand and manage their risk of stroke and death. 

“It could also be of importance in research. In this era of personalized medicine, better stratification of type 2 diabetes patients will help optimize clinical trials and further vital research into treatment, diagnosis, care and prevention.”

The research was a collaboration between the Karolinska Institutet, Gothenburg University and the Swedish National Diabetes Registry. Dr. Zabala and coauthors reported having no conflicts of interest.

Calculating the estimated glucose disposal rate (eGDR) as a proxy for the level of insulin resistance may be useful way to determine if someone with type 2 diabetes (T2D) is at risk for having a first stroke, Swedish researchers have found.

purestock/Thinkstock

In a large population-based study, the lower the eGDR score went, the higher the risk for having a first stroke became.

The eGDR score was also predictive of the chance of dying from any or a cardiovascular cause, Alexander Zabala, MD, reported at the annual meeting of the European Association for the Study of Diabetes (Abstract OP 01-4).

The link between insulin resistance and an increased risk for stroke has been known for some time, and not just in people with T2D. However, the current way of determining insulin resistance is not suitable for widespread practice.

“The goal standard technique for measuring insulin resistance is the euglycemic clamp method,” said Dr. Zabala, an internal medical resident at Södersjukhuset hospital and researcher at the Karolinska Institutet in Stockholm.

“For that reason, [the eGDR], a method based on readily available clinical factors – waist circumference, hypertension, and glycosylated hemoglobin was developed,” he explained. Body mass index can also be used in place of waist circumference, he qualified.

The eGDR has already been proven to be very precise in people with type 1 diabetes, said Dr. Zabala, and could be an “excellent tool to measure insulin resistance in a large patient population.”
 

Investigating the link between eGDR and first stroke risk

The aim of the study he presented was to see if changes in the eGDR were associated with changes in the risk of someone with T2D experiencing a first stroke, or dying from a cardiovascular or other cause.

An observational cohort was formed by first considering data on all adult patients with T2D who were logged in the Swedish National Diabetes Registry (NDR) during 2004-2016. Then anyone with a history of stroke, or with any missing data on the clinical variables needed to calculate the eGDR, were excluded.

This resulted in an overall population of 104,697 individuals, aged a mean of 63 years, who had developed T2D at around the age of 59 years. About 44% of the study population were women. The mean eGDR for the whole population was 5.6 mg/kg per min.

The study subjects were grouped according to four eGDR levels: 24,706 were in the lowest quartile of eGDR (less than 4 mg/kg per min), signifying the highest level of insulin resistance, and 18,762 were in the upper quartile of eGDR (greater than 8 mg/kg per min), signifying the lowest level of insulin resistance. The middle two groups had an eGDR between 4 and 6 mg/kg per min (40,187), and 6 and 8 mg/kg/min (21,042).

Data from the NDR were then combined with the Swedish Cause of Death register, the Swedish In-patient Care Diagnoses registry, and the Longitudinal Database for Health Insurance and Labour Market Studies (LISA) to determine the rates of stroke, ischemic stroke, hemorrhagic stroke, all-cause mortality, and cardiovascular mortality.
 

Increasing insulin resistance ups risk for stroke, death

After a median follow-up of 5.6 years, 4% (4,201) of the study population had had a stroke.

“We clearly see an increased occurrence of first-time stroke in the group with the lowest eGDR, indicating worst insulin resistance, in comparison with the group with the highest eGDR, indicating less insulin resistance,” Dr. Zabala reported.

After adjustment for potential confounding factors, including age at baseline, gender, diabetes duration, among other variables, the risk for stroke was lowest in those with a high eGDR value and highest for those with a low eGDR value.

Using individuals with the lowest eGDR (less than 4 mg/kg per min) and thus greatest risk of stroke as the reference, adjusted hazard ratios (aHR) for first-time stroke were: 0.60, 0.68, and 0.77 for those with an eGDR of greater than 8, 6-8, and 4-6 mg/kg per min, respectively.

The corresponding values for risk of ischemic stroke were 0.55, 0.68, and 0.75. Regarding hemorrhagic stroke, there was no statistically significant correlation between eGDR levels and stroke occurrence. This was due to the small number of cases recorded.

As for all-cause and cardiovascular mortality, a similar pattern was seen, with higher rates of death linked to increasing insulin resistance. Adjusted hazard ratios according to increasing insulin resistance (decreasing eGDR scores) for all-cause death were 0.68, 0.75, and 0.82 and for cardiovascular mortality were 0.65, 0.75, and 0.82.

A sensitivity analysis, using BMI instead of waist circumference to calculate the eGDR, showed a similar pattern, and “interestingly, a correlation between eGDR levels and risk of hemorrhagic stroke.” Dr. Zabala said.
 

Limitations and take-homes

Of course, this is an observational cohort study, so no conclusions on causality can be made and there are no data on the use of anti-diabetic treatments specifically. But there are strengths such as covering almost all adults with T2D in Sweden and a relatively long-follow-up time.

The findings suggest that “eGDR, which may reflect insulin resistance may be a useful risk marker for stroke and death in people with type 2 diabetes,” said Dr. Zabala.

“You had a very large cohort, and that certainly makes your results very valid,” observed Peter Novodvorsky, MUDr. (Hons), PhD, MRCP, a consultant diabetologist in Trenčín, Slovakia.

Dr. Novodvorsky, who chaired the session, picked up on the lack of information about how many people were taking newer diabetes drugs, such as the glucagon-like peptide 1 receptor antagonists and sodium glucose-lowering transport 2 inhibitors.

“As we all know, these might have protective effects which are not necessarily related to the glucose lowering or insulin resistance-lowering” effects, so could have influenced the results. In terms of how practical the eGDR is for clinical practice, Dr. Zabala observed in a press release: “eGDR could be used to help T2D patients better understand and manage their risk of stroke and death. 

“It could also be of importance in research. In this era of personalized medicine, better stratification of type 2 diabetes patients will help optimize clinical trials and further vital research into treatment, diagnosis, care and prevention.”

The research was a collaboration between the Karolinska Institutet, Gothenburg University and the Swedish National Diabetes Registry. Dr. Zabala and coauthors reported having no conflicts of interest.

Calculating the estimated glucose disposal rate (eGDR) as a proxy for the level of insulin resistance may be useful way to determine if someone with type 2 diabetes (T2D) is at risk for having a first stroke, Swedish researchers have found.

purestock/Thinkstock

In a large population-based study, the lower the eGDR score went, the higher the risk for having a first stroke became.

The eGDR score was also predictive of the chance of dying from any or a cardiovascular cause, Alexander Zabala, MD, reported at the annual meeting of the European Association for the Study of Diabetes (Abstract OP 01-4).

The link between insulin resistance and an increased risk for stroke has been known for some time, and not just in people with T2D. However, the current way of determining insulin resistance is not suitable for widespread practice.

“The goal standard technique for measuring insulin resistance is the euglycemic clamp method,” said Dr. Zabala, an internal medical resident at Södersjukhuset hospital and researcher at the Karolinska Institutet in Stockholm.

“For that reason, [the eGDR], a method based on readily available clinical factors – waist circumference, hypertension, and glycosylated hemoglobin was developed,” he explained. Body mass index can also be used in place of waist circumference, he qualified.

The eGDR has already been proven to be very precise in people with type 1 diabetes, said Dr. Zabala, and could be an “excellent tool to measure insulin resistance in a large patient population.”
 

Investigating the link between eGDR and first stroke risk

The aim of the study he presented was to see if changes in the eGDR were associated with changes in the risk of someone with T2D experiencing a first stroke, or dying from a cardiovascular or other cause.

An observational cohort was formed by first considering data on all adult patients with T2D who were logged in the Swedish National Diabetes Registry (NDR) during 2004-2016. Then anyone with a history of stroke, or with any missing data on the clinical variables needed to calculate the eGDR, were excluded.

This resulted in an overall population of 104,697 individuals, aged a mean of 63 years, who had developed T2D at around the age of 59 years. About 44% of the study population were women. The mean eGDR for the whole population was 5.6 mg/kg per min.

The study subjects were grouped according to four eGDR levels: 24,706 were in the lowest quartile of eGDR (less than 4 mg/kg per min), signifying the highest level of insulin resistance, and 18,762 were in the upper quartile of eGDR (greater than 8 mg/kg per min), signifying the lowest level of insulin resistance. The middle two groups had an eGDR between 4 and 6 mg/kg per min (40,187), and 6 and 8 mg/kg/min (21,042).

Data from the NDR were then combined with the Swedish Cause of Death register, the Swedish In-patient Care Diagnoses registry, and the Longitudinal Database for Health Insurance and Labour Market Studies (LISA) to determine the rates of stroke, ischemic stroke, hemorrhagic stroke, all-cause mortality, and cardiovascular mortality.
 

