Interventional Cardiology & Surgery

The Food and Drug Administration has approved Medtronic’s Harmony Transcatheter Pulmonary Valve (TPV) System to treat severe pulmonary regurgitation in pediatric and adult patients who have a native or surgically repaired right ventricular outflow tract (RVOT).

The Harmony TPV is the first nonsurgical heart valve to treat severe pulmonary valve regurgitation, which is common in patients with congenital heart disease, the agency said in a news release. Its use can delay the time before a patient needs open-heart surgery and potentially reduce the number of these surgeries required over a lifetime.

“The Harmony TPV provides a new treatment option for adult and pediatric patients with certain types of congenital heart disease,” Bram Zuckerman, MD, director of the Office of Cardiovascular Devices in the FDA’s Center for Devices and Radiological Health, said in the statement.

“It offers a less-invasive treatment alternative to open-heart surgery to patients with a leaky native or surgically repaired RVOT and may help patients improve their quality of life and return to their normal activities more quickly, thus fulfilling an unmet clinical need of many patients with congenital heart disease,” he said.

The Harmony valve, which was granted breakthrough device designation, is a 22-mm or 25-mm porcine pericardium valve, sewn to a nitinol frame. It is implanted with a 25-French delivery system using a coil-loading catheter.

The FDA approval was based on the 70-patient prospective, nonrandomized, multicenter Harmony TPV Clinical study, in which 100% of patients achieved the primary safety endpoint of no procedure or device-related deaths 30 days after implantation.

Among 65 patients with evaluable echocardiographic data, 89.2% met the primary effectiveness endpoint of no additional surgical or interventional device-related procedures and acceptable heart blood flow at 6 months.

Adverse events included irregular or abnormal heart rhythms in 23.9% of patients, including 14.1% ventricular tachycardia; leakage around the valve in 8.5%, including 1.4% major leakage; minor bleeding in 7.0%, narrowing of the pulmonary valve in 4.2%, and movement of the implant in 4.2%.

Follow-up was scheduled annually through 5 years and has been extended to 10 years as part of the postapproval study, the FDA noted.

The Harmony TPV device is contraindicated for patients with an infection in the heart or elsewhere, for patients who cannot tolerate blood-thinning medicines, and for those with a sensitivity to nitinol (titanium or nickel).

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

The Food and Drug Administration has approved Medtronic’s Harmony Transcatheter Pulmonary Valve (TPV) System to treat severe pulmonary regurgitation in pediatric and adult patients who have a native or surgically repaired right ventricular outflow tract (RVOT).

The Harmony TPV is the first nonsurgical heart valve to treat severe pulmonary valve regurgitation, which is common in patients with congenital heart disease, the agency said in a news release. Its use can delay the time before a patient needs open-heart surgery and potentially reduce the number of these surgeries required over a lifetime.

“The Harmony TPV provides a new treatment option for adult and pediatric patients with certain types of congenital heart disease,” Bram Zuckerman, MD, director of the Office of Cardiovascular Devices in the FDA’s Center for Devices and Radiological Health, said in the statement.

“It offers a less-invasive treatment alternative to open-heart surgery to patients with a leaky native or surgically repaired RVOT and may help patients improve their quality of life and return to their normal activities more quickly, thus fulfilling an unmet clinical need of many patients with congenital heart disease,” he said.

The Harmony valve, which was granted breakthrough device designation, is a 22-mm or 25-mm porcine pericardium valve, sewn to a nitinol frame. It is implanted with a 25-French delivery system using a coil-loading catheter.

The FDA approval was based on the 70-patient prospective, nonrandomized, multicenter Harmony TPV Clinical study, in which 100% of patients achieved the primary safety endpoint of no procedure or device-related deaths 30 days after implantation.

Among 65 patients with evaluable echocardiographic data, 89.2% met the primary effectiveness endpoint of no additional surgical or interventional device-related procedures and acceptable heart blood flow at 6 months.

Adverse events included irregular or abnormal heart rhythms in 23.9% of patients, including 14.1% ventricular tachycardia; leakage around the valve in 8.5%, including 1.4% major leakage; minor bleeding in 7.0%, narrowing of the pulmonary valve in 4.2%, and movement of the implant in 4.2%.

Follow-up was scheduled annually through 5 years and has been extended to 10 years as part of the postapproval study, the FDA noted.

The Harmony TPV device is contraindicated for patients with an infection in the heart or elsewhere, for patients who cannot tolerate blood-thinning medicines, and for those with a sensitivity to nitinol (titanium or nickel).

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

The Food and Drug Administration has approved Medtronic’s Harmony Transcatheter Pulmonary Valve (TPV) System to treat severe pulmonary regurgitation in pediatric and adult patients who have a native or surgically repaired right ventricular outflow tract (RVOT).

The Harmony TPV is the first nonsurgical heart valve to treat severe pulmonary valve regurgitation, which is common in patients with congenital heart disease, the agency said in a news release. Its use can delay the time before a patient needs open-heart surgery and potentially reduce the number of these surgeries required over a lifetime.

“The Harmony TPV provides a new treatment option for adult and pediatric patients with certain types of congenital heart disease,” Bram Zuckerman, MD, director of the Office of Cardiovascular Devices in the FDA’s Center for Devices and Radiological Health, said in the statement.

“It offers a less-invasive treatment alternative to open-heart surgery to patients with a leaky native or surgically repaired RVOT and may help patients improve their quality of life and return to their normal activities more quickly, thus fulfilling an unmet clinical need of many patients with congenital heart disease,” he said.

The Harmony valve, which was granted breakthrough device designation, is a 22-mm or 25-mm porcine pericardium valve, sewn to a nitinol frame. It is implanted with a 25-French delivery system using a coil-loading catheter.

The FDA approval was based on the 70-patient prospective, nonrandomized, multicenter Harmony TPV Clinical study, in which 100% of patients achieved the primary safety endpoint of no procedure or device-related deaths 30 days after implantation.

Among 65 patients with evaluable echocardiographic data, 89.2% met the primary effectiveness endpoint of no additional surgical or interventional device-related procedures and acceptable heart blood flow at 6 months.

Adverse events included irregular or abnormal heart rhythms in 23.9% of patients, including 14.1% ventricular tachycardia; leakage around the valve in 8.5%, including 1.4% major leakage; minor bleeding in 7.0%, narrowing of the pulmonary valve in 4.2%, and movement of the implant in 4.2%.

Follow-up was scheduled annually through 5 years and has been extended to 10 years as part of the postapproval study, the FDA noted.

The Harmony TPV device is contraindicated for patients with an infection in the heart or elsewhere, for patients who cannot tolerate blood-thinning medicines, and for those with a sensitivity to nitinol (titanium or nickel).

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

In a placebo-controlled randomized trial, a preprocedural dose of colchicine administered immediately before percutaneous coronary intervention (PCI) for an acute ST-segment elevated myocardial infarction (STEMI) did not reduce the no-reflow phenomenon or improve outcomes.

No-reflow, in which insufficient myocardial perfusion is present even though the coronary artery appears patent, was the primary outcome, and the proportion of patients experiencing this event was exactly the same (14.4%) in the colchicine and placebo groups, reported Yaser Jenab, MD, at CRT 2021 sponsored by MedStar Heart & Vascular Institute.

