Thrombosis

Five risk factors might help pinpoint patients at risk of developing device-related thrombus (DRT), itself an important risk factor for cerebrovascular events, in patients with implants for left atrial appendage occlusion (LAAO), new research suggests.

The identified independent predictors of DRT in the largest dedicated multicenter LAAO-DRT registry to date were presence of a hypercoagulability disorder, pericardial effusion, renal insufficiency, an implantation depth greater than 10 mm from the pulmonary ridge, and presence of nonparoxysmal atrial fibrillation (AFib).

“Unfortunately, most of them are not modifiable, like hypercoaguable disorders or nonparoxysmal atrial fibrillation. But we can avoid deep implants because that’s been associated with creating a little bit of a crater or valley where the clot can form,” senior author Mohamad Alkhouli, MD, said in an interview.

But most important, and “really why we wanted to do this,” he said, is that “we want to give the patient a realistic prediction of adverse events for this procedure.”

LAAO has taken off in recent years for preventing thrombus formation and stroke in patients with AFib. Predicting DRT is a priority for the LAAO field, the authors note, especially given its expansion to younger, lower-risk patients and the increasing procedural volumes.

“This is a problem, DRT, that’s been discussed a lot because this is a preventative procedure,” observed Dr. Alkhouli, professor of medicine at Mayo Medical School, Rochester, Minn.

“The actual stroke risk every year – even if you don’t take any blood thinner and you have a CHADsVASc score of 9, the highest – is 11%. So if the chance of having thrombus is close, then that’s not a good tradeoff.”

Previous studies have also identified implantation depth and nonparoxysmal AFib as risk factors for DRT. But most of them have been small, he noted, with one of the largest reporting 65 DRTs in four prospective trials.

To cast a wider net, the investigators, led by Trevor Simard, MD, also from the Mayo Clinic, invited more than 50 international sites to contribute data to the registry. Of these, 37 centers reported on 237 DRTs and 474 device-matched control subjects from the same site.

Three-fourths of patients received a first-generation Watchman or a FLEX device (Boston Scientific).

Medical regimens were similar between the DRT and control cohorts at discharge after LAA closure. Most patients were managed with single (36.3%) or dual antiplatelet therapy (26.2%) at the time of DRT diagnosis.

As reported July 19 in the Journal of the American College of Cardiology, the timing of DRT development varied widely, with 24.9% appearing in the first 45 days, 38.8% between days 45 and 180, 16.0% between days 180 to 365, and 20.3% beyond 1 year. At last known follow-up, one-quarter of patients had DRT.

The odds ratios for DRT associated with the five identified risk factors were:

• 17.50 (95% confidence interval, 3.39-90.45) for hypercoagulability disorder
• 13.45 (95% CI, 1.46-123.52) for pericardial effusion
• 4.02 (95% CI, 1.22-13.25) for renal insufficiency
• 2.41 (95% CI, 1.57-3.69) for implantation depth >10 mm
• 1.90 (95% CI, 1.22-2.97) for nonparoxysmal AFib

The risk for a composite of death, ischemic stroke, and systemic embolization was twofold higher in the DRT cohort than in the control cohort (29.5% vs. 14.4%; hazard ratio, 2.37; 95% CI, 1.58-3.56) and driven by a higher rate of ischemic stroke (16.9% vs. 3.6%; HR, 3.49; 95% CI, 1.35-9.00).

The incidence of bleeding and intracerebral hemorrhage, however, was similar in the DRT and control cohorts.

One of the surprises of the study was that medications prescribed in the short term after LAA closure were not associated with DRT, Dr. Alkhouli said. A previous meta-analysis of 66 studies by the investigators also found that antithrombotic regimen did not explain the heterogeneity of DRT formation.

“I think we’ll have to take that with a grain of salt, because there’s so many variations in the practice, and this is observational data. But that, in my mind, brings up a mechanistic issue,” he said.

It’s often recommended “that we should put patients on blood thinners for 3 months or 6 weeks, or whatever it is, to decrease the chance of thrombus, assuming the patients will have a normal endothelialization of the device,” Dr. Alkhouli said.

“Well, we know that’s not the reality,” he continued. “We know many patients don’t endothelialize, and, even if some patients do, there may be some endothelial damage. So I think the whole mechanism of prescribing a little bit of a blood thinner to avoid that risk may be missing the point. It’s a bit more complex than that, evidenced also by the fact that three-fourths of all the DRTs happened after 45 days, when patients are typically not taking a blood thinner.”

Based on the five independent risk factors, the investigators created a clinical DRT risk score that assigned 1 point for renal insufficiency, implantation depth greater than 10 mm from the pulmonary ridge, and nonparoxysmal AFib; and 4 points for iatrogenic pericardial effusion and for hypercoagulability disorder. Low risk was categorized as 1 point and high risk as 2 or more points.

The presence of one major risk factor or two minor risk factors, for example, led to a 2.1-fold increased risk for DRT, compared with those with no DRT risk factors.

The risk score will require validation in a prospective cohort but is “a step forward in addressing DRT” and triaging patients, Dr. Alkhouli said. The findings highlight the need to avoid deep device implantation and the importance of shared decision-making with patients, especially with those at high risk.

“And third, which is most important, I think, in my mind, is that it tells us not to put a blind eye to this topic and just say with improved devices it will go away,” he said. “That’s a bit unrealistic.”

In an accompanying editorial, Oussama Wazni, MD, Walid Saliba, MD, and Ayman A. Hussein, MD, all from the Cleveland Clinic, write that “the study sheds light on this yet unresolved issue, and the observations may help with risk stratification and optimization of procedural techniques.”

Whereas many of the nonmodifiable risk factors are helpful in shared decision-making decisions, they continue, “knowledge of these risk factors may not preclude implantation in patients who are otherwise at risk of both stroke off anticoagulation and bleeding on anticoagulation.”

Dr. Wazni and colleagues acknowledge that the small number of events in the study limits statistical power for definitive conclusions and say that further studies are needed to clarify the natural history of DRTs and their management, resolution, and impact on cardiovascular events.

Practitioners should also continue to cautiously assess for LAAO clinical indications for implant, according to the editorialists, who point out that the regulatory approval language in the United States was “flexible and nonspecific.”

“As the field grows wider, enhancing LAAO safety with optimal design, implantation, and periprocedural management is critically important, yet the main focus should remain on optimal patient selection for the purpose of achieving safe and successful outcomes,” the editorialists conclude.

Dr. Alkhouli has served as a consultant for Boston Scientific. Coauthor disclosures are listed in the paper. Dr. Wazni and Dr. Hussein have received research grant support from Boston Scientific. Dr. Wazni and Dr. Saliba have been consultants for Boston Scientific.

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

Five risk factors might help pinpoint patients at risk of developing device-related thrombus (DRT), itself an important risk factor for cerebrovascular events, in patients with implants for left atrial appendage occlusion (LAAO), new research suggests.

The identified independent predictors of DRT in the largest dedicated multicenter LAAO-DRT registry to date were presence of a hypercoagulability disorder, pericardial effusion, renal insufficiency, an implantation depth greater than 10 mm from the pulmonary ridge, and presence of nonparoxysmal atrial fibrillation (AFib).

“Unfortunately, most of them are not modifiable, like hypercoaguable disorders or nonparoxysmal atrial fibrillation. But we can avoid deep implants because that’s been associated with creating a little bit of a crater or valley where the clot can form,” senior author Mohamad Alkhouli, MD, said in an interview.

But most important, and “really why we wanted to do this,” he said, is that “we want to give the patient a realistic prediction of adverse events for this procedure.”

LAAO has taken off in recent years for preventing thrombus formation and stroke in patients with AFib. Predicting DRT is a priority for the LAAO field, the authors note, especially given its expansion to younger, lower-risk patients and the increasing procedural volumes.

“This is a problem, DRT, that’s been discussed a lot because this is a preventative procedure,” observed Dr. Alkhouli, professor of medicine at Mayo Medical School, Rochester, Minn.

“The actual stroke risk every year – even if you don’t take any blood thinner and you have a CHADsVASc score of 9, the highest – is 11%. So if the chance of having thrombus is close, then that’s not a good tradeoff.”

Previous studies have also identified implantation depth and nonparoxysmal AFib as risk factors for DRT. But most of them have been small, he noted, with one of the largest reporting 65 DRTs in four prospective trials.

To cast a wider net, the investigators, led by Trevor Simard, MD, also from the Mayo Clinic, invited more than 50 international sites to contribute data to the registry. Of these, 37 centers reported on 237 DRTs and 474 device-matched control subjects from the same site.

Three-fourths of patients received a first-generation Watchman or a FLEX device (Boston Scientific).

Medical regimens were similar between the DRT and control cohorts at discharge after LAA closure. Most patients were managed with single (36.3%) or dual antiplatelet therapy (26.2%) at the time of DRT diagnosis.

As reported July 19 in the Journal of the American College of Cardiology, the timing of DRT development varied widely, with 24.9% appearing in the first 45 days, 38.8% between days 45 and 180, 16.0% between days 180 to 365, and 20.3% beyond 1 year. At last known follow-up, one-quarter of patients had DRT.

The odds ratios for DRT associated with the five identified risk factors were:

• 17.50 (95% confidence interval, 3.39-90.45) for hypercoagulability disorder
• 13.45 (95% CI, 1.46-123.52) for pericardial effusion
• 4.02 (95% CI, 1.22-13.25) for renal insufficiency
• 2.41 (95% CI, 1.57-3.69) for implantation depth >10 mm
• 1.90 (95% CI, 1.22-2.97) for nonparoxysmal AFib

The risk for a composite of death, ischemic stroke, and systemic embolization was twofold higher in the DRT cohort than in the control cohort (29.5% vs. 14.4%; hazard ratio, 2.37; 95% CI, 1.58-3.56) and driven by a higher rate of ischemic stroke (16.9% vs. 3.6%; HR, 3.49; 95% CI, 1.35-9.00).

The incidence of bleeding and intracerebral hemorrhage, however, was similar in the DRT and control cohorts.

One of the surprises of the study was that medications prescribed in the short term after LAA closure were not associated with DRT, Dr. Alkhouli said. A previous meta-analysis of 66 studies by the investigators also found that antithrombotic regimen did not explain the heterogeneity of DRT formation.

“I think we’ll have to take that with a grain of salt, because there’s so many variations in the practice, and this is observational data. But that, in my mind, brings up a mechanistic issue,” he said.

It’s often recommended “that we should put patients on blood thinners for 3 months or 6 weeks, or whatever it is, to decrease the chance of thrombus, assuming the patients will have a normal endothelialization of the device,” Dr. Alkhouli said.

“Well, we know that’s not the reality,” he continued. “We know many patients don’t endothelialize, and, even if some patients do, there may be some endothelial damage. So I think the whole mechanism of prescribing a little bit of a blood thinner to avoid that risk may be missing the point. It’s a bit more complex than that, evidenced also by the fact that three-fourths of all the DRTs happened after 45 days, when patients are typically not taking a blood thinner.”

Based on the five independent risk factors, the investigators created a clinical DRT risk score that assigned 1 point for renal insufficiency, implantation depth greater than 10 mm from the pulmonary ridge, and nonparoxysmal AFib; and 4 points for iatrogenic pericardial effusion and for hypercoagulability disorder. Low risk was categorized as 1 point and high risk as 2 or more points.