Increasing insulin resistance ups risk for stroke, death

After a median follow-up of 5.6 years, 4% (4,201) of the study population had had a stroke.

“We clearly see an increased occurrence of first-time stroke in the group with the lowest eGDR, indicating worst insulin resistance, in comparison with the group with the highest eGDR, indicating less insulin resistance,” Dr. Zabala reported.

After adjustment for potential confounding factors, including age at baseline, gender, diabetes duration, among other variables, the risk for stroke was lowest in those with a high eGDR value and highest for those with a low eGDR value.

Using individuals with the lowest eGDR (less than 4 mg/kg per min) and thus greatest risk of stroke as the reference, adjusted hazard ratios (aHR) for first-time stroke were: 0.60, 0.68, and 0.77 for those with an eGDR of greater than 8, 6-8, and 4-6 mg/kg per min, respectively.

The corresponding values for risk of ischemic stroke were 0.55, 0.68, and 0.75. Regarding hemorrhagic stroke, there was no statistically significant correlation between eGDR levels and stroke occurrence. This was due to the small number of cases recorded.

As for all-cause and cardiovascular mortality, a similar pattern was seen, with higher rates of death linked to increasing insulin resistance. Adjusted hazard ratios according to increasing insulin resistance (decreasing eGDR scores) for all-cause death were 0.68, 0.75, and 0.82 and for cardiovascular mortality were 0.65, 0.75, and 0.82.

A sensitivity analysis, using BMI instead of waist circumference to calculate the eGDR, showed a similar pattern, and “interestingly, a correlation between eGDR levels and risk of hemorrhagic stroke.” Dr. Zabala said.
 

Limitations and take-homes

Of course, this is an observational cohort study, so no conclusions on causality can be made and there are no data on the use of anti-diabetic treatments specifically. But there are strengths such as covering almost all adults with T2D in Sweden and a relatively long-follow-up time.

The findings suggest that “eGDR, which may reflect insulin resistance may be a useful risk marker for stroke and death in people with type 2 diabetes,” said Dr. Zabala.

“You had a very large cohort, and that certainly makes your results very valid,” observed Peter Novodvorsky, MUDr. (Hons), PhD, MRCP, a consultant diabetologist in Trenčín, Slovakia.

Dr. Novodvorsky, who chaired the session, picked up on the lack of information about how many people were taking newer diabetes drugs, such as the glucagon-like peptide 1 receptor antagonists and sodium glucose-lowering transport 2 inhibitors.

“As we all know, these might have protective effects which are not necessarily related to the glucose lowering or insulin resistance-lowering” effects, so could have influenced the results. In terms of how practical the eGDR is for clinical practice, Dr. Zabala observed in a press release: “eGDR could be used to help T2D patients better understand and manage their risk of stroke and death. 

“It could also be of importance in research. In this era of personalized medicine, better stratification of type 2 diabetes patients will help optimize clinical trials and further vital research into treatment, diagnosis, care and prevention.”

The research was a collaboration between the Karolinska Institutet, Gothenburg University and the Swedish National Diabetes Registry. Dr. Zabala and coauthors reported having no conflicts of interest.

The plasma D-dimer assay has been used, along with clinical prediction scores, to rule out pulmonary embolism (PE) in critically ill patients for decades, but a new study suggests it may not be the right test to use in hospitalized COVID-19 patients.

The results showed that all hospitalized patients with COVID-19 and radiographic evidence of PE had plasma D-dimer levels of 0.05 mcg/mL or greater, the cutoff point for the diagnosis.

“If using D-dimer to exclude patients with PE, the increased values we found among 92.3% of patients suggest that this assay would be less useful than in the populations in which it was originally validated, among which a minority of patients had increased D-dimer values,” the authors write. “Setting higher D-dimer thresholds was associated with improved specificity at the cost of an increased false-negative rate that could be associated with an unacceptable patient safety risk.”

The inclusion of patients with D-dimer and computed tomography pulmonary angiography (CTPA) was necessary to estimate diagnostic performance, they note, but “this may have introduced selection bias by excluding patients unable to undergo CTPA.”

“Nonetheless, given the high pretest probability of PE and low specificity observed in this and other studies, these results suggest that use of D-dimer levels to exclude PE among patients hospitalized with COVID-19 may be inappropriate and have limited clinical utility,” they conclude.

Led by Constantine N. Logothetis, MD, from Morsani College of Medicine, University of South Florida, Tampa, the study was published online Oct. 8 as a Research Letter in JAMA Network Open.
 

Uncertain utility

The authors note that the availability of D-dimer samples routinely collected from hospitalized COVID-19 patients – as well as the heterogeneity of early, smaller studies – generated uncertainty about the utility of this assay.

This uncertainty prompted them to test the diagnostic accuracy of the D-dimer assay among a sample of 1,541 patients who were hospitalized with COVID-19 at their institution between January 2020 and February 2021 for a possible PE.

They compared plasma D-dimer concentrations with CTPA, the criterion standard for diagnosing PE, in 287 of those patients.

Overall, 118 patients (41.1%) required care in the ICU, and 27 patients (9.4%) died during hospitalization.

The investigators looked at the ability of plasma D-dimer levels collected on the same day as CTPA to diagnose PE.

Thirty-seven patients (12.9%) had radiographic evidence of PE, and 250 patients (87.1%) did not.

Overall, the vast majority of patients (92.3%; n = 265 patients) had plasma D-dimer levels of 0.05 mcg/mL or more, including all patients with PE and 225 of 250 patients without PE (91.2%).

The median D-dimer values were 1.0 mcg/mL for 250 patients without PE and 6.1 mcg/mL for 37 patients with PE.

D-dimer values ranged from 0.2 mcg/mL to 128 mcg/mL among patients without PE, and from 0.5 mcg/mL to more than 10,000 mcg/mL among patients with PE. Patients without PE had statistically significantly decreased mean D-dimer values (8.7 mcg/mL vs. 1.2 mcg/mL; P < .001).

A D-dimer concentration of 0.05 mcg/mL was associated with a sensitivity of 100%, specificity of 8.8%, negative predictive value (NPV) of 100%, positive predictive value (PPV) of 13.9%, and a negative likelihood ratio (NLR) of less than 0.1.

The age-adjusted threshold was associated with a sensitivity of 94.6%, specificity of 22.8%, NPV of 96.6%, PPV of 13.9%, and NLR of 0.24.

The authors note that all hospitalized patients with COVID-19 and radiographic evidence of PE had plasma D-dimer levels of 0.05 mcg/mL or greater.
 

D-dimer in VTE may not extrapolate to COVID-19

“The D-dimer test, which is a measure of circulating byproducts of blood clot dissolution, has long been incorporated into diagnostic algorithms for venous thromboembolic [VTE] disease, including deep vein thrombosis and pulmonary embolism. It is uncertain whether this diagnostic use of D-dimer testing can be extrapolated to the context of COVID-19 – an illness we now understand to be associated itself with intravascular thrombosis and fibrinolysis,” Matthew Tomey, MD, a cardiologist at Mount Sinai Morningside, New York, said in an interview.

“The authors of this study sought to evaluate the test characteristics of the D-dimer assay for diagnosis of pulmonary embolism in a consecutive series of 287 hospitalized patients with COVID-19 who underwent computed tomography pulmonary angiography (CTPA). This was a selected group of patients representing less than 20% of the 1,541 patients screened. Exclusion of data on the more than 80% of screened patients who did not undergo CTPA is a significant limitation of the study,” Dr. Tomey said.

“In the highly selected, small cohort studied, representing a group of patients at high pretest probability of pulmonary embolism, there was no patient with pulmonary embolism who had a D-dimer value less than 0.5 mcg/mL. Yet broad ranges of D-dimer values were observed in COVID-19 patients with (0.5 to >10,000 mcg/mL) and without (0.2 to 128 mcg/mL) pulmonary embolism,” he added.

Based on the presented data, it is likely true that very low levels of D-dimer decrease the likelihood of finding a pulmonary embolus on a CTPA, if it is performed, Dr. Tomey noted.

“Yet the data confirm that a wide range of D-dimer values can be observed in COVID-19 patients with or without pulmonary embolism. It is not clear at this time that D-dimer levels should be used as gatekeepers to diagnostic imaging studies such as CTPA when pretest suspicion of pulmonary embolism is high,” he said.

“This issue becomes relevant as we consider evolving data on use of anticoagulation in treatment of hospitalized patients with COVID-19. We learned this year that in critically ill patients hospitalized with COVID-19, routine therapeutic anticoagulation (with heparin) was not beneficial and potentially harmful when compared with usual thromboprophylaxis,” he concluded.