The hypothesis that colchicine would offer benefit in this setting was largely based on the Colchicine Cardiovascular Outcomes Trial (COLCOT). In that study, colchicine was associated with a 23% reduction in risk for major adverse cardiovascular events (MACE) relative to placebo when administered within 30 days after a myocardial infarction (hazard ratio, 0.77; P = .02).

The benefit in that trial was attributed to an anti-inflammatory effect, according to Dr. Jenab, associate professor of cardiology at Tehran (Iran) Heart Center. In particular as it relates to vascular disease, he cited experimental studies associating colchicine with a reduction in neutrophil activation and adherence to vascular endothelium.

The rationale for a preprocedural approach to colchicine was supplied by a subsequent time-to-treatment COLCOT analysis. In this study, MACE risk reduction for colchicine climbed to 48% (HR 0.52) for those treated within 3 days of the MI but largely disappeared (HR 0.96) if treatment was started at least 8 days post MI.
 

PodCAST-PCI trial

In the preprocedural study, called the PodCAST-PCI trial, 321 acute STEMI patients were randomized. Patients received a 1-mg dose of oral colchicine or placebo at the time PCI was scheduled. Another dose of colchicine (0.5 mg) or placebo was administered 1 hour after the procedure.

Of secondary outcomes, which included MACE at 1 month and 1 year, ST-segment resolution at 1 month, and change in inflammatory markers at 1 month, none were significant. Few even trended for significance.

For MACE, which included cardiac death, stroke, nonfatal MI, new hospitalization due to heart failure, or target vessel revascularization, the rates were lower in the colchicine group at 1 month (4.3% vs. 7.5%) and 1 year (9.3% vs. 11.2%), but neither approached significance.

For ST-segment resolution, the proportions were generally comparable among the colchicine and placebo groups, respectively, for the proportion below 50% (18.6% vs. 23.1%), between 50% and 70% (16.8% vs. 15.6%), and above 70% (64.6% vs. 61.3%).

The average troponin levels were nonsignificantly lower at 6 hours (1,847 vs. 2,883 ng/mL) in the colchicine group but higher at 48 hours (1,197 vs. 1,147 ng/mL). The average C-reactive protein (CRP) levels at 48 hours were nonsignificantly lower on colchicine (176.5 vs. 244.5 mg/L).

There were no significant differences in postprocedural perfusion, as measured with TIMI blood flow, or in the rate of stent thrombosis, which occurred in roughly 3% of each group of patients.

The small sample size was one limitation of this study, Dr. Jenab acknowledged. For this and other reasons, he cautioned that these data are not definitive and do not preclude a benefit on clinical outcomes in a study with a larger size, a different design, or different dosing.
 

Timing might be the issue

However, even if colchicine has a potential benefit in this setting, timing might be a major obstacle, according to Binata Shah, MD, associate director of research for the Cardiac Catheterization Laboratory at New York University.

“We have learned from our rheumatology colleagues that peak plasma levels of colchicine are not achieved for at least 1 hour after the full loading dose,” Dr. Shah said. “With us moving so quickly in a primary PCI setting, it is hard to imagine that colchicine would have had time to really kick in and exert its anti-inflammatory effect.”

Indeed, the problem might be worse than reaching the peak plasma level.

“Even though peak plasma levels occur as early as 1 hour after a full loading dose, we see that it takes about 24 hours to really see the effects translate downstream into more systemic inflammatory markers such as CRP and interleukin-6,” she added. If lowering these signals of inflammation is predictive of benefit, than this might be the biggest obstacle to benefit from colchicine in an urgent treatment setting.

Dr. Jenab and Dr. Shah reported no potential conflicts of interest.

In a placebo-controlled randomized trial, a preprocedural dose of colchicine administered immediately before percutaneous coronary intervention (PCI) for an acute ST-segment elevated myocardial infarction (STEMI) did not reduce the no-reflow phenomenon or improve outcomes.

No-reflow, in which insufficient myocardial perfusion is present even though the coronary artery appears patent, was the primary outcome, and the proportion of patients experiencing this event was exactly the same (14.4%) in the colchicine and placebo groups, reported Yaser Jenab, MD, at CRT 2021 sponsored by MedStar Heart & Vascular Institute.

The hypothesis that colchicine would offer benefit in this setting was largely based on the Colchicine Cardiovascular Outcomes Trial (COLCOT). In that study, colchicine was associated with a 23% reduction in risk for major adverse cardiovascular events (MACE) relative to placebo when administered within 30 days after a myocardial infarction (hazard ratio, 0.77; P = .02).

The benefit in that trial was attributed to an anti-inflammatory effect, according to Dr. Jenab, associate professor of cardiology at Tehran (Iran) Heart Center. In particular as it relates to vascular disease, he cited experimental studies associating colchicine with a reduction in neutrophil activation and adherence to vascular endothelium.

The rationale for a preprocedural approach to colchicine was supplied by a subsequent time-to-treatment COLCOT analysis. In this study, MACE risk reduction for colchicine climbed to 48% (HR 0.52) for those treated within 3 days of the MI but largely disappeared (HR 0.96) if treatment was started at least 8 days post MI.
 

PodCAST-PCI trial

In the preprocedural study, called the PodCAST-PCI trial, 321 acute STEMI patients were randomized. Patients received a 1-mg dose of oral colchicine or placebo at the time PCI was scheduled. Another dose of colchicine (0.5 mg) or placebo was administered 1 hour after the procedure.

Of secondary outcomes, which included MACE at 1 month and 1 year, ST-segment resolution at 1 month, and change in inflammatory markers at 1 month, none were significant. Few even trended for significance.

For MACE, which included cardiac death, stroke, nonfatal MI, new hospitalization due to heart failure, or target vessel revascularization, the rates were lower in the colchicine group at 1 month (4.3% vs. 7.5%) and 1 year (9.3% vs. 11.2%), but neither approached significance.

For ST-segment resolution, the proportions were generally comparable among the colchicine and placebo groups, respectively, for the proportion below 50% (18.6% vs. 23.1%), between 50% and 70% (16.8% vs. 15.6%), and above 70% (64.6% vs. 61.3%).

The average troponin levels were nonsignificantly lower at 6 hours (1,847 vs. 2,883 ng/mL) in the colchicine group but higher at 48 hours (1,197 vs. 1,147 ng/mL). The average C-reactive protein (CRP) levels at 48 hours were nonsignificantly lower on colchicine (176.5 vs. 244.5 mg/L).

There were no significant differences in postprocedural perfusion, as measured with TIMI blood flow, or in the rate of stent thrombosis, which occurred in roughly 3% of each group of patients.

The small sample size was one limitation of this study, Dr. Jenab acknowledged. For this and other reasons, he cautioned that these data are not definitive and do not preclude a benefit on clinical outcomes in a study with a larger size, a different design, or different dosing.
 

Timing might be the issue

However, even if colchicine has a potential benefit in this setting, timing might be a major obstacle, according to Binata Shah, MD, associate director of research for the Cardiac Catheterization Laboratory at New York University.

“We have learned from our rheumatology colleagues that peak plasma levels of colchicine are not achieved for at least 1 hour after the full loading dose,” Dr. Shah said. “With us moving so quickly in a primary PCI setting, it is hard to imagine that colchicine would have had time to really kick in and exert its anti-inflammatory effect.”