The presence of one major risk factor or two minor risk factors, for example, led to a 2.1-fold increased risk for DRT, compared with those with no DRT risk factors.

The risk score will require validation in a prospective cohort but is “a step forward in addressing DRT” and triaging patients, Dr. Alkhouli said. The findings highlight the need to avoid deep device implantation and the importance of shared decision-making with patients, especially with those at high risk.

“And third, which is most important, I think, in my mind, is that it tells us not to put a blind eye to this topic and just say with improved devices it will go away,” he said. “That’s a bit unrealistic.”

In an accompanying editorial, Oussama Wazni, MD, Walid Saliba, MD, and Ayman A. Hussein, MD, all from the Cleveland Clinic, write that “the study sheds light on this yet unresolved issue, and the observations may help with risk stratification and optimization of procedural techniques.”

Whereas many of the nonmodifiable risk factors are helpful in shared decision-making decisions, they continue, “knowledge of these risk factors may not preclude implantation in patients who are otherwise at risk of both stroke off anticoagulation and bleeding on anticoagulation.”

Dr. Wazni and colleagues acknowledge that the small number of events in the study limits statistical power for definitive conclusions and say that further studies are needed to clarify the natural history of DRTs and their management, resolution, and impact on cardiovascular events.

Practitioners should also continue to cautiously assess for LAAO clinical indications for implant, according to the editorialists, who point out that the regulatory approval language in the United States was “flexible and nonspecific.”

“As the field grows wider, enhancing LAAO safety with optimal design, implantation, and periprocedural management is critically important, yet the main focus should remain on optimal patient selection for the purpose of achieving safe and successful outcomes,” the editorialists conclude.

Dr. Alkhouli has served as a consultant for Boston Scientific. Coauthor disclosures are listed in the paper. Dr. Wazni and Dr. Hussein have received research grant support from Boston Scientific. Dr. Wazni and Dr. Saliba have been consultants for Boston Scientific.

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

Five risk factors might help pinpoint patients at risk of developing device-related thrombus (DRT), itself an important risk factor for cerebrovascular events, in patients with implants for left atrial appendage occlusion (LAAO), new research suggests.

The identified independent predictors of DRT in the largest dedicated multicenter LAAO-DRT registry to date were presence of a hypercoagulability disorder, pericardial effusion, renal insufficiency, an implantation depth greater than 10 mm from the pulmonary ridge, and presence of nonparoxysmal atrial fibrillation (AFib).

“Unfortunately, most of them are not modifiable, like hypercoaguable disorders or nonparoxysmal atrial fibrillation. But we can avoid deep implants because that’s been associated with creating a little bit of a crater or valley where the clot can form,” senior author Mohamad Alkhouli, MD, said in an interview.

But most important, and “really why we wanted to do this,” he said, is that “we want to give the patient a realistic prediction of adverse events for this procedure.”

LAAO has taken off in recent years for preventing thrombus formation and stroke in patients with AFib. Predicting DRT is a priority for the LAAO field, the authors note, especially given its expansion to younger, lower-risk patients and the increasing procedural volumes.

“This is a problem, DRT, that’s been discussed a lot because this is a preventative procedure,” observed Dr. Alkhouli, professor of medicine at Mayo Medical School, Rochester, Minn.

“The actual stroke risk every year – even if you don’t take any blood thinner and you have a CHADsVASc score of 9, the highest – is 11%. So if the chance of having thrombus is close, then that’s not a good tradeoff.”

Previous studies have also identified implantation depth and nonparoxysmal AFib as risk factors for DRT. But most of them have been small, he noted, with one of the largest reporting 65 DRTs in four prospective trials.

To cast a wider net, the investigators, led by Trevor Simard, MD, also from the Mayo Clinic, invited more than 50 international sites to contribute data to the registry. Of these, 37 centers reported on 237 DRTs and 474 device-matched control subjects from the same site.

Three-fourths of patients received a first-generation Watchman or a FLEX device (Boston Scientific).

Medical regimens were similar between the DRT and control cohorts at discharge after LAA closure. Most patients were managed with single (36.3%) or dual antiplatelet therapy (26.2%) at the time of DRT diagnosis.

As reported July 19 in the Journal of the American College of Cardiology, the timing of DRT development varied widely, with 24.9% appearing in the first 45 days, 38.8% between days 45 and 180, 16.0% between days 180 to 365, and 20.3% beyond 1 year. At last known follow-up, one-quarter of patients had DRT.

The odds ratios for DRT associated with the five identified risk factors were:

• 17.50 (95% confidence interval, 3.39-90.45) for hypercoagulability disorder
• 13.45 (95% CI, 1.46-123.52) for pericardial effusion
• 4.02 (95% CI, 1.22-13.25) for renal insufficiency
• 2.41 (95% CI, 1.57-3.69) for implantation depth >10 mm
• 1.90 (95% CI, 1.22-2.97) for nonparoxysmal AFib

The risk for a composite of death, ischemic stroke, and systemic embolization was twofold higher in the DRT cohort than in the control cohort (29.5% vs. 14.4%; hazard ratio, 2.37; 95% CI, 1.58-3.56) and driven by a higher rate of ischemic stroke (16.9% vs. 3.6%; HR, 3.49; 95% CI, 1.35-9.00).

The incidence of bleeding and intracerebral hemorrhage, however, was similar in the DRT and control cohorts.

One of the surprises of the study was that medications prescribed in the short term after LAA closure were not associated with DRT, Dr. Alkhouli said. A previous meta-analysis of 66 studies by the investigators also found that antithrombotic regimen did not explain the heterogeneity of DRT formation.

“I think we’ll have to take that with a grain of salt, because there’s so many variations in the practice, and this is observational data. But that, in my mind, brings up a mechanistic issue,” he said.

It’s often recommended “that we should put patients on blood thinners for 3 months or 6 weeks, or whatever it is, to decrease the chance of thrombus, assuming the patients will have a normal endothelialization of the device,” Dr. Alkhouli said.

“Well, we know that’s not the reality,” he continued. “We know many patients don’t endothelialize, and, even if some patients do, there may be some endothelial damage. So I think the whole mechanism of prescribing a little bit of a blood thinner to avoid that risk may be missing the point. It’s a bit more complex than that, evidenced also by the fact that three-fourths of all the DRTs happened after 45 days, when patients are typically not taking a blood thinner.”

Based on the five independent risk factors, the investigators created a clinical DRT risk score that assigned 1 point for renal insufficiency, implantation depth greater than 10 mm from the pulmonary ridge, and nonparoxysmal AFib; and 4 points for iatrogenic pericardial effusion and for hypercoagulability disorder. Low risk was categorized as 1 point and high risk as 2 or more points.

The presence of one major risk factor or two minor risk factors, for example, led to a 2.1-fold increased risk for DRT, compared with those with no DRT risk factors.

The risk score will require validation in a prospective cohort but is “a step forward in addressing DRT” and triaging patients, Dr. Alkhouli said. The findings highlight the need to avoid deep device implantation and the importance of shared decision-making with patients, especially with those at high risk.

“And third, which is most important, I think, in my mind, is that it tells us not to put a blind eye to this topic and just say with improved devices it will go away,” he said. “That’s a bit unrealistic.”

In an accompanying editorial, Oussama Wazni, MD, Walid Saliba, MD, and Ayman A. Hussein, MD, all from the Cleveland Clinic, write that “the study sheds light on this yet unresolved issue, and the observations may help with risk stratification and optimization of procedural techniques.”

Whereas many of the nonmodifiable risk factors are helpful in shared decision-making decisions, they continue, “knowledge of these risk factors may not preclude implantation in patients who are otherwise at risk of both stroke off anticoagulation and bleeding on anticoagulation.”

Dr. Wazni and colleagues acknowledge that the small number of events in the study limits statistical power for definitive conclusions and say that further studies are needed to clarify the natural history of DRTs and their management, resolution, and impact on cardiovascular events.

Practitioners should also continue to cautiously assess for LAAO clinical indications for implant, according to the editorialists, who point out that the regulatory approval language in the United States was “flexible and nonspecific.”

“As the field grows wider, enhancing LAAO safety with optimal design, implantation, and periprocedural management is critically important, yet the main focus should remain on optimal patient selection for the purpose of achieving safe and successful outcomes,” the editorialists conclude.

Dr. Alkhouli has served as a consultant for Boston Scientific. Coauthor disclosures are listed in the paper. Dr. Wazni and Dr. Hussein have received research grant support from Boston Scientific. Dr. Wazni and Dr. Saliba have been consultants for Boston Scientific.

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

Following a transcatheter aortic valve replacement (TAVR), direct oral anticoagulants (DOACs) are preferable to vitamin K antagonists (VKAs) in patients who are candidates for oral anticoagulants, according to data drawn from a large multicenter French TAVR registry.

When oral anticoagulation is appropriate following TAVR, such as in patients with atrial fibrillation, “DOACs are associated with improved survival and lower incidence of bleeding, compared to VKA,” reported a team of investigators led by Martine Gilard, MD, PhD, director of interventional cardiology, Brest (France) University Hospital Center.

The comparison, using propensity score matching, is not definitive, but it might be the best data currently available to support DOACs over VKA until a randomized trial is completed, according to Dr. Gilard, senior author of the newly published study.

Asked in an interview if DOACs should now be used preferentially after TAVR when patients are indicated for oral anticoagulation, Dr. Gilard replied, “My answer is yes.”

Of more than 24,000 TAVR patients in the French TAVI and FRANCE2 multicenter registries, which are linked to the French single-payer claims database (SNDS), 8,962 (36.4%) received an oral anticoagulant following their procedure. Of these, 2,180 (24.3%) received a DOAC and the remaining received VKA.

By linking data from the registries to the SNDS, outcomes were tracked. Propensity matching was employed to control for differences in baseline characteristics, including age, body mass index, functional class, diabetes, comorbidities, and past medical history.

On the primary endpoint of mortality at the end of 3 years, the rates were 35.6% and 31.2% for VKA and DOACs, respectively. This translated in a 37% greater hazard ratio for death among those treated with VKA (P < .005).

The rate of major bleeding, a secondary endpoint, was also higher (12.3% vs. 8.4%) and significantly different (HR, 1.65; P < .005) for VKA versus DOACs. The rates of ischemic stroke, acute coronary syndrome, and hemorrhagic stroke were all numerically higher in patients treated with VKA than DOACs, although none of these differences reached statistical significance.
 

Residual confounding cannot be discounted

“The large number of events allowed for taking into account a higher number of potential confounders with appropriate statistical power,” according to the authors. However, they acknowledged that residual confounding cannot be eliminated by propensity matching and conceded that prospective data are needed for a definitive comparison.

In an accompanying editorial, Daniele Giacoppo, MD, a cardiologist at Alto Vicentino Hospital, Santorso, Italy, enlarged on this point . In addition to the inherent limitations of retrospective data, he also noted that data from other studies addressing the same question have been inconsistent.

Of these studies, he pointed to the ATLANTIS trial, presented 2 months ago at the annual meeting of the American College of Cardiology. This study failed to show an advantage for the DOAC apixaban over VKA in TAVR patients for the primary composite outcome of time to death, myocardial infarction, systemic emboli, valve thrombosis, or major bleeding. Although this study was not limited to patients with an indication for oral anticoagulants, Dr. Giacoppo pointed out that there was no advantage, even among the subgroup of patients who did have an indication.
 