“As we strive to balance competing risks of bleeding and thrombosis, accurate diagnosis of pulmonary embolism is important to guide decision-making about therapeutic anticoagulation, including in COVID-19.”

Dr. Logothetis and Dr. Tomey have disclosed no relevant financial relationships.

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

The plasma D-dimer assay has been used, along with clinical prediction scores, to rule out pulmonary embolism (PE) in critically ill patients for decades, but a new study suggests it may not be the right test to use in hospitalized COVID-19 patients.

The results showed that all hospitalized patients with COVID-19 and radiographic evidence of PE had plasma D-dimer levels of 0.05 mcg/mL or greater, the cutoff point for the diagnosis.

“If using D-dimer to exclude patients with PE, the increased values we found among 92.3% of patients suggest that this assay would be less useful than in the populations in which it was originally validated, among which a minority of patients had increased D-dimer values,” the authors write. “Setting higher D-dimer thresholds was associated with improved specificity at the cost of an increased false-negative rate that could be associated with an unacceptable patient safety risk.”

The inclusion of patients with D-dimer and computed tomography pulmonary angiography (CTPA) was necessary to estimate diagnostic performance, they note, but “this may have introduced selection bias by excluding patients unable to undergo CTPA.”

“Nonetheless, given the high pretest probability of PE and low specificity observed in this and other studies, these results suggest that use of D-dimer levels to exclude PE among patients hospitalized with COVID-19 may be inappropriate and have limited clinical utility,” they conclude.

Led by Constantine N. Logothetis, MD, from Morsani College of Medicine, University of South Florida, Tampa, the study was published online Oct. 8 as a Research Letter in JAMA Network Open.
 

Uncertain utility

The authors note that the availability of D-dimer samples routinely collected from hospitalized COVID-19 patients – as well as the heterogeneity of early, smaller studies – generated uncertainty about the utility of this assay.

This uncertainty prompted them to test the diagnostic accuracy of the D-dimer assay among a sample of 1,541 patients who were hospitalized with COVID-19 at their institution between January 2020 and February 2021 for a possible PE.

They compared plasma D-dimer concentrations with CTPA, the criterion standard for diagnosing PE, in 287 of those patients.

Overall, 118 patients (41.1%) required care in the ICU, and 27 patients (9.4%) died during hospitalization.

The investigators looked at the ability of plasma D-dimer levels collected on the same day as CTPA to diagnose PE.

Thirty-seven patients (12.9%) had radiographic evidence of PE, and 250 patients (87.1%) did not.

Overall, the vast majority of patients (92.3%; n = 265 patients) had plasma D-dimer levels of 0.05 mcg/mL or more, including all patients with PE and 225 of 250 patients without PE (91.2%).

The median D-dimer values were 1.0 mcg/mL for 250 patients without PE and 6.1 mcg/mL for 37 patients with PE.

D-dimer values ranged from 0.2 mcg/mL to 128 mcg/mL among patients without PE, and from 0.5 mcg/mL to more than 10,000 mcg/mL among patients with PE. Patients without PE had statistically significantly decreased mean D-dimer values (8.7 mcg/mL vs. 1.2 mcg/mL; P < .001).

A D-dimer concentration of 0.05 mcg/mL was associated with a sensitivity of 100%, specificity of 8.8%, negative predictive value (NPV) of 100%, positive predictive value (PPV) of 13.9%, and a negative likelihood ratio (NLR) of less than 0.1.

The age-adjusted threshold was associated with a sensitivity of 94.6%, specificity of 22.8%, NPV of 96.6%, PPV of 13.9%, and NLR of 0.24.

The authors note that all hospitalized patients with COVID-19 and radiographic evidence of PE had plasma D-dimer levels of 0.05 mcg/mL or greater.
 

D-dimer in VTE may not extrapolate to COVID-19

“The D-dimer test, which is a measure of circulating byproducts of blood clot dissolution, has long been incorporated into diagnostic algorithms for venous thromboembolic [VTE] disease, including deep vein thrombosis and pulmonary embolism. It is uncertain whether this diagnostic use of D-dimer testing can be extrapolated to the context of COVID-19 – an illness we now understand to be associated itself with intravascular thrombosis and fibrinolysis,” Matthew Tomey, MD, a cardiologist at Mount Sinai Morningside, New York, said in an interview.

“The authors of this study sought to evaluate the test characteristics of the D-dimer assay for diagnosis of pulmonary embolism in a consecutive series of 287 hospitalized patients with COVID-19 who underwent computed tomography pulmonary angiography (CTPA). This was a selected group of patients representing less than 20% of the 1,541 patients screened. Exclusion of data on the more than 80% of screened patients who did not undergo CTPA is a significant limitation of the study,” Dr. Tomey said.

“In the highly selected, small cohort studied, representing a group of patients at high pretest probability of pulmonary embolism, there was no patient with pulmonary embolism who had a D-dimer value less than 0.5 mcg/mL. Yet broad ranges of D-dimer values were observed in COVID-19 patients with (0.5 to >10,000 mcg/mL) and without (0.2 to 128 mcg/mL) pulmonary embolism,” he added.

Based on the presented data, it is likely true that very low levels of D-dimer decrease the likelihood of finding a pulmonary embolus on a CTPA, if it is performed, Dr. Tomey noted.

“Yet the data confirm that a wide range of D-dimer values can be observed in COVID-19 patients with or without pulmonary embolism. It is not clear at this time that D-dimer levels should be used as gatekeepers to diagnostic imaging studies such as CTPA when pretest suspicion of pulmonary embolism is high,” he said.

“This issue becomes relevant as we consider evolving data on use of anticoagulation in treatment of hospitalized patients with COVID-19. We learned this year that in critically ill patients hospitalized with COVID-19, routine therapeutic anticoagulation (with heparin) was not beneficial and potentially harmful when compared with usual thromboprophylaxis,” he concluded.

“As we strive to balance competing risks of bleeding and thrombosis, accurate diagnosis of pulmonary embolism is important to guide decision-making about therapeutic anticoagulation, including in COVID-19.”

Dr. Logothetis and Dr. Tomey have disclosed no relevant financial relationships.

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

The plasma D-dimer assay has been used, along with clinical prediction scores, to rule out pulmonary embolism (PE) in critically ill patients for decades, but a new study suggests it may not be the right test to use in hospitalized COVID-19 patients.

The results showed that all hospitalized patients with COVID-19 and radiographic evidence of PE had plasma D-dimer levels of 0.05 mcg/mL or greater, the cutoff point for the diagnosis.

“If using D-dimer to exclude patients with PE, the increased values we found among 92.3% of patients suggest that this assay would be less useful than in the populations in which it was originally validated, among which a minority of patients had increased D-dimer values,” the authors write. “Setting higher D-dimer thresholds was associated with improved specificity at the cost of an increased false-negative rate that could be associated with an unacceptable patient safety risk.”

The inclusion of patients with D-dimer and computed tomography pulmonary angiography (CTPA) was necessary to estimate diagnostic performance, they note, but “this may have introduced selection bias by excluding patients unable to undergo CTPA.”

“Nonetheless, given the high pretest probability of PE and low specificity observed in this and other studies, these results suggest that use of D-dimer levels to exclude PE among patients hospitalized with COVID-19 may be inappropriate and have limited clinical utility,” they conclude.

Led by Constantine N. Logothetis, MD, from Morsani College of Medicine, University of South Florida, Tampa, the study was published online Oct. 8 as a Research Letter in JAMA Network Open.
 

Uncertain utility

The authors note that the availability of D-dimer samples routinely collected from hospitalized COVID-19 patients – as well as the heterogeneity of early, smaller studies – generated uncertainty about the utility of this assay.

This uncertainty prompted them to test the diagnostic accuracy of the D-dimer assay among a sample of 1,541 patients who were hospitalized with COVID-19 at their institution between January 2020 and February 2021 for a possible PE.

They compared plasma D-dimer concentrations with CTPA, the criterion standard for diagnosing PE, in 287 of those patients.

Overall, 118 patients (41.1%) required care in the ICU, and 27 patients (9.4%) died during hospitalization.

The investigators looked at the ability of plasma D-dimer levels collected on the same day as CTPA to diagnose PE.

Thirty-seven patients (12.9%) had radiographic evidence of PE, and 250 patients (87.1%) did not.

Overall, the vast majority of patients (92.3%; n = 265 patients) had plasma D-dimer levels of 0.05 mcg/mL or more, including all patients with PE and 225 of 250 patients without PE (91.2%).