Indeed, the problem might be worse than reaching the peak plasma level.

“Even though peak plasma levels occur as early as 1 hour after a full loading dose, we see that it takes about 24 hours to really see the effects translate downstream into more systemic inflammatory markers such as CRP and interleukin-6,” she added. If lowering these signals of inflammation is predictive of benefit, than this might be the biggest obstacle to benefit from colchicine in an urgent treatment setting.

Dr. Jenab and Dr. Shah reported no potential conflicts of interest.

In a placebo-controlled randomized trial, a preprocedural dose of colchicine administered immediately before percutaneous coronary intervention (PCI) for an acute ST-segment elevated myocardial infarction (STEMI) did not reduce the no-reflow phenomenon or improve outcomes.

No-reflow, in which insufficient myocardial perfusion is present even though the coronary artery appears patent, was the primary outcome, and the proportion of patients experiencing this event was exactly the same (14.4%) in the colchicine and placebo groups, reported Yaser Jenab, MD, at CRT 2021 sponsored by MedStar Heart & Vascular Institute.

The hypothesis that colchicine would offer benefit in this setting was largely based on the Colchicine Cardiovascular Outcomes Trial (COLCOT). In that study, colchicine was associated with a 23% reduction in risk for major adverse cardiovascular events (MACE) relative to placebo when administered within 30 days after a myocardial infarction (hazard ratio, 0.77; P = .02).

The benefit in that trial was attributed to an anti-inflammatory effect, according to Dr. Jenab, associate professor of cardiology at Tehran (Iran) Heart Center. In particular as it relates to vascular disease, he cited experimental studies associating colchicine with a reduction in neutrophil activation and adherence to vascular endothelium.

The rationale for a preprocedural approach to colchicine was supplied by a subsequent time-to-treatment COLCOT analysis. In this study, MACE risk reduction for colchicine climbed to 48% (HR 0.52) for those treated within 3 days of the MI but largely disappeared (HR 0.96) if treatment was started at least 8 days post MI.
 

PodCAST-PCI trial

In the preprocedural study, called the PodCAST-PCI trial, 321 acute STEMI patients were randomized. Patients received a 1-mg dose of oral colchicine or placebo at the time PCI was scheduled. Another dose of colchicine (0.5 mg) or placebo was administered 1 hour after the procedure.

Of secondary outcomes, which included MACE at 1 month and 1 year, ST-segment resolution at 1 month, and change in inflammatory markers at 1 month, none were significant. Few even trended for significance.

For MACE, which included cardiac death, stroke, nonfatal MI, new hospitalization due to heart failure, or target vessel revascularization, the rates were lower in the colchicine group at 1 month (4.3% vs. 7.5%) and 1 year (9.3% vs. 11.2%), but neither approached significance.

For ST-segment resolution, the proportions were generally comparable among the colchicine and placebo groups, respectively, for the proportion below 50% (18.6% vs. 23.1%), between 50% and 70% (16.8% vs. 15.6%), and above 70% (64.6% vs. 61.3%).

The average troponin levels were nonsignificantly lower at 6 hours (1,847 vs. 2,883 ng/mL) in the colchicine group but higher at 48 hours (1,197 vs. 1,147 ng/mL). The average C-reactive protein (CRP) levels at 48 hours were nonsignificantly lower on colchicine (176.5 vs. 244.5 mg/L).

There were no significant differences in postprocedural perfusion, as measured with TIMI blood flow, or in the rate of stent thrombosis, which occurred in roughly 3% of each group of patients.

The small sample size was one limitation of this study, Dr. Jenab acknowledged. For this and other reasons, he cautioned that these data are not definitive and do not preclude a benefit on clinical outcomes in a study with a larger size, a different design, or different dosing.
 

Timing might be the issue

However, even if colchicine has a potential benefit in this setting, timing might be a major obstacle, according to Binata Shah, MD, associate director of research for the Cardiac Catheterization Laboratory at New York University.

“We have learned from our rheumatology colleagues that peak plasma levels of colchicine are not achieved for at least 1 hour after the full loading dose,” Dr. Shah said. “With us moving so quickly in a primary PCI setting, it is hard to imagine that colchicine would have had time to really kick in and exert its anti-inflammatory effect.”

Indeed, the problem might be worse than reaching the peak plasma level.

“Even though peak plasma levels occur as early as 1 hour after a full loading dose, we see that it takes about 24 hours to really see the effects translate downstream into more systemic inflammatory markers such as CRP and interleukin-6,” she added. If lowering these signals of inflammation is predictive of benefit, than this might be the biggest obstacle to benefit from colchicine in an urgent treatment setting.

Dr. Jenab and Dr. Shah reported no potential conflicts of interest.

For a primary composite target-lesion failure outcome, a biodegradable polymer sirolimus-eluting stent showed superiority at 2 years over a durable polymer everolimus-eluting stent in patients undergoing percutaneous intervention (PCI) for an ST-segment elevated acute myocardial infarction (STEMI), according to a late-breaking trial presentation at CRT 2021.

As in the previously reported 1-year results from the BIOSTEMI trial, the advantage of the biodegradable device was “driven by lower rates of target-lesion revascularization,” reported Thomas Pilgrim, MD, of the University of Bern (Switzerland).

Drug-eluting stents have already been established as superior to bare-metal stents, but the question asked in this study is whether the polymer that carries antiproliferative drugs, such as sirolimus or everolimus, improves lesion-based outcomes if it is biodegradable rather than durable, Dr. Pilgrim explained.

The composite primary outcome was target-lesion failure defined by cardiac death, target-lesion MI, or clinically indicated target-lesion revascularization.

After 2 years of follow-up, the rates of target-lesion failure were 5.1% and 8.1% for the biodegradable and durable polymer stents, respectively. This 0.58 rate ratio was statistically significant, favoring the biodegradable stent.

The investigator-initiated BIOSTEMI trial randomized 1,300 patients to one of two drug-eluting stents with ultrathin struts. One was the Orsiro stent that employs a biodegradable polymer to deliver sirolimus. The other was the Xience Prime/Xpedition that uses a durable polymer stent to deliver everolimus.

The strut thicknesses of the Orsiro stent are 60 mcm for stents of 3.0 mm in diameter or smaller and 80 mcm for those with a larger diameter. The strut thickness of the Xience stent is 81 mcm regardless of diameter.

“Patients with an acute myocardial infarction are at increased risk of stent-related events due to exacerbated inflammatory response and delayed arterial healing,” Dr. Pilgrim said. The theoretical advantages of polymer that biodegrades include “mitigation of the arterial injury, facilitation of endothelialization, and reduced intimal hyperplasia,” he explained at the meeting sponsored by MedStar Heart & Vascular Institute.

The rates of cardiac death (2.9% vs. 3.2%) and target-vessel MI (2.9% vs. 3.2%) were lower for the biodegradable polymer stent, but not significantly. However, the rates of target-vessel revascularization at 2 years were 2.5% versus 5.1%. The associated rate ratio of 0.52 favoring the biodegradable stent was significant.

Similar results favoring the biodegradable polymer stent were observed at 1 year, but those earlier results factored in historical data from the BIOSCIENCE trial, using a Bayesian analysis, to improve the power of the comparison. In this 2-year analysis, the superiority of the biodegradable polymer stent to the durable polymer stent remained statistically significant even when excluding those historical controls.