Data are supportive in absence of trial results

In general, Dr. Giacoppo agreed that the French registry are generally supportive of DOACs over VKA in TAVR patients with an indication for oral anticoagulation, but he cautioned that blanket statements are difficult. He anticipates better information from a randomized trial called ENVISAGE-TAVI AF, which is comparing edoxaban with VKA following TAVR in atrial fibrillation patients who have an indication for oral anticoagulation, but he indicated that some individualization of choice will be needed among those high or low relative risks of thrombotic events or bleeding.

“The concerns related to DOACs after TAVR are most confined to patients without an indication for oral anticoagulation,” Dr. Giacoppo said in an interview. In patients with an indication, “oral anticoagulation alone without antithrombotic therapy significantly reduced the risk of bleeding” in several studies, he added, citing in particular the POPular TAVI trial.

Issues about when to employ – or not employ – both oral anticoagulation and antithrombotic therapy based on such factors as bleeding risk remain unresolved, but “in aggregate, waiting for additional high-quality data, the use of a DOAC in patients with an indication for oral anticoagulation who underwent TAVR seems to be safe,” Dr. Giacoppo said. He thinks that the “higher predictability of DOACS compared to vitamin K antagonists might translate into lower bleeding rates over time in a real-world, unselected population.”
 

Benefit-to-risk ratio requires attention

A similar concern about balancing risks and benefits of oral anticoagulation in TAVR patients with an indication for oral anticoagulation was emphasized by Ron Waksman, MD, associate director, division of cardiology, MedStar Washington (D.C.) Hospital Center.

“The TAVR population is elderly in general and so are at high risk for bleeding with any additional anticoagulation,” Dr. Waksman said. He cited data that bring into question the utility of using a DOAC in TAVR patients without an additional indication for anticoagulation, but he believes DOACs do make sense in those who were on and had an indication for a DOAC even before TAVR.

Patients who had atrial fibrillation or another indication “should continue to take the DOAC after TAVR. This population can be assumed to have less bleeding risk as they are vetted as safe for DOACs before their TAVR procedure,” he said.

Although mortality was the primary endpoint of the French registry evaluation, it is the bleeding risk that is a dominant concern, according to Romain Didier, MD, PhD, the first author of this study who performed this work in collaboration with Dr. Gilard.

“We really believe that VKA use in real life after TAVR, even with INR monitoring, is associated with a higher risk of bleeding as compared to DOACs,” he said. It is for this reason that “we currently use DOACs as a first choice in patients who require anticoagulant after TAVR.”

Dr. Gilard, Dr. Didier, and Dr. Giacoppo reported no potential conflicts of interest. Dr. Waksman reported financial relationships with Amgen, AstraZeneca, Boston Scientific, Cardioset, Cardiovascular Systems, Chiesi, MedAlliance, Medtronic, and Pi-Cardia.

Following a transcatheter aortic valve replacement (TAVR), direct oral anticoagulants (DOACs) are preferable to vitamin K antagonists (VKAs) in patients who are candidates for oral anticoagulants, according to data drawn from a large multicenter French TAVR registry.

When oral anticoagulation is appropriate following TAVR, such as in patients with atrial fibrillation, “DOACs are associated with improved survival and lower incidence of bleeding, compared to VKA,” reported a team of investigators led by Martine Gilard, MD, PhD, director of interventional cardiology, Brest (France) University Hospital Center.

The comparison, using propensity score matching, is not definitive, but it might be the best data currently available to support DOACs over VKA until a randomized trial is completed, according to Dr. Gilard, senior author of the newly published study.

Asked in an interview if DOACs should now be used preferentially after TAVR when patients are indicated for oral anticoagulation, Dr. Gilard replied, “My answer is yes.”

Of more than 24,000 TAVR patients in the French TAVI and FRANCE2 multicenter registries, which are linked to the French single-payer claims database (SNDS), 8,962 (36.4%) received an oral anticoagulant following their procedure. Of these, 2,180 (24.3%) received a DOAC and the remaining received VKA.

By linking data from the registries to the SNDS, outcomes were tracked. Propensity matching was employed to control for differences in baseline characteristics, including age, body mass index, functional class, diabetes, comorbidities, and past medical history.

On the primary endpoint of mortality at the end of 3 years, the rates were 35.6% and 31.2% for VKA and DOACs, respectively. This translated in a 37% greater hazard ratio for death among those treated with VKA (P < .005).

The rate of major bleeding, a secondary endpoint, was also higher (12.3% vs. 8.4%) and significantly different (HR, 1.65; P < .005) for VKA versus DOACs. The rates of ischemic stroke, acute coronary syndrome, and hemorrhagic stroke were all numerically higher in patients treated with VKA than DOACs, although none of these differences reached statistical significance.
 

Residual confounding cannot be discounted

“The large number of events allowed for taking into account a higher number of potential confounders with appropriate statistical power,” according to the authors. However, they acknowledged that residual confounding cannot be eliminated by propensity matching and conceded that prospective data are needed for a definitive comparison.

In an accompanying editorial, Daniele Giacoppo, MD, a cardiologist at Alto Vicentino Hospital, Santorso, Italy, enlarged on this point . In addition to the inherent limitations of retrospective data, he also noted that data from other studies addressing the same question have been inconsistent.

Of these studies, he pointed to the ATLANTIS trial, presented 2 months ago at the annual meeting of the American College of Cardiology. This study failed to show an advantage for the DOAC apixaban over VKA in TAVR patients for the primary composite outcome of time to death, myocardial infarction, systemic emboli, valve thrombosis, or major bleeding. Although this study was not limited to patients with an indication for oral anticoagulants, Dr. Giacoppo pointed out that there was no advantage, even among the subgroup of patients who did have an indication.
 

Data are supportive in absence of trial results

In general, Dr. Giacoppo agreed that the French registry are generally supportive of DOACs over VKA in TAVR patients with an indication for oral anticoagulation, but he cautioned that blanket statements are difficult. He anticipates better information from a randomized trial called ENVISAGE-TAVI AF, which is comparing edoxaban with VKA following TAVR in atrial fibrillation patients who have an indication for oral anticoagulation, but he indicated that some individualization of choice will be needed among those high or low relative risks of thrombotic events or bleeding.

“The concerns related to DOACs after TAVR are most confined to patients without an indication for oral anticoagulation,” Dr. Giacoppo said in an interview. In patients with an indication, “oral anticoagulation alone without antithrombotic therapy significantly reduced the risk of bleeding” in several studies, he added, citing in particular the POPular TAVI trial.

Issues about when to employ – or not employ – both oral anticoagulation and antithrombotic therapy based on such factors as bleeding risk remain unresolved, but “in aggregate, waiting for additional high-quality data, the use of a DOAC in patients with an indication for oral anticoagulation who underwent TAVR seems to be safe,” Dr. Giacoppo said. He thinks that the “higher predictability of DOACS compared to vitamin K antagonists might translate into lower bleeding rates over time in a real-world, unselected population.”
 

Benefit-to-risk ratio requires attention

A similar concern about balancing risks and benefits of oral anticoagulation in TAVR patients with an indication for oral anticoagulation was emphasized by Ron Waksman, MD, associate director, division of cardiology, MedStar Washington (D.C.) Hospital Center.

“The TAVR population is elderly in general and so are at high risk for bleeding with any additional anticoagulation,” Dr. Waksman said. He cited data that bring into question the utility of using a DOAC in TAVR patients without an additional indication for anticoagulation, but he believes DOACs do make sense in those who were on and had an indication for a DOAC even before TAVR.

Patients who had atrial fibrillation or another indication “should continue to take the DOAC after TAVR. This population can be assumed to have less bleeding risk as they are vetted as safe for DOACs before their TAVR procedure,” he said.

Although mortality was the primary endpoint of the French registry evaluation, it is the bleeding risk that is a dominant concern, according to Romain Didier, MD, PhD, the first author of this study who performed this work in collaboration with Dr. Gilard.

“We really believe that VKA use in real life after TAVR, even with INR monitoring, is associated with a higher risk of bleeding as compared to DOACs,” he said. It is for this reason that “we currently use DOACs as a first choice in patients who require anticoagulant after TAVR.”

Dr. Gilard, Dr. Didier, and Dr. Giacoppo reported no potential conflicts of interest. Dr. Waksman reported financial relationships with Amgen, AstraZeneca, Boston Scientific, Cardioset, Cardiovascular Systems, Chiesi, MedAlliance, Medtronic, and Pi-Cardia.

Following a transcatheter aortic valve replacement (TAVR), direct oral anticoagulants (DOACs) are preferable to vitamin K antagonists (VKAs) in patients who are candidates for oral anticoagulants, according to data drawn from a large multicenter French TAVR registry.

When oral anticoagulation is appropriate following TAVR, such as in patients with atrial fibrillation, “DOACs are associated with improved survival and lower incidence of bleeding, compared to VKA,” reported a team of investigators led by Martine Gilard, MD, PhD, director of interventional cardiology, Brest (France) University Hospital Center.

The comparison, using propensity score matching, is not definitive, but it might be the best data currently available to support DOACs over VKA until a randomized trial is completed, according to Dr. Gilard, senior author of the newly published study.

Asked in an interview if DOACs should now be used preferentially after TAVR when patients are indicated for oral anticoagulation, Dr. Gilard replied, “My answer is yes.”

Of more than 24,000 TAVR patients in the French TAVI and FRANCE2 multicenter registries, which are linked to the French single-payer claims database (SNDS), 8,962 (36.4%) received an oral anticoagulant following their procedure. Of these, 2,180 (24.3%) received a DOAC and the remaining received VKA.

By linking data from the registries to the SNDS, outcomes were tracked. Propensity matching was employed to control for differences in baseline characteristics, including age, body mass index, functional class, diabetes, comorbidities, and past medical history.

On the primary endpoint of mortality at the end of 3 years, the rates were 35.6% and 31.2% for VKA and DOACs, respectively. This translated in a 37% greater hazard ratio for death among those treated with VKA (P < .005).

The rate of major bleeding, a secondary endpoint, was also higher (12.3% vs. 8.4%) and significantly different (HR, 1.65; P < .005) for VKA versus DOACs. The rates of ischemic stroke, acute coronary syndrome, and hemorrhagic stroke were all numerically higher in patients treated with VKA than DOACs, although none of these differences reached statistical significance.
 

Residual confounding cannot be discounted

“The large number of events allowed for taking into account a higher number of potential confounders with appropriate statistical power,” according to the authors. However, they acknowledged that residual confounding cannot be eliminated by propensity matching and conceded that prospective data are needed for a definitive comparison.

In an accompanying editorial, Daniele Giacoppo, MD, a cardiologist at Alto Vicentino Hospital, Santorso, Italy, enlarged on this point . In addition to the inherent limitations of retrospective data, he also noted that data from other studies addressing the same question have been inconsistent.