The median D-dimer values were 1.0 mcg/mL for 250 patients without PE and 6.1 mcg/mL for 37 patients with PE.

D-dimer values ranged from 0.2 mcg/mL to 128 mcg/mL among patients without PE, and from 0.5 mcg/mL to more than 10,000 mcg/mL among patients with PE. Patients without PE had statistically significantly decreased mean D-dimer values (8.7 mcg/mL vs. 1.2 mcg/mL; P < .001).

A D-dimer concentration of 0.05 mcg/mL was associated with a sensitivity of 100%, specificity of 8.8%, negative predictive value (NPV) of 100%, positive predictive value (PPV) of 13.9%, and a negative likelihood ratio (NLR) of less than 0.1.

The age-adjusted threshold was associated with a sensitivity of 94.6%, specificity of 22.8%, NPV of 96.6%, PPV of 13.9%, and NLR of 0.24.

The authors note that all hospitalized patients with COVID-19 and radiographic evidence of PE had plasma D-dimer levels of 0.05 mcg/mL or greater.
 

D-dimer in VTE may not extrapolate to COVID-19

“The D-dimer test, which is a measure of circulating byproducts of blood clot dissolution, has long been incorporated into diagnostic algorithms for venous thromboembolic [VTE] disease, including deep vein thrombosis and pulmonary embolism. It is uncertain whether this diagnostic use of D-dimer testing can be extrapolated to the context of COVID-19 – an illness we now understand to be associated itself with intravascular thrombosis and fibrinolysis,” Matthew Tomey, MD, a cardiologist at Mount Sinai Morningside, New York, said in an interview.

“The authors of this study sought to evaluate the test characteristics of the D-dimer assay for diagnosis of pulmonary embolism in a consecutive series of 287 hospitalized patients with COVID-19 who underwent computed tomography pulmonary angiography (CTPA). This was a selected group of patients representing less than 20% of the 1,541 patients screened. Exclusion of data on the more than 80% of screened patients who did not undergo CTPA is a significant limitation of the study,” Dr. Tomey said.

“In the highly selected, small cohort studied, representing a group of patients at high pretest probability of pulmonary embolism, there was no patient with pulmonary embolism who had a D-dimer value less than 0.5 mcg/mL. Yet broad ranges of D-dimer values were observed in COVID-19 patients with (0.5 to >10,000 mcg/mL) and without (0.2 to 128 mcg/mL) pulmonary embolism,” he added.

Based on the presented data, it is likely true that very low levels of D-dimer decrease the likelihood of finding a pulmonary embolus on a CTPA, if it is performed, Dr. Tomey noted.

“Yet the data confirm that a wide range of D-dimer values can be observed in COVID-19 patients with or without pulmonary embolism. It is not clear at this time that D-dimer levels should be used as gatekeepers to diagnostic imaging studies such as CTPA when pretest suspicion of pulmonary embolism is high,” he said.

“This issue becomes relevant as we consider evolving data on use of anticoagulation in treatment of hospitalized patients with COVID-19. We learned this year that in critically ill patients hospitalized with COVID-19, routine therapeutic anticoagulation (with heparin) was not beneficial and potentially harmful when compared with usual thromboprophylaxis,” he concluded.

“As we strive to balance competing risks of bleeding and thrombosis, accurate diagnosis of pulmonary embolism is important to guide decision-making about therapeutic anticoagulation, including in COVID-19.”

Dr. Logothetis and Dr. Tomey have disclosed no relevant financial relationships.

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

Background: Despite the increased mortality rate of the novel coronavirus compared with influenza, little is understood about its pathogenicity. Prior studies have identified D-dimer levels, high Sequential Organ Failure Assessment score, and older age as markers for more severe disease and mortality. The specific cause of death of COVID-19 remains largely unknown.

This small case series piques interest in the potential underrecognized thromboembolic pathology of COVID-19. While not practice changing, this study highlights the importance of hospitalists staying attuned to further studies regarding VTE prophylaxis in COVID-19.

Bottom line: Autopsies of COVID-19 patients revealed a high incidence of thromboembolic events; COVID-19–induced coagulopathy may play an underrecognized role in pathogenesis.

Citation: Wichmann D et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020;173(4):268-77.

Dr. Fletcher is a hospitalist at the Lexington (Ky.) VA Health Care System.

Background: Despite the increased mortality rate of the novel coronavirus compared with influenza, little is understood about its pathogenicity. Prior studies have identified D-dimer levels, high Sequential Organ Failure Assessment score, and older age as markers for more severe disease and mortality. The specific cause of death of COVID-19 remains largely unknown.

This small case series piques interest in the potential underrecognized thromboembolic pathology of COVID-19. While not practice changing, this study highlights the importance of hospitalists staying attuned to further studies regarding VTE prophylaxis in COVID-19.

Bottom line: Autopsies of COVID-19 patients revealed a high incidence of thromboembolic events; COVID-19–induced coagulopathy may play an underrecognized role in pathogenesis.

Citation: Wichmann D et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020;173(4):268-77.

Dr. Fletcher is a hospitalist at the Lexington (Ky.) VA Health Care System.

Background: Despite the increased mortality rate of the novel coronavirus compared with influenza, little is understood about its pathogenicity. Prior studies have identified D-dimer levels, high Sequential Organ Failure Assessment score, and older age as markers for more severe disease and mortality. The specific cause of death of COVID-19 remains largely unknown.

This small case series piques interest in the potential underrecognized thromboembolic pathology of COVID-19. While not practice changing, this study highlights the importance of hospitalists staying attuned to further studies regarding VTE prophylaxis in COVID-19.

Bottom line: Autopsies of COVID-19 patients revealed a high incidence of thromboembolic events; COVID-19–induced coagulopathy may play an underrecognized role in pathogenesis.

Citation: Wichmann D et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020;173(4):268-77.

Dr. Fletcher is a hospitalist at the Lexington (Ky.) VA Health Care System.

A study that compared three types of direct oral anticoagulants (DOACs) found that rivaroxaban was associated with a much higher risk of overall and major gastrointestinal bleeding than apixaban or dabigatran.

The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.

DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.

These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,

Daily dosage may exacerbate risk

Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.

Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.

Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.

The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.

Overall, the study cohort was small, compared with previous registry studies.

Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
 

Clinicians should consider location of bleeding

Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.

“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.

“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
 

Other studies yield similar results

Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.

Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.

A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.

“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.

“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.

The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.

A study that compared three types of direct oral anticoagulants (DOACs) found that rivaroxaban was associated with a much higher risk of overall and major gastrointestinal bleeding than apixaban or dabigatran.

The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.

DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.

These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,

Daily dosage may exacerbate risk

Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.

Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.

Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.

The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.

Overall, the study cohort was small, compared with previous registry studies.

Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
 

Clinicians should consider location of bleeding

Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.

“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.

“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
 

Other studies yield similar results

Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.

Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.

A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.

“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.

“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.

The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.

A study that compared three types of direct oral anticoagulants (DOACs) found that rivaroxaban was associated with a much higher risk of overall and major gastrointestinal bleeding than apixaban or dabigatran.

The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.

DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.

These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,

Daily dosage may exacerbate risk

Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.

Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.

Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.

The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.

Overall, the study cohort was small, compared with previous registry studies.

Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
 

Clinicians should consider location of bleeding

Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.

“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.

“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
 

Other studies yield similar results

Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.

Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.

A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.

“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.

“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.

The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.

Circulating ketone bodies (KBs) are substantially elevated at presentation and 24 hours after ST-segment elevation myocardial infarction (STEMI), according to new research.

The study also showed that greater KB levels measured after 24 hours of reperfusion were associated with larger infarct size and reduced left ventricular ejection fraction (LVEF).

The findings suggest a potential role for ketone metabolism in response to myocardial ischemia, conclude researchers in their report, published in the October 5 issue of the Journal of the American College of Cardiology.

“Ketones serve as an alternative source of energy for the heart,” lead author Marie-Sophie L.Y. de Koning, MD, University Medical Center Groningen, the Netherlands, told this news organization.

“These results might suggest that ketone bodies may be an important fuel for the heart after myocardial ischemia.” The role of KBs in heart failure has been previously studied, but their role in myocardial infarction has not, Dr. De Koning said.

“In heart failure, metabolic changes occur that cause the heart to increasingly rely on ketone bodies as an important energy source. Accordingly, concentrations of circulating ketone bodies are elevated and higher concentrations have been linked with more severe heart failure,” she said.

”This might suggest that upregulation of ketone metabolism is a universal cardiac response to stress,” Dr. De Koning added. “But the role of ketone bodies in myocardial infarction remained largely unknown, and this triggered us to investigate circulating ketone bodies in patients presenting with STEMI.”