The advantage of the biodegradable polymer stent was confined to “device-oriented” outcomes, according to Dr. Pilgrim. When compared for important patient-oriented outcomes at 2 years, there were no significant differences. Rather, several were numerically more common, including death (4.2% vs. 3.8%) and MI (3.7% vs. 3.1%) in those who were randomized to the biodegradable polymer stent.

But these types of clinical outcomes are not necessarily related to stent assignment because “up to one-half of all events over the 2 years of follow-up were unrelated to the stent implanted,” Dr. Pilgrim said. He noted that high rates of events unrelated to the implanted stent have also been seen in follow-up of other comparative stent trials.

The superiority of the biodegradable stent is noteworthy. Although Dr. Pilgrim described the BIOSTEMI trial as “the first head-to-head comparison of two new-generation drug-eluting stents in patients undergoing a primary percutaneous intervention for acute myocardial infarction,” there have been several studies comparing stents for other indications. Significant differences have been uncommon.

“Over the last 10 years, we have seen a number of noninferiority stent trials, but only now are we seeing some superiority differences. This is a move in the right direction,” commented Sripal Bangalore, MD, director of the cardiovascular outcomes group, New York University.

However, he, like others, questioned whether the difference in outcomes in this trial could be fully attributed to the type of polymer. He noted that all stents could be characterized by multiple small and large differences in design and composition. Any specific characteristic, such as biodegradable polymer, might be an important contributor but not an isolated factor in the outcomes observed.

On the day that the 2-year results of the BIOSTEMI trial were presented at the CRT 2021 meeting they were simultaneously published in JACC: Cardiovascular Interventions.

Dr. Pilgrim reports financial relationships with several companies that make stent devices, including Biotronik and Boston Scientific. Dr. Bangalore reports no potential conflicts of interest.

For a primary composite target-lesion failure outcome, a biodegradable polymer sirolimus-eluting stent showed superiority at 2 years over a durable polymer everolimus-eluting stent in patients undergoing percutaneous intervention (PCI) for an ST-segment elevated acute myocardial infarction (STEMI), according to a late-breaking trial presentation at CRT 2021.

As in the previously reported 1-year results from the BIOSTEMI trial, the advantage of the biodegradable device was “driven by lower rates of target-lesion revascularization,” reported Thomas Pilgrim, MD, of the University of Bern (Switzerland).

Drug-eluting stents have already been established as superior to bare-metal stents, but the question asked in this study is whether the polymer that carries antiproliferative drugs, such as sirolimus or everolimus, improves lesion-based outcomes if it is biodegradable rather than durable, Dr. Pilgrim explained.

The composite primary outcome was target-lesion failure defined by cardiac death, target-lesion MI, or clinically indicated target-lesion revascularization.

After 2 years of follow-up, the rates of target-lesion failure were 5.1% and 8.1% for the biodegradable and durable polymer stents, respectively. This 0.58 rate ratio was statistically significant, favoring the biodegradable stent.

The investigator-initiated BIOSTEMI trial randomized 1,300 patients to one of two drug-eluting stents with ultrathin struts. One was the Orsiro stent that employs a biodegradable polymer to deliver sirolimus. The other was the Xience Prime/Xpedition that uses a durable polymer stent to deliver everolimus.

The strut thicknesses of the Orsiro stent are 60 mcm for stents of 3.0 mm in diameter or smaller and 80 mcm for those with a larger diameter. The strut thickness of the Xience stent is 81 mcm regardless of diameter.

“Patients with an acute myocardial infarction are at increased risk of stent-related events due to exacerbated inflammatory response and delayed arterial healing,” Dr. Pilgrim said. The theoretical advantages of polymer that biodegrades include “mitigation of the arterial injury, facilitation of endothelialization, and reduced intimal hyperplasia,” he explained at the meeting sponsored by MedStar Heart & Vascular Institute.

The rates of cardiac death (2.9% vs. 3.2%) and target-vessel MI (2.9% vs. 3.2%) were lower for the biodegradable polymer stent, but not significantly. However, the rates of target-vessel revascularization at 2 years were 2.5% versus 5.1%. The associated rate ratio of 0.52 favoring the biodegradable stent was significant.

Similar results favoring the biodegradable polymer stent were observed at 1 year, but those earlier results factored in historical data from the BIOSCIENCE trial, using a Bayesian analysis, to improve the power of the comparison. In this 2-year analysis, the superiority of the biodegradable polymer stent to the durable polymer stent remained statistically significant even when excluding those historical controls.

The advantage of the biodegradable polymer stent was confined to “device-oriented” outcomes, according to Dr. Pilgrim. When compared for important patient-oriented outcomes at 2 years, there were no significant differences. Rather, several were numerically more common, including death (4.2% vs. 3.8%) and MI (3.7% vs. 3.1%) in those who were randomized to the biodegradable polymer stent.

But these types of clinical outcomes are not necessarily related to stent assignment because “up to one-half of all events over the 2 years of follow-up were unrelated to the stent implanted,” Dr. Pilgrim said. He noted that high rates of events unrelated to the implanted stent have also been seen in follow-up of other comparative stent trials.

The superiority of the biodegradable stent is noteworthy. Although Dr. Pilgrim described the BIOSTEMI trial as “the first head-to-head comparison of two new-generation drug-eluting stents in patients undergoing a primary percutaneous intervention for acute myocardial infarction,” there have been several studies comparing stents for other indications. Significant differences have been uncommon.

“Over the last 10 years, we have seen a number of noninferiority stent trials, but only now are we seeing some superiority differences. This is a move in the right direction,” commented Sripal Bangalore, MD, director of the cardiovascular outcomes group, New York University.

However, he, like others, questioned whether the difference in outcomes in this trial could be fully attributed to the type of polymer. He noted that all stents could be characterized by multiple small and large differences in design and composition. Any specific characteristic, such as biodegradable polymer, might be an important contributor but not an isolated factor in the outcomes observed.

On the day that the 2-year results of the BIOSTEMI trial were presented at the CRT 2021 meeting they were simultaneously published in JACC: Cardiovascular Interventions.

Dr. Pilgrim reports financial relationships with several companies that make stent devices, including Biotronik and Boston Scientific. Dr. Bangalore reports no potential conflicts of interest.

For a primary composite target-lesion failure outcome, a biodegradable polymer sirolimus-eluting stent showed superiority at 2 years over a durable polymer everolimus-eluting stent in patients undergoing percutaneous intervention (PCI) for an ST-segment elevated acute myocardial infarction (STEMI), according to a late-breaking trial presentation at CRT 2021.

As in the previously reported 1-year results from the BIOSTEMI trial, the advantage of the biodegradable device was “driven by lower rates of target-lesion revascularization,” reported Thomas Pilgrim, MD, of the University of Bern (Switzerland).

Drug-eluting stents have already been established as superior to bare-metal stents, but the question asked in this study is whether the polymer that carries antiproliferative drugs, such as sirolimus or everolimus, improves lesion-based outcomes if it is biodegradable rather than durable, Dr. Pilgrim explained.

The composite primary outcome was target-lesion failure defined by cardiac death, target-lesion MI, or clinically indicated target-lesion revascularization.