Of these studies, he pointed to the ATLANTIS trial, presented 2 months ago at the annual meeting of the American College of Cardiology. This study failed to show an advantage for the DOAC apixaban over VKA in TAVR patients for the primary composite outcome of time to death, myocardial infarction, systemic emboli, valve thrombosis, or major bleeding. Although this study was not limited to patients with an indication for oral anticoagulants, Dr. Giacoppo pointed out that there was no advantage, even among the subgroup of patients who did have an indication.
 

Data are supportive in absence of trial results

In general, Dr. Giacoppo agreed that the French registry are generally supportive of DOACs over VKA in TAVR patients with an indication for oral anticoagulation, but he cautioned that blanket statements are difficult. He anticipates better information from a randomized trial called ENVISAGE-TAVI AF, which is comparing edoxaban with VKA following TAVR in atrial fibrillation patients who have an indication for oral anticoagulation, but he indicated that some individualization of choice will be needed among those high or low relative risks of thrombotic events or bleeding.

“The concerns related to DOACs after TAVR are most confined to patients without an indication for oral anticoagulation,” Dr. Giacoppo said in an interview. In patients with an indication, “oral anticoagulation alone without antithrombotic therapy significantly reduced the risk of bleeding” in several studies, he added, citing in particular the POPular TAVI trial.

Issues about when to employ – or not employ – both oral anticoagulation and antithrombotic therapy based on such factors as bleeding risk remain unresolved, but “in aggregate, waiting for additional high-quality data, the use of a DOAC in patients with an indication for oral anticoagulation who underwent TAVR seems to be safe,” Dr. Giacoppo said. He thinks that the “higher predictability of DOACS compared to vitamin K antagonists might translate into lower bleeding rates over time in a real-world, unselected population.”
 

Benefit-to-risk ratio requires attention

A similar concern about balancing risks and benefits of oral anticoagulation in TAVR patients with an indication for oral anticoagulation was emphasized by Ron Waksman, MD, associate director, division of cardiology, MedStar Washington (D.C.) Hospital Center.

“The TAVR population is elderly in general and so are at high risk for bleeding with any additional anticoagulation,” Dr. Waksman said. He cited data that bring into question the utility of using a DOAC in TAVR patients without an additional indication for anticoagulation, but he believes DOACs do make sense in those who were on and had an indication for a DOAC even before TAVR.

Patients who had atrial fibrillation or another indication “should continue to take the DOAC after TAVR. This population can be assumed to have less bleeding risk as they are vetted as safe for DOACs before their TAVR procedure,” he said.

Although mortality was the primary endpoint of the French registry evaluation, it is the bleeding risk that is a dominant concern, according to Romain Didier, MD, PhD, the first author of this study who performed this work in collaboration with Dr. Gilard.

“We really believe that VKA use in real life after TAVR, even with INR monitoring, is associated with a higher risk of bleeding as compared to DOACs,” he said. It is for this reason that “we currently use DOACs as a first choice in patients who require anticoagulant after TAVR.”

Dr. Gilard, Dr. Didier, and Dr. Giacoppo reported no potential conflicts of interest. Dr. Waksman reported financial relationships with Amgen, AstraZeneca, Boston Scientific, Cardioset, Cardiovascular Systems, Chiesi, MedAlliance, Medtronic, and Pi-Cardia.

Early treatment with low-molecular-weight heparin (LMWH) reduces the risk for death in patients with COVID-19, a retrospective cohort study shows.

Heparin could reduce the risk for blood clots, Andrea De Vito, MD, of the unit of infectious diseases at the University of Sassari, Italy, said during his online presentation of the findings at the 31st European Congress of Clinical Microbiology & Infectious Diseases.

“Several studies try to describe the role played by coagulopathies in COVID-19 death,” but the mechanism causing them is still unclear, Dr. De Vito explained.

Some guidelines have suggested heparin as a treatment for hospitalized COVID-19 patients, but few have looked at nonhospitalized patients. In fact, the National Institutes of Health discourages the use of heparin in nonhospitalized COVID-19 patients, and guidance for the home care of COVID-19 patients from the World Health Organization doesn’t mention heparin treatment at all, he said.

To examine the benefits of early heparin – whether administered at home or in the hospital – Dr. De Vito and colleagues looked at a cohort of older adults with COVID-19 who were evaluated or treated at an Italian university hospital.

“Some patients were hospitalized immediately after symptoms onset; other people preferred to call their general practitioner and started the treatment at home,” Dr. De Vito said in an interview. “Other people were hospitalized for worsening of symptoms later in the course of the disease.”

Of the 734 patients, 296 received heparin within 5 days of the onset of symptoms or a positive COVID-19 test. Of the remaining 438 patients, 196 received LMWH treatment later during the disease course, and the rest never received LMWH.

All patients who received early heparin were treated with LMWH 4,000 IU, or 6,000 IU if their body mass index was above 30 kg/m². This was reduced to 2,000 IU if estimated glomerular filtration rate (eGFR) dropped below 30 mL/min. None of the patients had previously received heparin.

Median age was slightly younger for patients who received early heparin than for those who did not (76.8 vs. 78.5 years).

Other demographic characteristics, such as sex and BMI, were similar in the two groups, as were rates of comorbidities, such as hypertension, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, kidney disease, and neurologic conditions. Also similar were the frequency of symptoms (such as fever, cough, and shortness of breath) and rates of treatment with remdesivir or steroids.

Rates of hospital admission were not significantly different between patients who received early heparin and those who did not (65% vs. 61%). There was also no significant difference in use of a venturi mask (35% vs. 28%), noninvasive ventilation (13% vs. 14%), or intubation (5% vs. 8%).

However, rates of death were significantly lower in patients who received early heparin than in those who did not (13% vs. 25%; P < .0001).

There was a trend toward shorter hospital stays for patients treated with early heparin, but the difference was not significant (median, 10 vs. 13 days; P = .08).

Researchers also conducted a separate analysis of 219 COVID-19 patients who received LMWH at home, regardless of when during their disease course they received it. These patients were significantly less likely to be hospitalized than were patients who did not receive LMWH at home (odds ratio, 0.2; P < .0001).

Comparatively, early heparin treatment had a greater effect on the risk for death and the risk for hospitalization than did other factors.

“Thromboemboli are a major complication of COVID. There is good consensus that hospitalized patients with COVID should receive anticoagulants prophylactically, although the best dose is being studied,” said Judy Stone, MD, an infectious disease physician and journalist who was not involved in the study.

“This study extends those findings of benefit from anticoagulants to nonhospitalized patients, with fewer deaths in those treated with low-molecular-weight heparin,” Dr. Stone told this news organization. “The major limitation is that the study is retrospective and observational. The next step would be to confirm these findings prospectively, randomizing a similar group to LMWH or no anticoagulation.”

Another limitation of the study is that some of the patients lived in nursing homes and might have received care from nurses that eliminated the need for hospitalization, Dr. De Vito added.

The study did not note any external funding. The authors have disclosed no relevant financial relationships. Dr. Stone is a member of the advisory committee for the C-Path CURE Drug Repurposing Collaboratory (CDRC) program and has written for Medscape.

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

Early treatment with low-molecular-weight heparin (LMWH) reduces the risk for death in patients with COVID-19, a retrospective cohort study shows.

Heparin could reduce the risk for blood clots, Andrea De Vito, MD, of the unit of infectious diseases at the University of Sassari, Italy, said during his online presentation of the findings at the 31st European Congress of Clinical Microbiology & Infectious Diseases.

“Several studies try to describe the role played by coagulopathies in COVID-19 death,” but the mechanism causing them is still unclear, Dr. De Vito explained.

Some guidelines have suggested heparin as a treatment for hospitalized COVID-19 patients, but few have looked at nonhospitalized patients. In fact, the National Institutes of Health discourages the use of heparin in nonhospitalized COVID-19 patients, and guidance for the home care of COVID-19 patients from the World Health Organization doesn’t mention heparin treatment at all, he said.

To examine the benefits of early heparin – whether administered at home or in the hospital – Dr. De Vito and colleagues looked at a cohort of older adults with COVID-19 who were evaluated or treated at an Italian university hospital.

“Some patients were hospitalized immediately after symptoms onset; other people preferred to call their general practitioner and started the treatment at home,” Dr. De Vito said in an interview. “Other people were hospitalized for worsening of symptoms later in the course of the disease.”

Of the 734 patients, 296 received heparin within 5 days of the onset of symptoms or a positive COVID-19 test. Of the remaining 438 patients, 196 received LMWH treatment later during the disease course, and the rest never received LMWH.

All patients who received early heparin were treated with LMWH 4,000 IU, or 6,000 IU if their body mass index was above 30 kg/m². This was reduced to 2,000 IU if estimated glomerular filtration rate (eGFR) dropped below 30 mL/min. None of the patients had previously received heparin.

Median age was slightly younger for patients who received early heparin than for those who did not (76.8 vs. 78.5 years).

Other demographic characteristics, such as sex and BMI, were similar in the two groups, as were rates of comorbidities, such as hypertension, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, kidney disease, and neurologic conditions. Also similar were the frequency of symptoms (such as fever, cough, and shortness of breath) and rates of treatment with remdesivir or steroids.

Rates of hospital admission were not significantly different between patients who received early heparin and those who did not (65% vs. 61%). There was also no significant difference in use of a venturi mask (35% vs. 28%), noninvasive ventilation (13% vs. 14%), or intubation (5% vs. 8%).

However, rates of death were significantly lower in patients who received early heparin than in those who did not (13% vs. 25%; P < .0001).

There was a trend toward shorter hospital stays for patients treated with early heparin, but the difference was not significant (median, 10 vs. 13 days; P = .08).

Researchers also conducted a separate analysis of 219 COVID-19 patients who received LMWH at home, regardless of when during their disease course they received it. These patients were significantly less likely to be hospitalized than were patients who did not receive LMWH at home (odds ratio, 0.2; P < .0001).

Comparatively, early heparin treatment had a greater effect on the risk for death and the risk for hospitalization than did other factors.

“Thromboemboli are a major complication of COVID. There is good consensus that hospitalized patients with COVID should receive anticoagulants prophylactically, although the best dose is being studied,” said Judy Stone, MD, an infectious disease physician and journalist who was not involved in the study.

“This study extends those findings of benefit from anticoagulants to nonhospitalized patients, with fewer deaths in those treated with low-molecular-weight heparin,” Dr. Stone told this news organization. “The major limitation is that the study is retrospective and observational. The next step would be to confirm these findings prospectively, randomizing a similar group to LMWH or no anticoagulation.”

Another limitation of the study is that some of the patients lived in nursing homes and might have received care from nurses that eliminated the need for hospitalization, Dr. De Vito added.

The study did not note any external funding. The authors have disclosed no relevant financial relationships. Dr. Stone is a member of the advisory committee for the C-Path CURE Drug Repurposing Collaboratory (CDRC) program and has written for Medscape.

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

Early treatment with low-molecular-weight heparin (LMWH) reduces the risk for death in patients with COVID-19, a retrospective cohort study shows.

Heparin could reduce the risk for blood clots, Andrea De Vito, MD, of the unit of infectious diseases at the University of Sassari, Italy, said during his online presentation of the findings at the 31st European Congress of Clinical Microbiology & Infectious Diseases.

“Several studies try to describe the role played by coagulopathies in COVID-19 death,” but the mechanism causing them is still unclear, Dr. De Vito explained.