She and her team measured circulating KBs in archived plasma samples from 369 participants in the randomized GIPS-III trial. The study had primarily looked at the effect of 4 months of metformin therapy, compared with placebo, on LVEF in nondiabetic patients with a first STEMI.

Blood samples had been taken at baseline before percutaneous coronary intervention (PCI), at 24 hours after reperfusion, and at 4 months.

The current study investigated longitudinal post-STEMI changes in the circulating KBs beta-hydroxybutyrate, acetoacetate, and acetone. It also looked at associations of KBs with infarct size and LVEF, both of which were measured with cardiac magnetic resonance (CMR) imaging 4 months after STEMI.

Circulating KB levels were three times higher at STEMI presentation than at 4 months. At presentation, the median total KB level was 520 μmol/L. It was still higher 24 hours after reperfusion than at 4 months (206 vs. 166 μmol/L; P < .001).

The 24-hour KB elevations were independently and positively associated with larger infarct size (P = .016) and lower LVEF (P = .012), the group reports.

“Our results indicate a possible role for ketone bodies during myocardial infarction,” Dr. De Koning said.

The KB elevations were probably followed by “an increase in cardiac ketone body metabolism, in order to fuel the heart that is energetically depleted.”

But the study didn’t explore cardiac KB consumption, Dr. De Koning cautioned, adding that the next steps in this research should be to investigate post-STEMI cardiac ketone metabolism and its pathophysiologic mechanisms. “This may facilitate future trials to study therapeutic effects of ketone body supplementation during or after STEMI.”

The current findings “form an essential basis for our understanding of the role of KBs in ischemia/reperfusion,” write Salva R. Yurista, MD, PhD, and colleagues, Massachusetts General Hospital and Harvard Medical School, Boston, in an accompanying editorial.

“Although the appeal of enhancing KBs as a therapeutic approach is understandable, additional rigorous preclinical and clinical studies will be required to test this therapeutic hypothesis and determine the mechanisms contributing to any benefits observed,” they note.

”Exposure to cardiac stress, such as ischemia, infarction, or heart failure, will stimulate the release of neurohormones, pro-inflammatory cytokines, and natriuretic peptides, which may play roles in stimulating ketogenesis or the production of ketone bodies,” Dr. Yurista told this news organization.

The increased circulating ketone concentrations and myocardial ketone oxidation that were associated with poor functional outcomes have been reported in other clinical contexts, including heart failure with reduced ejection fraction, heart failure with preserved cardiac function, diabetic cardiomyopathy, and arrhythmogenic cardiomyopathy, he said.

Dr. Yurista agrees that KBs could have therapeutic merit.

“Circulating ketone concentrations determine the contribution of ketones to the cardiac diet,” he said. “Thus, increasing cardiac delivery of ketone bodies through supplementation or other means to the heart undergoing stress, including STEMI and heart failure, could have therapeutic potential.”

The GIPS-III trial was supported by the Netherlands Organization for Health Research and Development (ZonMw). Neither Dr. De Koning nor the other authors report relevant financial relationships. Dr. Yurista and the other editorialists report no relevant relationships.

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

Circulating ketone bodies (KBs) are substantially elevated at presentation and 24 hours after ST-segment elevation myocardial infarction (STEMI), according to new research.

The study also showed that greater KB levels measured after 24 hours of reperfusion were associated with larger infarct size and reduced left ventricular ejection fraction (LVEF).

The findings suggest a potential role for ketone metabolism in response to myocardial ischemia, conclude researchers in their report, published in the October 5 issue of the Journal of the American College of Cardiology.

“Ketones serve as an alternative source of energy for the heart,” lead author Marie-Sophie L.Y. de Koning, MD, University Medical Center Groningen, the Netherlands, told this news organization.

“These results might suggest that ketone bodies may be an important fuel for the heart after myocardial ischemia.” The role of KBs in heart failure has been previously studied, but their role in myocardial infarction has not, Dr. De Koning said.

“In heart failure, metabolic changes occur that cause the heart to increasingly rely on ketone bodies as an important energy source. Accordingly, concentrations of circulating ketone bodies are elevated and higher concentrations have been linked with more severe heart failure,” she said.

”This might suggest that upregulation of ketone metabolism is a universal cardiac response to stress,” Dr. De Koning added. “But the role of ketone bodies in myocardial infarction remained largely unknown, and this triggered us to investigate circulating ketone bodies in patients presenting with STEMI.”

She and her team measured circulating KBs in archived plasma samples from 369 participants in the randomized GIPS-III trial. The study had primarily looked at the effect of 4 months of metformin therapy, compared with placebo, on LVEF in nondiabetic patients with a first STEMI.

Blood samples had been taken at baseline before percutaneous coronary intervention (PCI), at 24 hours after reperfusion, and at 4 months.

The current study investigated longitudinal post-STEMI changes in the circulating KBs beta-hydroxybutyrate, acetoacetate, and acetone. It also looked at associations of KBs with infarct size and LVEF, both of which were measured with cardiac magnetic resonance (CMR) imaging 4 months after STEMI.

Circulating KB levels were three times higher at STEMI presentation than at 4 months. At presentation, the median total KB level was 520 μmol/L. It was still higher 24 hours after reperfusion than at 4 months (206 vs. 166 μmol/L; P < .001).

The 24-hour KB elevations were independently and positively associated with larger infarct size (P = .016) and lower LVEF (P = .012), the group reports.

“Our results indicate a possible role for ketone bodies during myocardial infarction,” Dr. De Koning said.

The KB elevations were probably followed by “an increase in cardiac ketone body metabolism, in order to fuel the heart that is energetically depleted.”

But the study didn’t explore cardiac KB consumption, Dr. De Koning cautioned, adding that the next steps in this research should be to investigate post-STEMI cardiac ketone metabolism and its pathophysiologic mechanisms. “This may facilitate future trials to study therapeutic effects of ketone body supplementation during or after STEMI.”

The current findings “form an essential basis for our understanding of the role of KBs in ischemia/reperfusion,” write Salva R. Yurista, MD, PhD, and colleagues, Massachusetts General Hospital and Harvard Medical School, Boston, in an accompanying editorial.

“Although the appeal of enhancing KBs as a therapeutic approach is understandable, additional rigorous preclinical and clinical studies will be required to test this therapeutic hypothesis and determine the mechanisms contributing to any benefits observed,” they note.

”Exposure to cardiac stress, such as ischemia, infarction, or heart failure, will stimulate the release of neurohormones, pro-inflammatory cytokines, and natriuretic peptides, which may play roles in stimulating ketogenesis or the production of ketone bodies,” Dr. Yurista told this news organization.

The increased circulating ketone concentrations and myocardial ketone oxidation that were associated with poor functional outcomes have been reported in other clinical contexts, including heart failure with reduced ejection fraction, heart failure with preserved cardiac function, diabetic cardiomyopathy, and arrhythmogenic cardiomyopathy, he said.

Dr. Yurista agrees that KBs could have therapeutic merit.

“Circulating ketone concentrations determine the contribution of ketones to the cardiac diet,” he said. “Thus, increasing cardiac delivery of ketone bodies through supplementation or other means to the heart undergoing stress, including STEMI and heart failure, could have therapeutic potential.”

The GIPS-III trial was supported by the Netherlands Organization for Health Research and Development (ZonMw). Neither Dr. De Koning nor the other authors report relevant financial relationships. Dr. Yurista and the other editorialists report no relevant relationships.

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

Circulating ketone bodies (KBs) are substantially elevated at presentation and 24 hours after ST-segment elevation myocardial infarction (STEMI), according to new research.

The study also showed that greater KB levels measured after 24 hours of reperfusion were associated with larger infarct size and reduced left ventricular ejection fraction (LVEF).

The findings suggest a potential role for ketone metabolism in response to myocardial ischemia, conclude researchers in their report, published in the October 5 issue of the Journal of the American College of Cardiology.

“Ketones serve as an alternative source of energy for the heart,” lead author Marie-Sophie L.Y. de Koning, MD, University Medical Center Groningen, the Netherlands, told this news organization.

“These results might suggest that ketone bodies may be an important fuel for the heart after myocardial ischemia.” The role of KBs in heart failure has been previously studied, but their role in myocardial infarction has not, Dr. De Koning said.

“In heart failure, metabolic changes occur that cause the heart to increasingly rely on ketone bodies as an important energy source. Accordingly, concentrations of circulating ketone bodies are elevated and higher concentrations have been linked with more severe heart failure,” she said.

”This might suggest that upregulation of ketone metabolism is a universal cardiac response to stress,” Dr. De Koning added. “But the role of ketone bodies in myocardial infarction remained largely unknown, and this triggered us to investigate circulating ketone bodies in patients presenting with STEMI.”