After 2 years of follow-up, the rates of target-lesion failure were 5.1% and 8.1% for the biodegradable and durable polymer stents, respectively. This 0.58 rate ratio was statistically significant, favoring the biodegradable stent.

The investigator-initiated BIOSTEMI trial randomized 1,300 patients to one of two drug-eluting stents with ultrathin struts. One was the Orsiro stent that employs a biodegradable polymer to deliver sirolimus. The other was the Xience Prime/Xpedition that uses a durable polymer stent to deliver everolimus.

The strut thicknesses of the Orsiro stent are 60 mcm for stents of 3.0 mm in diameter or smaller and 80 mcm for those with a larger diameter. The strut thickness of the Xience stent is 81 mcm regardless of diameter.

“Patients with an acute myocardial infarction are at increased risk of stent-related events due to exacerbated inflammatory response and delayed arterial healing,” Dr. Pilgrim said. The theoretical advantages of polymer that biodegrades include “mitigation of the arterial injury, facilitation of endothelialization, and reduced intimal hyperplasia,” he explained at the meeting sponsored by MedStar Heart & Vascular Institute.

The rates of cardiac death (2.9% vs. 3.2%) and target-vessel MI (2.9% vs. 3.2%) were lower for the biodegradable polymer stent, but not significantly. However, the rates of target-vessel revascularization at 2 years were 2.5% versus 5.1%. The associated rate ratio of 0.52 favoring the biodegradable stent was significant.

Similar results favoring the biodegradable polymer stent were observed at 1 year, but those earlier results factored in historical data from the BIOSCIENCE trial, using a Bayesian analysis, to improve the power of the comparison. In this 2-year analysis, the superiority of the biodegradable polymer stent to the durable polymer stent remained statistically significant even when excluding those historical controls.

The advantage of the biodegradable polymer stent was confined to “device-oriented” outcomes, according to Dr. Pilgrim. When compared for important patient-oriented outcomes at 2 years, there were no significant differences. Rather, several were numerically more common, including death (4.2% vs. 3.8%) and MI (3.7% vs. 3.1%) in those who were randomized to the biodegradable polymer stent.

But these types of clinical outcomes are not necessarily related to stent assignment because “up to one-half of all events over the 2 years of follow-up were unrelated to the stent implanted,” Dr. Pilgrim said. He noted that high rates of events unrelated to the implanted stent have also been seen in follow-up of other comparative stent trials.

The superiority of the biodegradable stent is noteworthy. Although Dr. Pilgrim described the BIOSTEMI trial as “the first head-to-head comparison of two new-generation drug-eluting stents in patients undergoing a primary percutaneous intervention for acute myocardial infarction,” there have been several studies comparing stents for other indications. Significant differences have been uncommon.

“Over the last 10 years, we have seen a number of noninferiority stent trials, but only now are we seeing some superiority differences. This is a move in the right direction,” commented Sripal Bangalore, MD, director of the cardiovascular outcomes group, New York University.

However, he, like others, questioned whether the difference in outcomes in this trial could be fully attributed to the type of polymer. He noted that all stents could be characterized by multiple small and large differences in design and composition. Any specific characteristic, such as biodegradable polymer, might be an important contributor but not an isolated factor in the outcomes observed.

On the day that the 2-year results of the BIOSTEMI trial were presented at the CRT 2021 meeting they were simultaneously published in JACC: Cardiovascular Interventions.

Dr. Pilgrim reports financial relationships with several companies that make stent devices, including Biotronik and Boston Scientific. Dr. Bangalore reports no potential conflicts of interest.

For patients undergoing transcatheter aortic valve replacement (TAVR), the intentional laceration technique of diseased valve leaflets called BASILICA is effective and reasonably safe for preventing coronary artery obstruction, according to a late-breaking study presented at CRT 2021 sponsored by MedStar Heart & Vascular Institute.

In a series of 214 patients entered into a registry over a recent 30-month period, leaflets posing risk were effectively traversed with the technique in 95% of cases, and complication rates were reasonably low with 30-day stroke and death rate of 3.4%, reported Jaffar M. Khan, BMBCH, PhD, cardiovascular branch of the National Heart, Lung, and Blood Institute.

The rate of complications is acceptable given the large potential risk, according to Dr. Khan. If coronary obstruction occurs, reported mortality rates have been as high as 50%. The 1-year survival rate in the registry following BASILICA was 84%.
 

Results should ‘push people toward BASILICA’

The acronym BASILICA stands for bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction. In the procedure, performed immediately before TAVR, guidewires are introduced to first traverse and then lacerate aortic leaflets threatening obstruction of a coronary artery.

In cases where diseased valve leaflets pose a risk of coronary obstruction, most interventionalists “are comfortable with surgery when patients are at low or intermediate risk, but the choices for high-risk patients are a snorkel stent or BASILICA. Given the limits of snorkel stenting, these data should be reassuring and push people toward BASILICA,” Dr. Khan said.

The 214 patients were entered into the registry from June 2015 to December 2020. The mean age was 74.9 years. Of valves treated, 73% were failed bioprosthetic devices. The remaining were native aortic valves. Solo BASILICA was performed in most patients, but 21.5% underwent a doppio procedure, meaning the laceration of two leaflets.

Despite BASILICA, 10 patients (4.7%) had some degree of coronary obstruction, including 5 with partial obstruction of the main coronary artery and 1 with partial obstruction of the right coronary artery. All of these partial obstructions were successfully treated with orthotopic stents.

An obstruction of the right coronary artery was successfully treated with balloon angioplasty. Another patient with significant left main coronary artery obstruction required cardiopulmonary bypass but was successfully treated with snorkel stenting. Of two patients with complete obstruction of the left main coronary artery caused by the skirt of the TAVR device, one died in hospital despite several maneuvers to restore perfusion.

Procedural complications included a mitral chord laceration, which subsequently led to valve replacement, and three guidewire transversals into surrounding tissue that did not result in serious sequelae. Hypotension requiring pressors occurred in 8.5%.

There was a “slight trend” for worse outcomes in those undergoing doppio rather than solo BASILICA, but the difference did not reach statistical significance. Cerebral embolic protection was offered to a minority of patients in this series. The trend for a lower risk of stroke in this group did not reach significance, Dr. Khan reported.
 

Best for high-volume centers, for now

Although these data support the conclusion that BASILICA “is feasible in a real-world setting,” Dr. Khan acknowledged that BASILICA might not be appropriate at low-volume centers. Dr. Khan cited data that indicates obstruction of a coronary artery by a diseased leaflet occurs in less than 1% of TAVR cases.

“Not every site doing a handful of TAVRs is going to want to tackle these cases, but those working in a high-volume center will from time to time encounter patients with coronary obstruction or who are at increased risk,” Dr. Khan said.

In North America, there has been a proctoring program to disseminate the skills required to perform BASILICA, according to Dr. Khan, who explained that proctors typically participate in two or three cases before these are performed without supervision.

So far, the uptake of BASILICA has been limited.

“BASILICA has not been catching on in EUROPE,” said Didier F. Loulmet, MD, chief of cardiac surgery at Tisch Hospital, New York University Langone Health. There might be several reasons, but Dr. Loulmet said that lack of a comparable proctoring program is one factor.”