Some guidelines have suggested heparin as a treatment for hospitalized COVID-19 patients, but few have looked at nonhospitalized patients. In fact, the National Institutes of Health discourages the use of heparin in nonhospitalized COVID-19 patients, and guidance for the home care of COVID-19 patients from the World Health Organization doesn’t mention heparin treatment at all, he said.

To examine the benefits of early heparin – whether administered at home or in the hospital – Dr. De Vito and colleagues looked at a cohort of older adults with COVID-19 who were evaluated or treated at an Italian university hospital.

“Some patients were hospitalized immediately after symptoms onset; other people preferred to call their general practitioner and started the treatment at home,” Dr. De Vito said in an interview. “Other people were hospitalized for worsening of symptoms later in the course of the disease.”

Of the 734 patients, 296 received heparin within 5 days of the onset of symptoms or a positive COVID-19 test. Of the remaining 438 patients, 196 received LMWH treatment later during the disease course, and the rest never received LMWH.

All patients who received early heparin were treated with LMWH 4,000 IU, or 6,000 IU if their body mass index was above 30 kg/m². This was reduced to 2,000 IU if estimated glomerular filtration rate (eGFR) dropped below 30 mL/min. None of the patients had previously received heparin.

Median age was slightly younger for patients who received early heparin than for those who did not (76.8 vs. 78.5 years).

Other demographic characteristics, such as sex and BMI, were similar in the two groups, as were rates of comorbidities, such as hypertension, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, kidney disease, and neurologic conditions. Also similar were the frequency of symptoms (such as fever, cough, and shortness of breath) and rates of treatment with remdesivir or steroids.

Rates of hospital admission were not significantly different between patients who received early heparin and those who did not (65% vs. 61%). There was also no significant difference in use of a venturi mask (35% vs. 28%), noninvasive ventilation (13% vs. 14%), or intubation (5% vs. 8%).

However, rates of death were significantly lower in patients who received early heparin than in those who did not (13% vs. 25%; P < .0001).

There was a trend toward shorter hospital stays for patients treated with early heparin, but the difference was not significant (median, 10 vs. 13 days; P = .08).

Researchers also conducted a separate analysis of 219 COVID-19 patients who received LMWH at home, regardless of when during their disease course they received it. These patients were significantly less likely to be hospitalized than were patients who did not receive LMWH at home (odds ratio, 0.2; P < .0001).

Comparatively, early heparin treatment had a greater effect on the risk for death and the risk for hospitalization than did other factors.

“Thromboemboli are a major complication of COVID. There is good consensus that hospitalized patients with COVID should receive anticoagulants prophylactically, although the best dose is being studied,” said Judy Stone, MD, an infectious disease physician and journalist who was not involved in the study.

“This study extends those findings of benefit from anticoagulants to nonhospitalized patients, with fewer deaths in those treated with low-molecular-weight heparin,” Dr. Stone told this news organization. “The major limitation is that the study is retrospective and observational. The next step would be to confirm these findings prospectively, randomizing a similar group to LMWH or no anticoagulation.”

Another limitation of the study is that some of the patients lived in nursing homes and might have received care from nurses that eliminated the need for hospitalization, Dr. De Vito added.

The study did not note any external funding. The authors have disclosed no relevant financial relationships. Dr. Stone is a member of the advisory committee for the C-Path CURE Drug Repurposing Collaboratory (CDRC) program and has written for Medscape.

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

The U.S. Food and Drug Administration has approved 1-month – as short as 28 days – dual antiplatelet therapy (DAPT) labeling for Xience stents in patients at high risk for bleeding, Abbott announced on June 30.

Patients who receive stents are typically on DAPT regimens such as aspirin and P2Y12 inhibitors for 6 to 12 months to prevent blood clots, but high-bleeding risk patients can experience bleeding during prolonged DAPT.

“The new FDA approval for DAPT for the XIENCE family of stents provides interventional cardiologists confidence they are delivering the best care to patients with high bleeding risk. A short DAPT duration minimizes risks for high bleeding risk patients and allows them to return to daily life sooner and with more assurance,” Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York and the global principal investigator for Abbott’s Short DAPT program (XIENCE 28 and XIENCE 90), said in a news release.

The new labeling comes on the heels of European CE Mark approval for the Xience stents with DAPT as short as 28 days, “giving Xience stents the shortest DAPT indication in the world,” the company noted.

Results of the XIENCE 28 trial were used to support the new CE Mark DAPT indication. The trial showed no increase in death of myocardial infarction between 1 and 6 months and a significantly lower risk for severe bleeding with the Xience stent and 1-month DAPT, compared with 6-month DAPT in more than 1,600 high-bleeding risk patients.

The XIENCE 90 trial involving more than 2,000 high-bleeding risk patients reported no difference in death or MI between 3 and 12 months with Xience and 3-month DAPT versus 12-month DAPT.

Abbott scored a second win, also announcing FDA and CE Mark approval of its next-generation Xience Skypoint stent in high-bleeding risk patients with 1-month DAPT.

“XIENCE Skypoint is easier to place and allows physicians to treat larger blood vessels through improved stent expansion that can open clogged vessels more effectively,” the company said.

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

The U.S. Food and Drug Administration has approved 1-month – as short as 28 days – dual antiplatelet therapy (DAPT) labeling for Xience stents in patients at high risk for bleeding, Abbott announced on June 30.

Patients who receive stents are typically on DAPT regimens such as aspirin and P2Y12 inhibitors for 6 to 12 months to prevent blood clots, but high-bleeding risk patients can experience bleeding during prolonged DAPT.

“The new FDA approval for DAPT for the XIENCE family of stents provides interventional cardiologists confidence they are delivering the best care to patients with high bleeding risk. A short DAPT duration minimizes risks for high bleeding risk patients and allows them to return to daily life sooner and with more assurance,” Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York and the global principal investigator for Abbott’s Short DAPT program (XIENCE 28 and XIENCE 90), said in a news release.

The new labeling comes on the heels of European CE Mark approval for the Xience stents with DAPT as short as 28 days, “giving Xience stents the shortest DAPT indication in the world,” the company noted.

Results of the XIENCE 28 trial were used to support the new CE Mark DAPT indication. The trial showed no increase in death of myocardial infarction between 1 and 6 months and a significantly lower risk for severe bleeding with the Xience stent and 1-month DAPT, compared with 6-month DAPT in more than 1,600 high-bleeding risk patients.

The XIENCE 90 trial involving more than 2,000 high-bleeding risk patients reported no difference in death or MI between 3 and 12 months with Xience and 3-month DAPT versus 12-month DAPT.

Abbott scored a second win, also announcing FDA and CE Mark approval of its next-generation Xience Skypoint stent in high-bleeding risk patients with 1-month DAPT.

“XIENCE Skypoint is easier to place and allows physicians to treat larger blood vessels through improved stent expansion that can open clogged vessels more effectively,” the company said.

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

The U.S. Food and Drug Administration has approved 1-month – as short as 28 days – dual antiplatelet therapy (DAPT) labeling for Xience stents in patients at high risk for bleeding, Abbott announced on June 30.

Patients who receive stents are typically on DAPT regimens such as aspirin and P2Y12 inhibitors for 6 to 12 months to prevent blood clots, but high-bleeding risk patients can experience bleeding during prolonged DAPT.

“The new FDA approval for DAPT for the XIENCE family of stents provides interventional cardiologists confidence they are delivering the best care to patients with high bleeding risk. A short DAPT duration minimizes risks for high bleeding risk patients and allows them to return to daily life sooner and with more assurance,” Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York and the global principal investigator for Abbott’s Short DAPT program (XIENCE 28 and XIENCE 90), said in a news release.

The new labeling comes on the heels of European CE Mark approval for the Xience stents with DAPT as short as 28 days, “giving Xience stents the shortest DAPT indication in the world,” the company noted.

Results of the XIENCE 28 trial were used to support the new CE Mark DAPT indication. The trial showed no increase in death of myocardial infarction between 1 and 6 months and a significantly lower risk for severe bleeding with the Xience stent and 1-month DAPT, compared with 6-month DAPT in more than 1,600 high-bleeding risk patients.

The XIENCE 90 trial involving more than 2,000 high-bleeding risk patients reported no difference in death or MI between 3 and 12 months with Xience and 3-month DAPT versus 12-month DAPT.

Abbott scored a second win, also announcing FDA and CE Mark approval of its next-generation Xience Skypoint stent in high-bleeding risk patients with 1-month DAPT.

“XIENCE Skypoint is easier to place and allows physicians to treat larger blood vessels through improved stent expansion that can open clogged vessels more effectively,” the company said.

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

Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.

In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.

And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.

The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.

“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.

“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.

Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.

“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”

They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”  

Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.

The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.

“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.

“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”

Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.

Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.

The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.

Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.

In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.

Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).

Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.

However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
 

Study boosts confidence

Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.

“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.

“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.

The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.

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

Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.

In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.

And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.

The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.

“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.

“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.

Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.

“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”

They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”  

Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.

The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.

“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.

“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”

Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.

Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.

The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.

Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.

In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.

Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).

Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.

However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
 

Study boosts confidence

Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.

“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.

“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.

The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.

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

Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.

In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.

And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.

The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.

“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.

“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.

Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.

“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”

They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”  

Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.

The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.

“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.

“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”

Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.

Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.

The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.

Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.

In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.

Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).

Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.

However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
 

Study boosts confidence

Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.

“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.

“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.

The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Three or more weeks of oral anticoagulation (OAC) sometimes isn’t up to the job of clearing any potentially embolic left atrial (LA) thrombi before procedures like cardioversion or catheter ablation in patients with atrial fibrillation (AF). Such OAC-defiant LA thrombi aren’t common, nor are they rare enough to ignore, suggests a new meta-analysis that might also have identified features that predispose to them.

Such predictors of LA clots that persist despite OAC could potentially guide selective use of transesophageal echocardiography (TEE) instead of more routine policies to either use or not use TEE for thrombus rule-out before rhythm-control procedures, researchers propose.

Their prevalence was about 2.7% among the study’s more than 14,000 patients who received at least 3 weeks of OAC with either vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) before undergoing TEE.

But OAC-resistant LA thrombi were two- to four-times as common in patients with than without certain features, including AF other than paroxysmal and higher CHADS2 and CHA2DS2-VASc stroke risk-stratification scores.

“TEE imaging in select patients at an elevated risk of LA thrombus, despite anticoagulation status, may be a reasonable approach to minimize the risk of thromboembolic complications following cardioversion or catheter ablation,” propose the study’s authors, led by Antony Lurie, BMSC, Population Health Research Institute, Hamilton, Ont. Their report was published in the June 15 issue of the Journal of the American College of Cardiology.

Guidelines don’t encourage TEE before cardioversion in patients who have been on OAC for at least 3 weeks, the group notes, and policies on TEE use before AF ablation vary widely regardless of anticoagulation status.

The current study suggests that 3 weeks of OAC isn’t enough for a substantial number of patients, who might be put at thromboembolic risk if TEE were to be skipped before rhythm-control procedures.

Conversely, many patients unlikely to have LA thrombi get preprocedure TEE anyway. That can happen “irrespective of how long they’ve been anticoagulated, their pattern of atrial fibrillation, or their stroke risk,” senior author Jorge A. Wong, MD, MPH, Population Health Research Institute and McMaster University, Hamilton, Ont., told this news organization.