She and her team measured circulating KBs in archived plasma samples from 369 participants in the randomized GIPS-III trial. The study had primarily looked at the effect of 4 months of metformin therapy, compared with placebo, on LVEF in nondiabetic patients with a first STEMI.

Blood samples had been taken at baseline before percutaneous coronary intervention (PCI), at 24 hours after reperfusion, and at 4 months.

The current study investigated longitudinal post-STEMI changes in the circulating KBs beta-hydroxybutyrate, acetoacetate, and acetone. It also looked at associations of KBs with infarct size and LVEF, both of which were measured with cardiac magnetic resonance (CMR) imaging 4 months after STEMI.

Circulating KB levels were three times higher at STEMI presentation than at 4 months. At presentation, the median total KB level was 520 μmol/L. It was still higher 24 hours after reperfusion than at 4 months (206 vs. 166 μmol/L; P < .001).

The 24-hour KB elevations were independently and positively associated with larger infarct size (P = .016) and lower LVEF (P = .012), the group reports.

“Our results indicate a possible role for ketone bodies during myocardial infarction,” Dr. De Koning said.

The KB elevations were probably followed by “an increase in cardiac ketone body metabolism, in order to fuel the heart that is energetically depleted.”

But the study didn’t explore cardiac KB consumption, Dr. De Koning cautioned, adding that the next steps in this research should be to investigate post-STEMI cardiac ketone metabolism and its pathophysiologic mechanisms. “This may facilitate future trials to study therapeutic effects of ketone body supplementation during or after STEMI.”

The current findings “form an essential basis for our understanding of the role of KBs in ischemia/reperfusion,” write Salva R. Yurista, MD, PhD, and colleagues, Massachusetts General Hospital and Harvard Medical School, Boston, in an accompanying editorial.

“Although the appeal of enhancing KBs as a therapeutic approach is understandable, additional rigorous preclinical and clinical studies will be required to test this therapeutic hypothesis and determine the mechanisms contributing to any benefits observed,” they note.

”Exposure to cardiac stress, such as ischemia, infarction, or heart failure, will stimulate the release of neurohormones, pro-inflammatory cytokines, and natriuretic peptides, which may play roles in stimulating ketogenesis or the production of ketone bodies,” Dr. Yurista told this news organization.

The increased circulating ketone concentrations and myocardial ketone oxidation that were associated with poor functional outcomes have been reported in other clinical contexts, including heart failure with reduced ejection fraction, heart failure with preserved cardiac function, diabetic cardiomyopathy, and arrhythmogenic cardiomyopathy, he said.

Dr. Yurista agrees that KBs could have therapeutic merit.

“Circulating ketone concentrations determine the contribution of ketones to the cardiac diet,” he said. “Thus, increasing cardiac delivery of ketone bodies through supplementation or other means to the heart undergoing stress, including STEMI and heart failure, could have therapeutic potential.”

The GIPS-III trial was supported by the Netherlands Organization for Health Research and Development (ZonMw). Neither Dr. De Koning nor the other authors report relevant financial relationships. Dr. Yurista and the other editorialists report no relevant relationships.

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

A new series of cases of cerebral venous sinus thrombosis (CVST) linked to the adenoviral vector COVID-19 vaccines has been reported, confirming the severity of the reaction and the associated high mortality rate.

The new series comes from an international registry of consecutive patients who experienced CVST within 28 days of COVID-19 vaccination between March 29 and June 18, 2021, from 81 hospitals in 19 countries.

The cases are described in an article published online on Sept. 28. in JAMA Neurology.

“This is a reliable description on the clinical condition of these patients with CVST associated with COVID-19 vaccination. It is striking that this a much worse condition than CVST not associated with COVID-19 vaccination, with a much higher rate of intracerebral hemorrhage and coma and a much higher mortality rate,” senior author Jonathan M. Coutinho, MD, Amsterdam University Medical Centers, told this news organization.

These data confirm the observations from an earlier U.K. cohort in which cases of cerebral venous thrombosis linked to COVID-19 vaccination occurred.

“This is the biggest series, and as an international series, it gives a broader perspective from a larger range of countries,” Dr. Coutinho said. “All the data together show that, although this side effect is rare, the consequences are very severe,” he added.

In the current study, the researchers regarded CVST as being linked to the vaccine if it was accompanied by thrombosis with thrombocytopenia syndrome (TTS), as evidenced by thrombosis and new-onset thrombocytopenia.

In the cohort of 116 patients with CVST after COVID-19 vaccination, 78 (67.2%) had thrombosis with TTS and were thus classified as having had a vaccine-related adverse event. These patients were frequently comatose at presentation (24%) and often had intracerebral hemorrhage (68%) and concomitant thromboembolism (36%); 47% died during hospitalization.

These patients were compared with the 38 patients in the same cohort who had CVST but in whom there was no indication of concomitant thrombosis and thrombocytopenia. The case patients were also compared with a control group of 207 patients with CVST who were included in a separate international registry before the COVID-19 pandemic.

Mortality rates were much higher among the patients deemed to have had a vaccine-related CVST. The in-hospital mortality rate was 47%, compared with 5% among the patients in the same cohort who did not have TTS and 3.9% among the prepandemic control group.

The mortality rate was even higher (61%) among patients in the TTS group for whom the diagnosis was made before the condition garnered attention in the scientific community. The mortality rate was 42% among patients diagnosed later.

Of the 78 patients in whom CVST and TTS occurred after COVID-19 vaccination in this cohort, 76 had received the AstraZeneca vaccine (in 75 patients, CVST and TTS occurred after the first vaccination; in one patient, they occurred after the second vaccination). One patient had received the Johnson & Johnson vaccine, and one had received the Pfizer vaccine.

“After more analysis, the case after the Pfizer vaccination is not believed to be caused by the vaccine,” Dr. Coutinho said. “In that case, the patient had a platelet count just below the lower limit and was taking an immunomodulator drug that is known to be associated with thrombocytopenia.”

For two patients who received the AstraZeneca vaccine, there was also an alternative explanation for the thrombocytopenia.

Dr. Coutinho also pointed out that the Johnson & Johnson vaccine has been used mainly in the United States, and these data were largely from other countries.

The median time from vaccination to CVST symptom onset was 9 days in the TTS group. The median platelet count at hospital admission among patients with postvaccination CVST-TTS was 45. Three patients presented with a normal platelet count and developed thrombocytopenia during admission; two patients presented with mild thrombocytopenia, 30 presented with moderate thrombocytopenia, and 43 presented with severe thrombocytopenia.

Antibodies against platelet factor 4 (PF4) were measured in 69 patients with TTS, of whom 63 (91%) tested positive (the one patient in whom TTS occurred after the patient received the Pfizer vaccine did not test positive). However, the researchers note that sensitivity varies among different PF4 ELISA tests. Findings of platelet activation assays were positive in all 36 tested patients.

In the TTS group, 52 patients (67%) received immunomodulation therapy, most often intravenous immunoglobulins (IVIG). Among patients treated with IVIG, the mortality rate was lower (28%).
 

Different from CVST linked to natural COVID-19 infection

Dr. Coutinho noted that CVST can occur in natural SARS-CoV-2 infection but that vaccine-associated CVST is very different.

“In natural COVID-19 infection, there is an increased risk of thrombosis, and some patients can get CVST as a part of this, but in these cases, this is not accompanied by thrombocytopenia. While the CVST in natural COVID-19 infection is also associated with a bad prognosis, this is more to do with the underlying disease. It is normally the very sick COVID patients who develop CVST, and these patients usually die from the underlying disease rather than the CVST itself,” he explained.

“Clinicians need to be aware of vaccine-related CVST, as it requires very specific and rapid treatment,” Dr. Coutinho stressed.

“Patients presenting with an extremely severe headache (unlike any headache they’ve had before) or with seizures or a focal deficit (weakness in arm or problems with speaking or vision) within 4 weeks of an adenovirus COVID-19 vaccination should ring alarm bells. It is important to do diagnostics quickly, with a platelet count the most important first step, and a rapid CT/MRI scan,” he said.

Other tests that should be conducted are D-dimer for thrombosis and the PF4 antibody test. But results for the PF4 antibody test can take days to come back, and clinicians shouldn’t wait for that, Dr. Coutinho notes.

“Specific treatment needs to be given immediately – with anticoagulation (preferably nonheparin) and immunomodulation with IVIG to stop the immune reaction. Platelets should not be given – that may seem counterintuitive in patients with a low platelet count, but giving platelets makes it worse,” he said.
 

Is there a geographic difference?

Dr. Coutinho pointed out that fewer cases of this vaccine-related CVST are being reported at the current time.