“This is a relatively complex procedure performed in a small number of patients, so building up expertise is quite a challenge, particularly in small centers,” he added. He encouraged proctoring as “the way that it has to be propagated.”

The results presented by Dr. Khan on March 6 at CRT 2021 were simultaneously published in JACC: Cardiovascular Interventions.

Dr. Khan has patents on several devices, including catheters to lacerate valve leaflet. Dr. Loulmet reported no potential conflicts of interest.

For patients undergoing transcatheter aortic valve replacement (TAVR), the intentional laceration technique of diseased valve leaflets called BASILICA is effective and reasonably safe for preventing coronary artery obstruction, according to a late-breaking study presented at CRT 2021 sponsored by MedStar Heart & Vascular Institute.

In a series of 214 patients entered into a registry over a recent 30-month period, leaflets posing risk were effectively traversed with the technique in 95% of cases, and complication rates were reasonably low with 30-day stroke and death rate of 3.4%, reported Jaffar M. Khan, BMBCH, PhD, cardiovascular branch of the National Heart, Lung, and Blood Institute.

The rate of complications is acceptable given the large potential risk, according to Dr. Khan. If coronary obstruction occurs, reported mortality rates have been as high as 50%. The 1-year survival rate in the registry following BASILICA was 84%.
 

Results should ‘push people toward BASILICA’

The acronym BASILICA stands for bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction. In the procedure, performed immediately before TAVR, guidewires are introduced to first traverse and then lacerate aortic leaflets threatening obstruction of a coronary artery.

In cases where diseased valve leaflets pose a risk of coronary obstruction, most interventionalists “are comfortable with surgery when patients are at low or intermediate risk, but the choices for high-risk patients are a snorkel stent or BASILICA. Given the limits of snorkel stenting, these data should be reassuring and push people toward BASILICA,” Dr. Khan said.

The 214 patients were entered into the registry from June 2015 to December 2020. The mean age was 74.9 years. Of valves treated, 73% were failed bioprosthetic devices. The remaining were native aortic valves. Solo BASILICA was performed in most patients, but 21.5% underwent a doppio procedure, meaning the laceration of two leaflets.

Despite BASILICA, 10 patients (4.7%) had some degree of coronary obstruction, including 5 with partial obstruction of the main coronary artery and 1 with partial obstruction of the right coronary artery. All of these partial obstructions were successfully treated with orthotopic stents.

An obstruction of the right coronary artery was successfully treated with balloon angioplasty. Another patient with significant left main coronary artery obstruction required cardiopulmonary bypass but was successfully treated with snorkel stenting. Of two patients with complete obstruction of the left main coronary artery caused by the skirt of the TAVR device, one died in hospital despite several maneuvers to restore perfusion.

Procedural complications included a mitral chord laceration, which subsequently led to valve replacement, and three guidewire transversals into surrounding tissue that did not result in serious sequelae. Hypotension requiring pressors occurred in 8.5%.

There was a “slight trend” for worse outcomes in those undergoing doppio rather than solo BASILICA, but the difference did not reach statistical significance. Cerebral embolic protection was offered to a minority of patients in this series. The trend for a lower risk of stroke in this group did not reach significance, Dr. Khan reported.
 

Best for high-volume centers, for now

Although these data support the conclusion that BASILICA “is feasible in a real-world setting,” Dr. Khan acknowledged that BASILICA might not be appropriate at low-volume centers. Dr. Khan cited data that indicates obstruction of a coronary artery by a diseased leaflet occurs in less than 1% of TAVR cases.

“Not every site doing a handful of TAVRs is going to want to tackle these cases, but those working in a high-volume center will from time to time encounter patients with coronary obstruction or who are at increased risk,” Dr. Khan said.

In North America, there has been a proctoring program to disseminate the skills required to perform BASILICA, according to Dr. Khan, who explained that proctors typically participate in two or three cases before these are performed without supervision.

So far, the uptake of BASILICA has been limited.

“BASILICA has not been catching on in EUROPE,” said Didier F. Loulmet, MD, chief of cardiac surgery at Tisch Hospital, New York University Langone Health. There might be several reasons, but Dr. Loulmet said that lack of a comparable proctoring program is one factor.”

“This is a relatively complex procedure performed in a small number of patients, so building up expertise is quite a challenge, particularly in small centers,” he added. He encouraged proctoring as “the way that it has to be propagated.”

The results presented by Dr. Khan on March 6 at CRT 2021 were simultaneously published in JACC: Cardiovascular Interventions.

Dr. Khan has patents on several devices, including catheters to lacerate valve leaflet. Dr. Loulmet reported no potential conflicts of interest.

For patients undergoing transcatheter aortic valve replacement (TAVR), the intentional laceration technique of diseased valve leaflets called BASILICA is effective and reasonably safe for preventing coronary artery obstruction, according to a late-breaking study presented at CRT 2021 sponsored by MedStar Heart & Vascular Institute.

In a series of 214 patients entered into a registry over a recent 30-month period, leaflets posing risk were effectively traversed with the technique in 95% of cases, and complication rates were reasonably low with 30-day stroke and death rate of 3.4%, reported Jaffar M. Khan, BMBCH, PhD, cardiovascular branch of the National Heart, Lung, and Blood Institute.

The rate of complications is acceptable given the large potential risk, according to Dr. Khan. If coronary obstruction occurs, reported mortality rates have been as high as 50%. The 1-year survival rate in the registry following BASILICA was 84%.
 

Results should ‘push people toward BASILICA’

The acronym BASILICA stands for bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction. In the procedure, performed immediately before TAVR, guidewires are introduced to first traverse and then lacerate aortic leaflets threatening obstruction of a coronary artery.

In cases where diseased valve leaflets pose a risk of coronary obstruction, most interventionalists “are comfortable with surgery when patients are at low or intermediate risk, but the choices for high-risk patients are a snorkel stent or BASILICA. Given the limits of snorkel stenting, these data should be reassuring and push people toward BASILICA,” Dr. Khan said.

The 214 patients were entered into the registry from June 2015 to December 2020. The mean age was 74.9 years. Of valves treated, 73% were failed bioprosthetic devices. The remaining were native aortic valves. Solo BASILICA was performed in most patients, but 21.5% underwent a doppio procedure, meaning the laceration of two leaflets.

Despite BASILICA, 10 patients (4.7%) had some degree of coronary obstruction, including 5 with partial obstruction of the main coronary artery and 1 with partial obstruction of the right coronary artery. All of these partial obstructions were successfully treated with orthotopic stents.

An obstruction of the right coronary artery was successfully treated with balloon angioplasty. Another patient with significant left main coronary artery obstruction required cardiopulmonary bypass but was successfully treated with snorkel stenting. Of two patients with complete obstruction of the left main coronary artery caused by the skirt of the TAVR device, one died in hospital despite several maneuvers to restore perfusion.

Procedural complications included a mitral chord laceration, which subsequently led to valve replacement, and three guidewire transversals into surrounding tissue that did not result in serious sequelae. Hypotension requiring pressors occurred in 8.5%.

There was a “slight trend” for worse outcomes in those undergoing doppio rather than solo BASILICA, but the difference did not reach statistical significance. Cerebral embolic protection was offered to a minority of patients in this series. The trend for a lower risk of stroke in this group did not reach significance, Dr. Khan reported.
 