But “TEE is an invasive imaging modality, so it is associated with small element of risk.” The current study, Dr. Wong said, points to potential risk-stratification tools clinicians might use to guide more selective TEE screening.

“At sites where TEEs are done all the time for patients undergoing ablation, one could use several of these risk markers to perhaps tailor use of TEE in individuals,” Dr. Wong said. “For example, in people with paroxysmal atrial fibrillation, we found that the risk of left atrial appendage clot was approximately 1% or less.” Screening by TEE might reasonably be avoided in such patients.

“Fortunately, continued oral anticoagulation already yields low peri-procedural stroke rates,” observes an accompanying editorial from Paulus Kirchhof, MD, and Christoph Sinning, MD, from the University Heart & Vascular Center and German Centre of Cardiovascular Research, Hamburg.

“Based on this new analysis of existing data, a risk-based use of TEE imaging in anticoagulated patients could enable further improvement in the safe delivery of rhythm control interventions in patients with AF,” the editorialists agree.

The meta-analysis covered 10 prospective and 25 retrospective studies with a total of 14,653 patients that reported whether LA thrombus was present in patients with AF or atrial flutter (AFL) who underwent TEE after at least 3 weeks of VKA or DOAC therapy. Reports for 30 of the studies identified patients by rhythm-control procedure, and the remaining five didn’t specify TEE indications.

The weighted mean prevalence of LA thrombus at TEE was 2.73% (95% confidence interval, 1.95%-3.80%). The finding was not significantly changed in separate sensitivity analyses, the report says, including one limited to studies with low risk of bias and others excluding patients with valvular AF, interrupted OAC, heparin bridging, or subtherapeutic anticoagulation, respectively.

Patients treated with VKA and DOACs showed similar prevalences of LA thrombi, with means of 2.80% and 3.12%, respectively (P = .674). The prevalence was significantly higher in patients:

• with nonparoxysmal than with paroxysmal AF/AFL (4.81% vs. 1.03%; P < .001)
• undergoing cardioversion than ablation (5.55% vs. 1.65; P < .001)
• with CHA2DS2-VASc scores of at least 3 than with scores of 2 or less (6.31% vs. 1.06%; P < .001).

A limitation of the study, observe Dr. Kirchhof and Dr. Sinning, “is that all patients had a clinical indication for a TEE, which might be a selection bias. When a thrombus was found on TEE, clinical judgment led to postponing of the procedure,” thereby avoiding potential thromboembolism.

“Thus, the paper cannot demonstrate that presence of a thrombus on TEE is related to peri-procedural ischemic stroke,” they write.

The literature puts the risk for stroke or systemic embolism at well under 1% for patients anticoagulated with either VKA or DOACs for at least 3 weeks prior to cardioversion, in contrast to the nearly 3% prevalence of LA appendage thrombus by TEE in the current analysis, Dr. Wong observed.

“So we’re seeing a lot more left atrial appendage thrombus than we would see stroke,” but there wasn’t a way to determine whether that increases the stroke risk, he agreed.Dr. Wong, Dr. Lurie, and the other authors report no relevant conflicts. Dr. Kirchhof discloses receiving partial support “from several drug and device companies active in atrial fibrillation” and to being listed as inventor on two AF-related patents held by the University of Birmingham. Dr. Sinning reports no relevant relationships. 

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

Three or more weeks of oral anticoagulation (OAC) sometimes isn’t up to the job of clearing any potentially embolic left atrial (LA) thrombi before procedures like cardioversion or catheter ablation in patients with atrial fibrillation (AF). Such OAC-defiant LA thrombi aren’t common, nor are they rare enough to ignore, suggests a new meta-analysis that might also have identified features that predispose to them.

Such predictors of LA clots that persist despite OAC could potentially guide selective use of transesophageal echocardiography (TEE) instead of more routine policies to either use or not use TEE for thrombus rule-out before rhythm-control procedures, researchers propose.

Their prevalence was about 2.7% among the study’s more than 14,000 patients who received at least 3 weeks of OAC with either vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) before undergoing TEE.

But OAC-resistant LA thrombi were two- to four-times as common in patients with than without certain features, including AF other than paroxysmal and higher CHADS2 and CHA2DS2-VASc stroke risk-stratification scores.

“TEE imaging in select patients at an elevated risk of LA thrombus, despite anticoagulation status, may be a reasonable approach to minimize the risk of thromboembolic complications following cardioversion or catheter ablation,” propose the study’s authors, led by Antony Lurie, BMSC, Population Health Research Institute, Hamilton, Ont. Their report was published in the June 15 issue of the Journal of the American College of Cardiology.

Guidelines don’t encourage TEE before cardioversion in patients who have been on OAC for at least 3 weeks, the group notes, and policies on TEE use before AF ablation vary widely regardless of anticoagulation status.

The current study suggests that 3 weeks of OAC isn’t enough for a substantial number of patients, who might be put at thromboembolic risk if TEE were to be skipped before rhythm-control procedures.

Conversely, many patients unlikely to have LA thrombi get preprocedure TEE anyway. That can happen “irrespective of how long they’ve been anticoagulated, their pattern of atrial fibrillation, or their stroke risk,” senior author Jorge A. Wong, MD, MPH, Population Health Research Institute and McMaster University, Hamilton, Ont., told this news organization.

But “TEE is an invasive imaging modality, so it is associated with small element of risk.” The current study, Dr. Wong said, points to potential risk-stratification tools clinicians might use to guide more selective TEE screening.

“At sites where TEEs are done all the time for patients undergoing ablation, one could use several of these risk markers to perhaps tailor use of TEE in individuals,” Dr. Wong said. “For example, in people with paroxysmal atrial fibrillation, we found that the risk of left atrial appendage clot was approximately 1% or less.” Screening by TEE might reasonably be avoided in such patients.

“Fortunately, continued oral anticoagulation already yields low peri-procedural stroke rates,” observes an accompanying editorial from Paulus Kirchhof, MD, and Christoph Sinning, MD, from the University Heart & Vascular Center and German Centre of Cardiovascular Research, Hamburg.

“Based on this new analysis of existing data, a risk-based use of TEE imaging in anticoagulated patients could enable further improvement in the safe delivery of rhythm control interventions in patients with AF,” the editorialists agree.

The meta-analysis covered 10 prospective and 25 retrospective studies with a total of 14,653 patients that reported whether LA thrombus was present in patients with AF or atrial flutter (AFL) who underwent TEE after at least 3 weeks of VKA or DOAC therapy. Reports for 30 of the studies identified patients by rhythm-control procedure, and the remaining five didn’t specify TEE indications.

The weighted mean prevalence of LA thrombus at TEE was 2.73% (95% confidence interval, 1.95%-3.80%). The finding was not significantly changed in separate sensitivity analyses, the report says, including one limited to studies with low risk of bias and others excluding patients with valvular AF, interrupted OAC, heparin bridging, or subtherapeutic anticoagulation, respectively.

Patients treated with VKA and DOACs showed similar prevalences of LA thrombi, with means of 2.80% and 3.12%, respectively (P = .674). The prevalence was significantly higher in patients:

• with nonparoxysmal than with paroxysmal AF/AFL (4.81% vs. 1.03%; P < .001)
• undergoing cardioversion than ablation (5.55% vs. 1.65; P < .001)
• with CHA2DS2-VASc scores of at least 3 than with scores of 2 or less (6.31% vs. 1.06%; P < .001).

A limitation of the study, observe Dr. Kirchhof and Dr. Sinning, “is that all patients had a clinical indication for a TEE, which might be a selection bias. When a thrombus was found on TEE, clinical judgment led to postponing of the procedure,” thereby avoiding potential thromboembolism.

“Thus, the paper cannot demonstrate that presence of a thrombus on TEE is related to peri-procedural ischemic stroke,” they write.

The literature puts the risk for stroke or systemic embolism at well under 1% for patients anticoagulated with either VKA or DOACs for at least 3 weeks prior to cardioversion, in contrast to the nearly 3% prevalence of LA appendage thrombus by TEE in the current analysis, Dr. Wong observed.

“So we’re seeing a lot more left atrial appendage thrombus than we would see stroke,” but there wasn’t a way to determine whether that increases the stroke risk, he agreed.Dr. Wong, Dr. Lurie, and the other authors report no relevant conflicts. Dr. Kirchhof discloses receiving partial support “from several drug and device companies active in atrial fibrillation” and to being listed as inventor on two AF-related patents held by the University of Birmingham. Dr. Sinning reports no relevant relationships. 

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

Three or more weeks of oral anticoagulation (OAC) sometimes isn’t up to the job of clearing any potentially embolic left atrial (LA) thrombi before procedures like cardioversion or catheter ablation in patients with atrial fibrillation (AF). Such OAC-defiant LA thrombi aren’t common, nor are they rare enough to ignore, suggests a new meta-analysis that might also have identified features that predispose to them.

Such predictors of LA clots that persist despite OAC could potentially guide selective use of transesophageal echocardiography (TEE) instead of more routine policies to either use or not use TEE for thrombus rule-out before rhythm-control procedures, researchers propose.

Their prevalence was about 2.7% among the study’s more than 14,000 patients who received at least 3 weeks of OAC with either vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) before undergoing TEE.

But OAC-resistant LA thrombi were two- to four-times as common in patients with than without certain features, including AF other than paroxysmal and higher CHADS2 and CHA2DS2-VASc stroke risk-stratification scores.

“TEE imaging in select patients at an elevated risk of LA thrombus, despite anticoagulation status, may be a reasonable approach to minimize the risk of thromboembolic complications following cardioversion or catheter ablation,” propose the study’s authors, led by Antony Lurie, BMSC, Population Health Research Institute, Hamilton, Ont. Their report was published in the June 15 issue of the Journal of the American College of Cardiology.

Guidelines don’t encourage TEE before cardioversion in patients who have been on OAC for at least 3 weeks, the group notes, and policies on TEE use before AF ablation vary widely regardless of anticoagulation status.

The current study suggests that 3 weeks of OAC isn’t enough for a substantial number of patients, who might be put at thromboembolic risk if TEE were to be skipped before rhythm-control procedures.

Conversely, many patients unlikely to have LA thrombi get preprocedure TEE anyway. That can happen “irrespective of how long they’ve been anticoagulated, their pattern of atrial fibrillation, or their stroke risk,” senior author Jorge A. Wong, MD, MPH, Population Health Research Institute and McMaster University, Hamilton, Ont., told this news organization.

But “TEE is an invasive imaging modality, so it is associated with small element of risk.” The current study, Dr. Wong said, points to potential risk-stratification tools clinicians might use to guide more selective TEE screening.

“At sites where TEEs are done all the time for patients undergoing ablation, one could use several of these risk markers to perhaps tailor use of TEE in individuals,” Dr. Wong said. “For example, in people with paroxysmal atrial fibrillation, we found that the risk of left atrial appendage clot was approximately 1% or less.” Screening by TEE might reasonably be avoided in such patients.

“Fortunately, continued oral anticoagulation already yields low peri-procedural stroke rates,” observes an accompanying editorial from Paulus Kirchhof, MD, and Christoph Sinning, MD, from the University Heart & Vascular Center and German Centre of Cardiovascular Research, Hamburg.