“We are not sure why this is the case. These adenovirus vaccines are not being used much now in Western countries, but our collaboration covers many less developed countries in South America and Asia, which are relying heavily on these vaccines. We are now shifting focus to these countries, but so far we have only seen a handful of cases from these areas,” he said.

He suggested that this may be because these countries started their vaccination programs later and are vaccinating their elderly (who are not so susceptible to this side effect) first, or it may be because of some environmental or genetic factor that has not yet been discovered.

“This is now an important research question – is the risk of vaccine-induced CVST the same in different countries or ethnicities? This could influence decisions on future vaccine strategies,” Dr. Coutinho said.

“So far, female sex is the strongest risk factor for vaccine-induced CVST. In our cohort, 81% of cases were in women. In addition, 95% were White, but that doesn’t allow us to conclude that this is a risk factor, as the majority of people who have been vaccinated are White. So, we have no clear insight into that yet,” he said.

In a comment for this news organization, the lead author of the previous U.K. report of a series of 70 cases of cerebral venous thrombosis linked to COVID-19 vaccination, Richard Perry, PhD, University College Hospital, London, described this new report as “an excellent study, with many of the same strengths and weaknesses as our study and has very similar results.”

Dr. Perry noted that the two studies used slightly different definitions of vaccine-induced thrombotic thrombocytopenia, but the cases reported appear to be very similar overall. “It is reassuring and gratifying to see that they have made such similar observations,” he said.

“And as they have drawn their cases from a broad range of countries whereas ours were all from the U.K., this provides evidence that the observations from both studies are reasonably generalizable,” he added.

Dr. Perry pointed out that this new report states that TTS occurred in one patient after the patient had received a second dose of the AstraZeneca vaccine. “I would like to know more about this case, because we didn’t see any cases after a second dose in our cohort,” he said.

Dr. Coutinho responded that he didn’t believe this was the first reported case after the second dose.

The study did not receive any specific funding. Dr. Coutinho has received grants paid to his institution from Boehringer Ingelheim and Bayer and payments paid to his institution for data safety monitoring board participation by Bayer.

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

A new series of cases of cerebral venous sinus thrombosis (CVST) linked to the adenoviral vector COVID-19 vaccines has been reported, confirming the severity of the reaction and the associated high mortality rate.

The new series comes from an international registry of consecutive patients who experienced CVST within 28 days of COVID-19 vaccination between March 29 and June 18, 2021, from 81 hospitals in 19 countries.

The cases are described in an article published online on Sept. 28. in JAMA Neurology.

“This is a reliable description on the clinical condition of these patients with CVST associated with COVID-19 vaccination. It is striking that this a much worse condition than CVST not associated with COVID-19 vaccination, with a much higher rate of intracerebral hemorrhage and coma and a much higher mortality rate,” senior author Jonathan M. Coutinho, MD, Amsterdam University Medical Centers, told this news organization.

These data confirm the observations from an earlier U.K. cohort in which cases of cerebral venous thrombosis linked to COVID-19 vaccination occurred.

“This is the biggest series, and as an international series, it gives a broader perspective from a larger range of countries,” Dr. Coutinho said. “All the data together show that, although this side effect is rare, the consequences are very severe,” he added.

In the current study, the researchers regarded CVST as being linked to the vaccine if it was accompanied by thrombosis with thrombocytopenia syndrome (TTS), as evidenced by thrombosis and new-onset thrombocytopenia.

In the cohort of 116 patients with CVST after COVID-19 vaccination, 78 (67.2%) had thrombosis with TTS and were thus classified as having had a vaccine-related adverse event. These patients were frequently comatose at presentation (24%) and often had intracerebral hemorrhage (68%) and concomitant thromboembolism (36%); 47% died during hospitalization.

These patients were compared with the 38 patients in the same cohort who had CVST but in whom there was no indication of concomitant thrombosis and thrombocytopenia. The case patients were also compared with a control group of 207 patients with CVST who were included in a separate international registry before the COVID-19 pandemic.

Mortality rates were much higher among the patients deemed to have had a vaccine-related CVST. The in-hospital mortality rate was 47%, compared with 5% among the patients in the same cohort who did not have TTS and 3.9% among the prepandemic control group.

The mortality rate was even higher (61%) among patients in the TTS group for whom the diagnosis was made before the condition garnered attention in the scientific community. The mortality rate was 42% among patients diagnosed later.

Of the 78 patients in whom CVST and TTS occurred after COVID-19 vaccination in this cohort, 76 had received the AstraZeneca vaccine (in 75 patients, CVST and TTS occurred after the first vaccination; in one patient, they occurred after the second vaccination). One patient had received the Johnson & Johnson vaccine, and one had received the Pfizer vaccine.

“After more analysis, the case after the Pfizer vaccination is not believed to be caused by the vaccine,” Dr. Coutinho said. “In that case, the patient had a platelet count just below the lower limit and was taking an immunomodulator drug that is known to be associated with thrombocytopenia.”

For two patients who received the AstraZeneca vaccine, there was also an alternative explanation for the thrombocytopenia.

Dr. Coutinho also pointed out that the Johnson & Johnson vaccine has been used mainly in the United States, and these data were largely from other countries.

The median time from vaccination to CVST symptom onset was 9 days in the TTS group. The median platelet count at hospital admission among patients with postvaccination CVST-TTS was 45. Three patients presented with a normal platelet count and developed thrombocytopenia during admission; two patients presented with mild thrombocytopenia, 30 presented with moderate thrombocytopenia, and 43 presented with severe thrombocytopenia.

Antibodies against platelet factor 4 (PF4) were measured in 69 patients with TTS, of whom 63 (91%) tested positive (the one patient in whom TTS occurred after the patient received the Pfizer vaccine did not test positive). However, the researchers note that sensitivity varies among different PF4 ELISA tests. Findings of platelet activation assays were positive in all 36 tested patients.

In the TTS group, 52 patients (67%) received immunomodulation therapy, most often intravenous immunoglobulins (IVIG). Among patients treated with IVIG, the mortality rate was lower (28%).
 

Different from CVST linked to natural COVID-19 infection

Dr. Coutinho noted that CVST can occur in natural SARS-CoV-2 infection but that vaccine-associated CVST is very different.

“In natural COVID-19 infection, there is an increased risk of thrombosis, and some patients can get CVST as a part of this, but in these cases, this is not accompanied by thrombocytopenia. While the CVST in natural COVID-19 infection is also associated with a bad prognosis, this is more to do with the underlying disease. It is normally the very sick COVID patients who develop CVST, and these patients usually die from the underlying disease rather than the CVST itself,” he explained.

“Clinicians need to be aware of vaccine-related CVST, as it requires very specific and rapid treatment,” Dr. Coutinho stressed.

“Patients presenting with an extremely severe headache (unlike any headache they’ve had before) or with seizures or a focal deficit (weakness in arm or problems with speaking or vision) within 4 weeks of an adenovirus COVID-19 vaccination should ring alarm bells. It is important to do diagnostics quickly, with a platelet count the most important first step, and a rapid CT/MRI scan,” he said.

Other tests that should be conducted are D-dimer for thrombosis and the PF4 antibody test. But results for the PF4 antibody test can take days to come back, and clinicians shouldn’t wait for that, Dr. Coutinho notes.

“Specific treatment needs to be given immediately – with anticoagulation (preferably nonheparin) and immunomodulation with IVIG to stop the immune reaction. Platelets should not be given – that may seem counterintuitive in patients with a low platelet count, but giving platelets makes it worse,” he said.
 

Is there a geographic difference?

Dr. Coutinho pointed out that fewer cases of this vaccine-related CVST are being reported at the current time.

“We are not sure why this is the case. These adenovirus vaccines are not being used much now in Western countries, but our collaboration covers many less developed countries in South America and Asia, which are relying heavily on these vaccines. We are now shifting focus to these countries, but so far we have only seen a handful of cases from these areas,” he said.

He suggested that this may be because these countries started their vaccination programs later and are vaccinating their elderly (who are not so susceptible to this side effect) first, or it may be because of some environmental or genetic factor that has not yet been discovered.

“This is now an important research question – is the risk of vaccine-induced CVST the same in different countries or ethnicities? This could influence decisions on future vaccine strategies,” Dr. Coutinho said.

“So far, female sex is the strongest risk factor for vaccine-induced CVST. In our cohort, 81% of cases were in women. In addition, 95% were White, but that doesn’t allow us to conclude that this is a risk factor, as the majority of people who have been vaccinated are White. So, we have no clear insight into that yet,” he said.