Best for high-volume centers, for now

Although these data support the conclusion that BASILICA “is feasible in a real-world setting,” Dr. Khan acknowledged that BASILICA might not be appropriate at low-volume centers. Dr. Khan cited data that indicates obstruction of a coronary artery by a diseased leaflet occurs in less than 1% of TAVR cases.

“Not every site doing a handful of TAVRs is going to want to tackle these cases, but those working in a high-volume center will from time to time encounter patients with coronary obstruction or who are at increased risk,” Dr. Khan said.

In North America, there has been a proctoring program to disseminate the skills required to perform BASILICA, according to Dr. Khan, who explained that proctors typically participate in two or three cases before these are performed without supervision.

So far, the uptake of BASILICA has been limited.

“BASILICA has not been catching on in EUROPE,” said Didier F. Loulmet, MD, chief of cardiac surgery at Tisch Hospital, New York University Langone Health. There might be several reasons, but Dr. Loulmet said that lack of a comparable proctoring program is one factor.”

“This is a relatively complex procedure performed in a small number of patients, so building up expertise is quite a challenge, particularly in small centers,” he added. He encouraged proctoring as “the way that it has to be propagated.”

The results presented by Dr. Khan on March 6 at CRT 2021 were simultaneously published in JACC: Cardiovascular Interventions.

Dr. Khan has patents on several devices, including catheters to lacerate valve leaflet. Dr. Loulmet reported no potential conflicts of interest.

Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.

In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.

There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
 

DOACs discouraged in patients with mechanical or bioprosthetic valves

In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.

In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.

There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
 

Registry shows trends in prescribing

In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.

Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.

In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).

The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).

“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.

The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.

“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
 

Expert: One percent is ‘very small number’

David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.

“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.

“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.

Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.

In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.

There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
 

DOACs discouraged in patients with mechanical or bioprosthetic valves

In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.

In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.

There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
 

Registry shows trends in prescribing

In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.

Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.

In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).

The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).

“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.

The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.

“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
 

Expert: One percent is ‘very small number’

David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.

“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.

“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.

Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.

In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.

There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
 

DOACs discouraged in patients with mechanical or bioprosthetic valves

In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.

In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.

There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
 

Registry shows trends in prescribing

In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.

Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.

In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).

The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).

“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.

The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.

“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
 

Expert: One percent is ‘very small number’

David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.

“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.

“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.

In patients with acute ischemic stroke, the use of thrombolysis in the late window of 4.5-9 hours after symptom onset was not associated with an increase in clot migration that would cause reduced clot accessibility to endovascular therapy, a new analysis from the EXTEND trial shows.

“There was no significant difference in the incidence of clot migration leading to clot inaccessibility in patients who received placebo or (intravenous) thrombolysis,” the authors report.

“Our results found no convincing evidence against the use of bridging thrombolysis before endovascular therapy in patients with acute ischemic stroke who present outside the 4.5-hour window,” they conclude.

“This information is important because it provides some comfort for neurointerventionists that IV thrombolysis does not unduly increase the risk of clot migration,” senior author, Bernard Yan, DMedSci, FRACP, told this news organization.

The study was published online in Stroke on Feb. 16.

The Australian researchers explain that endovascular thrombectomy is the standard of care in patients presenting with acute ischemic stroke caused by large-vessel occlusion, and current treatment guidelines recommend bridging thrombolysis for all patients receiving thrombectomy within the 4.5-hour time window.

While thrombectomy is also recommended in selected patients up to 24 hours after onset of symptoms, it remains unclear whether thrombolysis pretreatment should be administered in this setting.

One of the issues that might affect use of thrombolysis is distal clot migration. As proximal clot location is a crucial factor determining suitability for endovascular clot retrieval, distal migration may prevent successful thrombectomy, they note.   

“Clot migration can happen any time and makes life more difficult for the neurointerventionist who performs the endovascular clot retrieval,” added Dr. Yan, who is a neurologist and neurointerventionist at the Royal Melbourne Hospital, Australia.

In the current paper, the researchers report a retrospective analysis of data from the EXTEND trial of late thrombolysis, defined as 4.5-9 hours after symptom onset, to investigate the association between thrombolysis and clot migration leading to clot irretrievability.

The analysis included a total of 220 patients (109 patients in the placebo group and 111 in the thrombolysis group).

Results showed that retrievable clot was seen on baseline imaging in 69% of patients in the placebo group and 61% in the thrombolysis group. Clot resolution occurred in 28% of patients in the placebo group and 50% in the thrombolysis group. 

No significant difference was observed in the incidence of clot migration leading to inaccessibility between groups. Clot migration from a retrievable to nonretrievable location occurred in 19% of the placebo group and 14% of the thrombolysis group, with an odds ratio for clot migration in the thrombolysis group of 0.70 (95% confidence interval, 0.35-1.44). This outcome was consistent across subgroups.

The researchers note that, to their knowledge, this is the first randomized controlled study to assess the effect of thrombolysis on clot migration and accessibility in an extended time window.

They acknowledge that a limitation of this study is that they only assessed clot migration from a retrievable to a nonretrievable location; therefore, the true frequency of any clot migration occurring was likely to be higher, and this could explain why other reports have found higher odds ratios of clot migration.

But they point out that they chose to limit their analysis in this way specifically to guide decision-making regarding bridging thrombolysis incorporating endovascular therapy in the extended time window.

“The findings of this study are highly relevant in the current clinical environment, where there are multiple ongoing trials looking at removing thrombolysis pretreatment within the 4.5-hour time window in thrombectomy patients,” the authors write.  

“We have demonstrated that thrombolysis in the 4.5- to 9-hour window is not associated with reduced clot accessibility, and this information will be useful in future trial designs incorporating this extended time window,” they add.

Commenting on the study for this news organization, Michael Hill, MD, University of Calgary (Alta.), said: “Thrombus migration does happen and is likely part of the natural history of ischemic stroke, which may be influenced by therapeutics such as thrombolysis. This paper’s top-line result is that thrombus migration occurs in both treated and untreated groups – and therefore that this is really an observation of natural history.”

Dr. Hill says that, at present, patients should be treated with thrombolysis before endovascular therapy if they are eligible, and these results do not change that recommendation. 

“The results of the ongoing trials comparing direct thrombectomy with thrombolysis plus thrombectomy will help to understand the potential clinical outcome relevance of this phenomenon,” he added.

The EXTEND trial was supported by grants from the Australian National Health and Medical Research Council of Australia and the Commonwealth Scientific and Industrial Research Organization Flagship Program. Dr. Yan reported no relevant financial relationships.

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

In patients with acute ischemic stroke, the use of thrombolysis in the late window of 4.5-9 hours after symptom onset was not associated with an increase in clot migration that would cause reduced clot accessibility to endovascular therapy, a new analysis from the EXTEND trial shows.

“There was no significant difference in the incidence of clot migration leading to clot inaccessibility in patients who received placebo or (intravenous) thrombolysis,” the authors report.

“Our results found no convincing evidence against the use of bridging thrombolysis before endovascular therapy in patients with acute ischemic stroke who present outside the 4.5-hour window,” they conclude.