“Based on this new analysis of existing data, a risk-based use of TEE imaging in anticoagulated patients could enable further improvement in the safe delivery of rhythm control interventions in patients with AF,” the editorialists agree.

The meta-analysis covered 10 prospective and 25 retrospective studies with a total of 14,653 patients that reported whether LA thrombus was present in patients with AF or atrial flutter (AFL) who underwent TEE after at least 3 weeks of VKA or DOAC therapy. Reports for 30 of the studies identified patients by rhythm-control procedure, and the remaining five didn’t specify TEE indications.

The weighted mean prevalence of LA thrombus at TEE was 2.73% (95% confidence interval, 1.95%-3.80%). The finding was not significantly changed in separate sensitivity analyses, the report says, including one limited to studies with low risk of bias and others excluding patients with valvular AF, interrupted OAC, heparin bridging, or subtherapeutic anticoagulation, respectively.

Patients treated with VKA and DOACs showed similar prevalences of LA thrombi, with means of 2.80% and 3.12%, respectively (P = .674). The prevalence was significantly higher in patients:

• with nonparoxysmal than with paroxysmal AF/AFL (4.81% vs. 1.03%; P < .001)
• undergoing cardioversion than ablation (5.55% vs. 1.65; P < .001)
• with CHA2DS2-VASc scores of at least 3 than with scores of 2 or less (6.31% vs. 1.06%; P < .001).

A limitation of the study, observe Dr. Kirchhof and Dr. Sinning, “is that all patients had a clinical indication for a TEE, which might be a selection bias. When a thrombus was found on TEE, clinical judgment led to postponing of the procedure,” thereby avoiding potential thromboembolism.

“Thus, the paper cannot demonstrate that presence of a thrombus on TEE is related to peri-procedural ischemic stroke,” they write.

The literature puts the risk for stroke or systemic embolism at well under 1% for patients anticoagulated with either VKA or DOACs for at least 3 weeks prior to cardioversion, in contrast to the nearly 3% prevalence of LA appendage thrombus by TEE in the current analysis, Dr. Wong observed.

“So we’re seeing a lot more left atrial appendage thrombus than we would see stroke,” but there wasn’t a way to determine whether that increases the stroke risk, he agreed.Dr. Wong, Dr. Lurie, and the other authors report no relevant conflicts. Dr. Kirchhof discloses receiving partial support “from several drug and device companies active in atrial fibrillation” and to being listed as inventor on two AF-related patents held by the University of Birmingham. Dr. Sinning reports no relevant relationships. 

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

A new clinical score has been developed, and externally validated, to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR).

“Despite the TAVR iterations, we recognize that bleeding remains a very important and perhaps also neglected issue. Indeed, no specifically developed standard algorithm existed before this to assess bleeding risk post-TAVR,” lead author Eliano Pio Navarese, MD, PhD, said in an interview.

Although bleeding rates can be as high as 9% at 30 days and between 3% and 11% in the first year, only a few studies have applied existing scores to TAVR patients, he noted.

The PREDICT-TAVR score includes six common variables and can be calculated by hand using a simple nomogram or a web-based calculator, with a dedicated website in the works, said Dr. Navarese, Nicolaus Copernicus University and SIRO MEDICINE Network, Bydgoszcz, Poland, and the University of Alberta, Edmonton.

A strength of the score is that machine-learning methods were used and the choice of variables optimized through recursive feature elimination and cross validation to remove the weakest variables, he said. Artificial intelligence, including use of random forest, naïve Bayes, and logistic regression classifiers, was also applied to the algorithms and the results cross-checked with standard multivariate analysis.

“It was a tremendous effort in terms of the analytics conducted,” Dr. Navarese said. “This is not a simple score but the integration of the most sophisticated machine learning methods and algorithms.”

Details are published in the June 14 issue of JACC: Cardiovascular Interventions.

The six variables used to calculate 30-day bleeding risk after TAVR and the points assigned to each are:

• blood hemoglobin (0-10 points)
• serum iron concentration (0-5 points)
• common femoral artery diameter (0-3 points)
•  (0-3 points)
• dual antiplatelet therapy (DAPT; 0-2 points)
• oral anticoagulation therapy (0-2 points)

The six items were selected among 104 baseline variables from 5,185 consecutive patients undergoing transfemoral TAVR in the prospective RISPEVA (Registro Italiano GISE sull’Impianto di Valvola Aortica Percutanea) registry between March 2012 and December 2019, then validated in 5,043 patients in the prospective POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) between January 2013 and December 2019.

In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days.

PREDICT-TAVR exhibited high discriminatory power for bleeding events at 30 days, as reflected by an area under the curve (AUC) of 0.80 (95% confidence interval, 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was consistent at 0.79 (95% CI, 0.75-0.83).

PREDICT-TAVR also outperformed scores not developed for TAVR, such as the PARIS score for patients undergoing percutaneous coronary intervention (AUC, 0.69) and the well-validated HAS-BLED for patients receiving anticoagulation (AUC, 0.58; P < .001 for both).

In the validation cohort, the AUC for bleeding complications at 30 days was 0.78 (95% CI, 0.72-0.82) versus an AUC of 0.68 for PARIS and 0.66 for HAS-BLED.

A HAS-BLED score of 4 predicted a higher rate of severe bleeding and mortality in the year after transfemoral TAVR in the 2018 Japanese OCEAN-TAVI study.
 

Bleeding events by risk categories

Risk score quartiles identified as low risk were 8 points or less, as moderate risk were 8 to less than 10 points, as high risk were 10 to less than 12 points, and as very-high-risk score were above 12 points.

In the derivation cohort, 30-day bleeding events across quartiles were 0.8%, 1.1%, 2.5%, and 8.5%, respectively (overall P < .001).

Compared with the lowest quartile, bleeding risk was numerically higher for the second quartile (odds ratio, 1.75) and significantly higher in the third (OR, 2.0) and fourth (OR, 2.49) quartiles (P < .001 for both).

A landmark cumulative-event analysis showed a significantly greater risk of bleeding for the two highest quartiles up to 30 days; however, these differences were no longer significant from 30 days to 1 year, likely because of a limited number of events, the authors suggest. Similar results were seen in the validation cohort.

The number of patients in the high- and very-high-risk groups isn’t trivial, and bleeding rates reached as high as 12.6% in the highest quartile, Dr. Navarese observed. Guidelines recommend DAPT for 3 to 6 months after TAVR; however, emerging data, including a recent meta-analysis, suggest monotherapy may be a very good option.

“So, if you had a high bleeding risk and are considering postprocedural DAPT or anticoagulation, I would think twice rather than administering dual antiplatelet therapy or anticoagulation for a long time, or at least, I would consider the impact of this score on this choice,” he said.

Subgroup analyses showed AUCs ranging from 0.77 to 0.81 for subgroups such as age older than 80 years, diabetes, obesity, female sex, previous PCI, and New York Heart Association class III or IV.

Serum iron showed the highest AUC in the primary PREDICT-TAVR model; however, should iron levels be unavailable, a simplified score modeled without iron levels retained predictive power, yielding AUCs for 30-day bleeding of 0.78 in the derivation cohort and 0.75 in the validation cohort.

“PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes,” Dr. Navarese said. “Of course, future prospective biological and clinical investigations are needed to elucidate the score and the role of the score’s treatable risk traits in reducing post-TAVR bleeding complications.”

Commenting for this news organization, Sunil Rao, MD, Duke University, Durham, N.C., said anemia is a covariant in many risk models for bleeding and vascular complications in PCI and acute coronary syndrome, but hemoglobin and iron levels are collinear.

“The problem I think is when you throw hemoglobin and iron in the same model, just by play of chance, one variable can knock out the other one,” he said. “So I don’t know necessarily if we need to start measuring iron on everyone. We certainly should be measuring hemoglobin, which I think most people will have, and if a patient has pre-existing anemia, that should be a red flag for us.”

Age and Society of Thoracic Surgeons (STS) risk score did not reach statistical significance in the model – likely reflecting the high-/extremely-high-risk patient population with an average STS score of 7.7 and average age of 82 years – but may become more important as TAVR is applied more widely, Dr. Rao and Zachary Wegermann, MD, Duke Clinical Research Institute, write in an accompanying editorial.

They also point out that the study was limited by a low rate of bleeding events, and, importantly, the score can’t distinguish between minor or major bleeding.

“It’s worth trying to repeat the analyses in lower-risk patients because we may find other covariates that are important,” Dr. Rao said in an interview. “The other thing we need to get to is probably being a little bit more sophisticated. The variables included in these models are the ones that are measured; they’re also the ones that are clinically apparent.”

“But there’s a whole area of genomic medicine, proteomic medicine, metabolomic medicine that, as it starts developing and becomes more and more sophisticated, my suspicion is that we’re going to get even more precise and accurate about patients’ risk, and it’s going to become more individualized, rather than just measuring variables like age and lab values,” he said.

In the meantime, having variables documented in the electronic health record, with hard stops deployed if variables aren’t measured, is “a step in the right direction,” he added.

Dr. Navarese has received research grants from Abbott, Amgen, and Medtronic and received lecture fees and honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. Dr. Rao and Dr. Wegermann report no relevant financial disclosures.

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

A new clinical score has been developed, and externally validated, to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR).

“Despite the TAVR iterations, we recognize that bleeding remains a very important and perhaps also neglected issue. Indeed, no specifically developed standard algorithm existed before this to assess bleeding risk post-TAVR,” lead author Eliano Pio Navarese, MD, PhD, said in an interview.

Although bleeding rates can be as high as 9% at 30 days and between 3% and 11% in the first year, only a few studies have applied existing scores to TAVR patients, he noted.

The PREDICT-TAVR score includes six common variables and can be calculated by hand using a simple nomogram or a web-based calculator, with a dedicated website in the works, said Dr. Navarese, Nicolaus Copernicus University and SIRO MEDICINE Network, Bydgoszcz, Poland, and the University of Alberta, Edmonton.

A strength of the score is that machine-learning methods were used and the choice of variables optimized through recursive feature elimination and cross validation to remove the weakest variables, he said. Artificial intelligence, including use of random forest, naïve Bayes, and logistic regression classifiers, was also applied to the algorithms and the results cross-checked with standard multivariate analysis.

“It was a tremendous effort in terms of the analytics conducted,” Dr. Navarese said. “This is not a simple score but the integration of the most sophisticated machine learning methods and algorithms.”

Details are published in the June 14 issue of JACC: Cardiovascular Interventions.

The six variables used to calculate 30-day bleeding risk after TAVR and the points assigned to each are:

• blood hemoglobin (0-10 points)
• serum iron concentration (0-5 points)
• common femoral artery diameter (0-3 points)
•  (0-3 points)
• dual antiplatelet therapy (DAPT; 0-2 points)
• oral anticoagulation therapy (0-2 points)

The six items were selected among 104 baseline variables from 5,185 consecutive patients undergoing transfemoral TAVR in the prospective RISPEVA (Registro Italiano GISE sull’Impianto di Valvola Aortica Percutanea) registry between March 2012 and December 2019, then validated in 5,043 patients in the prospective POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) between January 2013 and December 2019.

In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days.

PREDICT-TAVR exhibited high discriminatory power for bleeding events at 30 days, as reflected by an area under the curve (AUC) of 0.80 (95% confidence interval, 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was consistent at 0.79 (95% CI, 0.75-0.83).