In a comment for this news organization, the lead author of the previous U.K. report of a series of 70 cases of cerebral venous thrombosis linked to COVID-19 vaccination, Richard Perry, PhD, University College Hospital, London, described this new report as “an excellent study, with many of the same strengths and weaknesses as our study and has very similar results.”

Dr. Perry noted that the two studies used slightly different definitions of vaccine-induced thrombotic thrombocytopenia, but the cases reported appear to be very similar overall. “It is reassuring and gratifying to see that they have made such similar observations,” he said.

“And as they have drawn their cases from a broad range of countries whereas ours were all from the U.K., this provides evidence that the observations from both studies are reasonably generalizable,” he added.

Dr. Perry pointed out that this new report states that TTS occurred in one patient after the patient had received a second dose of the AstraZeneca vaccine. “I would like to know more about this case, because we didn’t see any cases after a second dose in our cohort,” he said.

Dr. Coutinho responded that he didn’t believe this was the first reported case after the second dose.

The study did not receive any specific funding. Dr. Coutinho has received grants paid to his institution from Boehringer Ingelheim and Bayer and payments paid to his institution for data safety monitoring board participation by Bayer.

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

A new series of cases of cerebral venous sinus thrombosis (CVST) linked to the adenoviral vector COVID-19 vaccines has been reported, confirming the severity of the reaction and the associated high mortality rate.

The new series comes from an international registry of consecutive patients who experienced CVST within 28 days of COVID-19 vaccination between March 29 and June 18, 2021, from 81 hospitals in 19 countries.

The cases are described in an article published online on Sept. 28. in JAMA Neurology.

“This is a reliable description on the clinical condition of these patients with CVST associated with COVID-19 vaccination. It is striking that this a much worse condition than CVST not associated with COVID-19 vaccination, with a much higher rate of intracerebral hemorrhage and coma and a much higher mortality rate,” senior author Jonathan M. Coutinho, MD, Amsterdam University Medical Centers, told this news organization.

These data confirm the observations from an earlier U.K. cohort in which cases of cerebral venous thrombosis linked to COVID-19 vaccination occurred.

“This is the biggest series, and as an international series, it gives a broader perspective from a larger range of countries,” Dr. Coutinho said. “All the data together show that, although this side effect is rare, the consequences are very severe,” he added.

In the current study, the researchers regarded CVST as being linked to the vaccine if it was accompanied by thrombosis with thrombocytopenia syndrome (TTS), as evidenced by thrombosis and new-onset thrombocytopenia.

In the cohort of 116 patients with CVST after COVID-19 vaccination, 78 (67.2%) had thrombosis with TTS and were thus classified as having had a vaccine-related adverse event. These patients were frequently comatose at presentation (24%) and often had intracerebral hemorrhage (68%) and concomitant thromboembolism (36%); 47% died during hospitalization.

These patients were compared with the 38 patients in the same cohort who had CVST but in whom there was no indication of concomitant thrombosis and thrombocytopenia. The case patients were also compared with a control group of 207 patients with CVST who were included in a separate international registry before the COVID-19 pandemic.

Mortality rates were much higher among the patients deemed to have had a vaccine-related CVST. The in-hospital mortality rate was 47%, compared with 5% among the patients in the same cohort who did not have TTS and 3.9% among the prepandemic control group.

The mortality rate was even higher (61%) among patients in the TTS group for whom the diagnosis was made before the condition garnered attention in the scientific community. The mortality rate was 42% among patients diagnosed later.

Of the 78 patients in whom CVST and TTS occurred after COVID-19 vaccination in this cohort, 76 had received the AstraZeneca vaccine (in 75 patients, CVST and TTS occurred after the first vaccination; in one patient, they occurred after the second vaccination). One patient had received the Johnson & Johnson vaccine, and one had received the Pfizer vaccine.

“After more analysis, the case after the Pfizer vaccination is not believed to be caused by the vaccine,” Dr. Coutinho said. “In that case, the patient had a platelet count just below the lower limit and was taking an immunomodulator drug that is known to be associated with thrombocytopenia.”

For two patients who received the AstraZeneca vaccine, there was also an alternative explanation for the thrombocytopenia.

Dr. Coutinho also pointed out that the Johnson & Johnson vaccine has been used mainly in the United States, and these data were largely from other countries.

The median time from vaccination to CVST symptom onset was 9 days in the TTS group. The median platelet count at hospital admission among patients with postvaccination CVST-TTS was 45. Three patients presented with a normal platelet count and developed thrombocytopenia during admission; two patients presented with mild thrombocytopenia, 30 presented with moderate thrombocytopenia, and 43 presented with severe thrombocytopenia.

Antibodies against platelet factor 4 (PF4) were measured in 69 patients with TTS, of whom 63 (91%) tested positive (the one patient in whom TTS occurred after the patient received the Pfizer vaccine did not test positive). However, the researchers note that sensitivity varies among different PF4 ELISA tests. Findings of platelet activation assays were positive in all 36 tested patients.

In the TTS group, 52 patients (67%) received immunomodulation therapy, most often intravenous immunoglobulins (IVIG). Among patients treated with IVIG, the mortality rate was lower (28%).
 

Different from CVST linked to natural COVID-19 infection

Dr. Coutinho noted that CVST can occur in natural SARS-CoV-2 infection but that vaccine-associated CVST is very different.

“In natural COVID-19 infection, there is an increased risk of thrombosis, and some patients can get CVST as a part of this, but in these cases, this is not accompanied by thrombocytopenia. While the CVST in natural COVID-19 infection is also associated with a bad prognosis, this is more to do with the underlying disease. It is normally the very sick COVID patients who develop CVST, and these patients usually die from the underlying disease rather than the CVST itself,” he explained.

“Clinicians need to be aware of vaccine-related CVST, as it requires very specific and rapid treatment,” Dr. Coutinho stressed.

“Patients presenting with an extremely severe headache (unlike any headache they’ve had before) or with seizures or a focal deficit (weakness in arm or problems with speaking or vision) within 4 weeks of an adenovirus COVID-19 vaccination should ring alarm bells. It is important to do diagnostics quickly, with a platelet count the most important first step, and a rapid CT/MRI scan,” he said.

Other tests that should be conducted are D-dimer for thrombosis and the PF4 antibody test. But results for the PF4 antibody test can take days to come back, and clinicians shouldn’t wait for that, Dr. Coutinho notes.

“Specific treatment needs to be given immediately – with anticoagulation (preferably nonheparin) and immunomodulation with IVIG to stop the immune reaction. Platelets should not be given – that may seem counterintuitive in patients with a low platelet count, but giving platelets makes it worse,” he said.
 

Is there a geographic difference?

Dr. Coutinho pointed out that fewer cases of this vaccine-related CVST are being reported at the current time.

“We are not sure why this is the case. These adenovirus vaccines are not being used much now in Western countries, but our collaboration covers many less developed countries in South America and Asia, which are relying heavily on these vaccines. We are now shifting focus to these countries, but so far we have only seen a handful of cases from these areas,” he said.

He suggested that this may be because these countries started their vaccination programs later and are vaccinating their elderly (who are not so susceptible to this side effect) first, or it may be because of some environmental or genetic factor that has not yet been discovered.

“This is now an important research question – is the risk of vaccine-induced CVST the same in different countries or ethnicities? This could influence decisions on future vaccine strategies,” Dr. Coutinho said.

“So far, female sex is the strongest risk factor for vaccine-induced CVST. In our cohort, 81% of cases were in women. In addition, 95% were White, but that doesn’t allow us to conclude that this is a risk factor, as the majority of people who have been vaccinated are White. So, we have no clear insight into that yet,” he said.

In a comment for this news organization, the lead author of the previous U.K. report of a series of 70 cases of cerebral venous thrombosis linked to COVID-19 vaccination, Richard Perry, PhD, University College Hospital, London, described this new report as “an excellent study, with many of the same strengths and weaknesses as our study and has very similar results.”

Dr. Perry noted that the two studies used slightly different definitions of vaccine-induced thrombotic thrombocytopenia, but the cases reported appear to be very similar overall. “It is reassuring and gratifying to see that they have made such similar observations,” he said.

“And as they have drawn their cases from a broad range of countries whereas ours were all from the U.K., this provides evidence that the observations from both studies are reasonably generalizable,” he added.

Dr. Perry pointed out that this new report states that TTS occurred in one patient after the patient had received a second dose of the AstraZeneca vaccine. “I would like to know more about this case, because we didn’t see any cases after a second dose in our cohort,” he said.

Dr. Coutinho responded that he didn’t believe this was the first reported case after the second dose.

The study did not receive any specific funding. Dr. Coutinho has received grants paid to his institution from Boehringer Ingelheim and Bayer and payments paid to his institution for data safety monitoring board participation by Bayer.

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