PREDICT-TAVR also outperformed scores not developed for TAVR, such as the PARIS score for patients undergoing percutaneous coronary intervention (AUC, 0.69) and the well-validated HAS-BLED for patients receiving anticoagulation (AUC, 0.58; P < .001 for both).

In the validation cohort, the AUC for bleeding complications at 30 days was 0.78 (95% CI, 0.72-0.82) versus an AUC of 0.68 for PARIS and 0.66 for HAS-BLED.

A HAS-BLED score of 4 predicted a higher rate of severe bleeding and mortality in the year after transfemoral TAVR in the 2018 Japanese OCEAN-TAVI study.
 

Bleeding events by risk categories

Risk score quartiles identified as low risk were 8 points or less, as moderate risk were 8 to less than 10 points, as high risk were 10 to less than 12 points, and as very-high-risk score were above 12 points.

In the derivation cohort, 30-day bleeding events across quartiles were 0.8%, 1.1%, 2.5%, and 8.5%, respectively (overall P < .001).

Compared with the lowest quartile, bleeding risk was numerically higher for the second quartile (odds ratio, 1.75) and significantly higher in the third (OR, 2.0) and fourth (OR, 2.49) quartiles (P < .001 for both).

A landmark cumulative-event analysis showed a significantly greater risk of bleeding for the two highest quartiles up to 30 days; however, these differences were no longer significant from 30 days to 1 year, likely because of a limited number of events, the authors suggest. Similar results were seen in the validation cohort.

The number of patients in the high- and very-high-risk groups isn’t trivial, and bleeding rates reached as high as 12.6% in the highest quartile, Dr. Navarese observed. Guidelines recommend DAPT for 3 to 6 months after TAVR; however, emerging data, including a recent meta-analysis, suggest monotherapy may be a very good option.

“So, if you had a high bleeding risk and are considering postprocedural DAPT or anticoagulation, I would think twice rather than administering dual antiplatelet therapy or anticoagulation for a long time, or at least, I would consider the impact of this score on this choice,” he said.

Subgroup analyses showed AUCs ranging from 0.77 to 0.81 for subgroups such as age older than 80 years, diabetes, obesity, female sex, previous PCI, and New York Heart Association class III or IV.

Serum iron showed the highest AUC in the primary PREDICT-TAVR model; however, should iron levels be unavailable, a simplified score modeled without iron levels retained predictive power, yielding AUCs for 30-day bleeding of 0.78 in the derivation cohort and 0.75 in the validation cohort.

“PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes,” Dr. Navarese said. “Of course, future prospective biological and clinical investigations are needed to elucidate the score and the role of the score’s treatable risk traits in reducing post-TAVR bleeding complications.”

Commenting for this news organization, Sunil Rao, MD, Duke University, Durham, N.C., said anemia is a covariant in many risk models for bleeding and vascular complications in PCI and acute coronary syndrome, but hemoglobin and iron levels are collinear.

“The problem I think is when you throw hemoglobin and iron in the same model, just by play of chance, one variable can knock out the other one,” he said. “So I don’t know necessarily if we need to start measuring iron on everyone. We certainly should be measuring hemoglobin, which I think most people will have, and if a patient has pre-existing anemia, that should be a red flag for us.”

Age and Society of Thoracic Surgeons (STS) risk score did not reach statistical significance in the model – likely reflecting the high-/extremely-high-risk patient population with an average STS score of 7.7 and average age of 82 years – but may become more important as TAVR is applied more widely, Dr. Rao and Zachary Wegermann, MD, Duke Clinical Research Institute, write in an accompanying editorial.

They also point out that the study was limited by a low rate of bleeding events, and, importantly, the score can’t distinguish between minor or major bleeding.

“It’s worth trying to repeat the analyses in lower-risk patients because we may find other covariates that are important,” Dr. Rao said in an interview. “The other thing we need to get to is probably being a little bit more sophisticated. The variables included in these models are the ones that are measured; they’re also the ones that are clinically apparent.”

“But there’s a whole area of genomic medicine, proteomic medicine, metabolomic medicine that, as it starts developing and becomes more and more sophisticated, my suspicion is that we’re going to get even more precise and accurate about patients’ risk, and it’s going to become more individualized, rather than just measuring variables like age and lab values,” he said.

In the meantime, having variables documented in the electronic health record, with hard stops deployed if variables aren’t measured, is “a step in the right direction,” he added.

Dr. Navarese has received research grants from Abbott, Amgen, and Medtronic and received lecture fees and honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. Dr. Rao and Dr. Wegermann report no relevant financial disclosures.

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

A new clinical score has been developed, and externally validated, to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR).

“Despite the TAVR iterations, we recognize that bleeding remains a very important and perhaps also neglected issue. Indeed, no specifically developed standard algorithm existed before this to assess bleeding risk post-TAVR,” lead author Eliano Pio Navarese, MD, PhD, said in an interview.

Although bleeding rates can be as high as 9% at 30 days and between 3% and 11% in the first year, only a few studies have applied existing scores to TAVR patients, he noted.

The PREDICT-TAVR score includes six common variables and can be calculated by hand using a simple nomogram or a web-based calculator, with a dedicated website in the works, said Dr. Navarese, Nicolaus Copernicus University and SIRO MEDICINE Network, Bydgoszcz, Poland, and the University of Alberta, Edmonton.

A strength of the score is that machine-learning methods were used and the choice of variables optimized through recursive feature elimination and cross validation to remove the weakest variables, he said. Artificial intelligence, including use of random forest, naïve Bayes, and logistic regression classifiers, was also applied to the algorithms and the results cross-checked with standard multivariate analysis.

“It was a tremendous effort in terms of the analytics conducted,” Dr. Navarese said. “This is not a simple score but the integration of the most sophisticated machine learning methods and algorithms.”

Details are published in the June 14 issue of JACC: Cardiovascular Interventions.

The six variables used to calculate 30-day bleeding risk after TAVR and the points assigned to each are:

• blood hemoglobin (0-10 points)
• serum iron concentration (0-5 points)
• common femoral artery diameter (0-3 points)
•  (0-3 points)
• dual antiplatelet therapy (DAPT; 0-2 points)
• oral anticoagulation therapy (0-2 points)

The six items were selected among 104 baseline variables from 5,185 consecutive patients undergoing transfemoral TAVR in the prospective RISPEVA (Registro Italiano GISE sull’Impianto di Valvola Aortica Percutanea) registry between March 2012 and December 2019, then validated in 5,043 patients in the prospective POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) between January 2013 and December 2019.

In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days.

PREDICT-TAVR exhibited high discriminatory power for bleeding events at 30 days, as reflected by an area under the curve (AUC) of 0.80 (95% confidence interval, 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was consistent at 0.79 (95% CI, 0.75-0.83).

PREDICT-TAVR also outperformed scores not developed for TAVR, such as the PARIS score for patients undergoing percutaneous coronary intervention (AUC, 0.69) and the well-validated HAS-BLED for patients receiving anticoagulation (AUC, 0.58; P < .001 for both).

In the validation cohort, the AUC for bleeding complications at 30 days was 0.78 (95% CI, 0.72-0.82) versus an AUC of 0.68 for PARIS and 0.66 for HAS-BLED.

A HAS-BLED score of 4 predicted a higher rate of severe bleeding and mortality in the year after transfemoral TAVR in the 2018 Japanese OCEAN-TAVI study.
 

Bleeding events by risk categories

Risk score quartiles identified as low risk were 8 points or less, as moderate risk were 8 to less than 10 points, as high risk were 10 to less than 12 points, and as very-high-risk score were above 12 points.

In the derivation cohort, 30-day bleeding events across quartiles were 0.8%, 1.1%, 2.5%, and 8.5%, respectively (overall P < .001).

Compared with the lowest quartile, bleeding risk was numerically higher for the second quartile (odds ratio, 1.75) and significantly higher in the third (OR, 2.0) and fourth (OR, 2.49) quartiles (P < .001 for both).

A landmark cumulative-event analysis showed a significantly greater risk of bleeding for the two highest quartiles up to 30 days; however, these differences were no longer significant from 30 days to 1 year, likely because of a limited number of events, the authors suggest. Similar results were seen in the validation cohort.

The number of patients in the high- and very-high-risk groups isn’t trivial, and bleeding rates reached as high as 12.6% in the highest quartile, Dr. Navarese observed. Guidelines recommend DAPT for 3 to 6 months after TAVR; however, emerging data, including a recent meta-analysis, suggest monotherapy may be a very good option.

“So, if you had a high bleeding risk and are considering postprocedural DAPT or anticoagulation, I would think twice rather than administering dual antiplatelet therapy or anticoagulation for a long time, or at least, I would consider the impact of this score on this choice,” he said.

Subgroup analyses showed AUCs ranging from 0.77 to 0.81 for subgroups such as age older than 80 years, diabetes, obesity, female sex, previous PCI, and New York Heart Association class III or IV.

Serum iron showed the highest AUC in the primary PREDICT-TAVR model; however, should iron levels be unavailable, a simplified score modeled without iron levels retained predictive power, yielding AUCs for 30-day bleeding of 0.78 in the derivation cohort and 0.75 in the validation cohort.

“PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes,” Dr. Navarese said. “Of course, future prospective biological and clinical investigations are needed to elucidate the score and the role of the score’s treatable risk traits in reducing post-TAVR bleeding complications.”

Commenting for this news organization, Sunil Rao, MD, Duke University, Durham, N.C., said anemia is a covariant in many risk models for bleeding and vascular complications in PCI and acute coronary syndrome, but hemoglobin and iron levels are collinear.

“The problem I think is when you throw hemoglobin and iron in the same model, just by play of chance, one variable can knock out the other one,” he said. “So I don’t know necessarily if we need to start measuring iron on everyone. We certainly should be measuring hemoglobin, which I think most people will have, and if a patient has pre-existing anemia, that should be a red flag for us.”

Age and Society of Thoracic Surgeons (STS) risk score did not reach statistical significance in the model – likely reflecting the high-/extremely-high-risk patient population with an average STS score of 7.7 and average age of 82 years – but may become more important as TAVR is applied more widely, Dr. Rao and Zachary Wegermann, MD, Duke Clinical Research Institute, write in an accompanying editorial.

They also point out that the study was limited by a low rate of bleeding events, and, importantly, the score can’t distinguish between minor or major bleeding.

“It’s worth trying to repeat the analyses in lower-risk patients because we may find other covariates that are important,” Dr. Rao said in an interview. “The other thing we need to get to is probably being a little bit more sophisticated. The variables included in these models are the ones that are measured; they’re also the ones that are clinically apparent.”

“But there’s a whole area of genomic medicine, proteomic medicine, metabolomic medicine that, as it starts developing and becomes more and more sophisticated, my suspicion is that we’re going to get even more precise and accurate about patients’ risk, and it’s going to become more individualized, rather than just measuring variables like age and lab values,” he said.

In the meantime, having variables documented in the electronic health record, with hard stops deployed if variables aren’t measured, is “a step in the right direction,” he added.

Dr. Navarese has received research grants from Abbott, Amgen, and Medtronic and received lecture fees and honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. Dr. Rao and Dr. Wegermann report no relevant financial disclosures.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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