“This information is important because it provides some comfort for neurointerventionists that IV thrombolysis does not unduly increase the risk of clot migration,” senior author, Bernard Yan, DMedSci, FRACP, told this news organization.

The study was published online in Stroke on Feb. 16.

The Australian researchers explain that endovascular thrombectomy is the standard of care in patients presenting with acute ischemic stroke caused by large-vessel occlusion, and current treatment guidelines recommend bridging thrombolysis for all patients receiving thrombectomy within the 4.5-hour time window.

While thrombectomy is also recommended in selected patients up to 24 hours after onset of symptoms, it remains unclear whether thrombolysis pretreatment should be administered in this setting.

One of the issues that might affect use of thrombolysis is distal clot migration. As proximal clot location is a crucial factor determining suitability for endovascular clot retrieval, distal migration may prevent successful thrombectomy, they note.   

“Clot migration can happen any time and makes life more difficult for the neurointerventionist who performs the endovascular clot retrieval,” added Dr. Yan, who is a neurologist and neurointerventionist at the Royal Melbourne Hospital, Australia.

In the current paper, the researchers report a retrospective analysis of data from the EXTEND trial of late thrombolysis, defined as 4.5-9 hours after symptom onset, to investigate the association between thrombolysis and clot migration leading to clot irretrievability.

The analysis included a total of 220 patients (109 patients in the placebo group and 111 in the thrombolysis group).

Results showed that retrievable clot was seen on baseline imaging in 69% of patients in the placebo group and 61% in the thrombolysis group. Clot resolution occurred in 28% of patients in the placebo group and 50% in the thrombolysis group. 

No significant difference was observed in the incidence of clot migration leading to inaccessibility between groups. Clot migration from a retrievable to nonretrievable location occurred in 19% of the placebo group and 14% of the thrombolysis group, with an odds ratio for clot migration in the thrombolysis group of 0.70 (95% confidence interval, 0.35-1.44). This outcome was consistent across subgroups.

The researchers note that, to their knowledge, this is the first randomized controlled study to assess the effect of thrombolysis on clot migration and accessibility in an extended time window.

They acknowledge that a limitation of this study is that they only assessed clot migration from a retrievable to a nonretrievable location; therefore, the true frequency of any clot migration occurring was likely to be higher, and this could explain why other reports have found higher odds ratios of clot migration.

But they point out that they chose to limit their analysis in this way specifically to guide decision-making regarding bridging thrombolysis incorporating endovascular therapy in the extended time window.

“The findings of this study are highly relevant in the current clinical environment, where there are multiple ongoing trials looking at removing thrombolysis pretreatment within the 4.5-hour time window in thrombectomy patients,” the authors write.  

“We have demonstrated that thrombolysis in the 4.5- to 9-hour window is not associated with reduced clot accessibility, and this information will be useful in future trial designs incorporating this extended time window,” they add.

Commenting on the study for this news organization, Michael Hill, MD, University of Calgary (Alta.), said: “Thrombus migration does happen and is likely part of the natural history of ischemic stroke, which may be influenced by therapeutics such as thrombolysis. This paper’s top-line result is that thrombus migration occurs in both treated and untreated groups – and therefore that this is really an observation of natural history.”

Dr. Hill says that, at present, patients should be treated with thrombolysis before endovascular therapy if they are eligible, and these results do not change that recommendation. 

“The results of the ongoing trials comparing direct thrombectomy with thrombolysis plus thrombectomy will help to understand the potential clinical outcome relevance of this phenomenon,” he added.

The EXTEND trial was supported by grants from the Australian National Health and Medical Research Council of Australia and the Commonwealth Scientific and Industrial Research Organization Flagship Program. Dr. Yan reported no relevant financial relationships.

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

In patients with acute ischemic stroke, the use of thrombolysis in the late window of 4.5-9 hours after symptom onset was not associated with an increase in clot migration that would cause reduced clot accessibility to endovascular therapy, a new analysis from the EXTEND trial shows.

“There was no significant difference in the incidence of clot migration leading to clot inaccessibility in patients who received placebo or (intravenous) thrombolysis,” the authors report.

“Our results found no convincing evidence against the use of bridging thrombolysis before endovascular therapy in patients with acute ischemic stroke who present outside the 4.5-hour window,” they conclude.

“This information is important because it provides some comfort for neurointerventionists that IV thrombolysis does not unduly increase the risk of clot migration,” senior author, Bernard Yan, DMedSci, FRACP, told this news organization.

The study was published online in Stroke on Feb. 16.

The Australian researchers explain that endovascular thrombectomy is the standard of care in patients presenting with acute ischemic stroke caused by large-vessel occlusion, and current treatment guidelines recommend bridging thrombolysis for all patients receiving thrombectomy within the 4.5-hour time window.

While thrombectomy is also recommended in selected patients up to 24 hours after onset of symptoms, it remains unclear whether thrombolysis pretreatment should be administered in this setting.

One of the issues that might affect use of thrombolysis is distal clot migration. As proximal clot location is a crucial factor determining suitability for endovascular clot retrieval, distal migration may prevent successful thrombectomy, they note.   

“Clot migration can happen any time and makes life more difficult for the neurointerventionist who performs the endovascular clot retrieval,” added Dr. Yan, who is a neurologist and neurointerventionist at the Royal Melbourne Hospital, Australia.

In the current paper, the researchers report a retrospective analysis of data from the EXTEND trial of late thrombolysis, defined as 4.5-9 hours after symptom onset, to investigate the association between thrombolysis and clot migration leading to clot irretrievability.

The analysis included a total of 220 patients (109 patients in the placebo group and 111 in the thrombolysis group).

Results showed that retrievable clot was seen on baseline imaging in 69% of patients in the placebo group and 61% in the thrombolysis group. Clot resolution occurred in 28% of patients in the placebo group and 50% in the thrombolysis group. 

No significant difference was observed in the incidence of clot migration leading to inaccessibility between groups. Clot migration from a retrievable to nonretrievable location occurred in 19% of the placebo group and 14% of the thrombolysis group, with an odds ratio for clot migration in the thrombolysis group of 0.70 (95% confidence interval, 0.35-1.44). This outcome was consistent across subgroups.

The researchers note that, to their knowledge, this is the first randomized controlled study to assess the effect of thrombolysis on clot migration and accessibility in an extended time window.

They acknowledge that a limitation of this study is that they only assessed clot migration from a retrievable to a nonretrievable location; therefore, the true frequency of any clot migration occurring was likely to be higher, and this could explain why other reports have found higher odds ratios of clot migration.

But they point out that they chose to limit their analysis in this way specifically to guide decision-making regarding bridging thrombolysis incorporating endovascular therapy in the extended time window.

“The findings of this study are highly relevant in the current clinical environment, where there are multiple ongoing trials looking at removing thrombolysis pretreatment within the 4.5-hour time window in thrombectomy patients,” the authors write.  

“We have demonstrated that thrombolysis in the 4.5- to 9-hour window is not associated with reduced clot accessibility, and this information will be useful in future trial designs incorporating this extended time window,” they add.

Commenting on the study for this news organization, Michael Hill, MD, University of Calgary (Alta.), said: “Thrombus migration does happen and is likely part of the natural history of ischemic stroke, which may be influenced by therapeutics such as thrombolysis. This paper’s top-line result is that thrombus migration occurs in both treated and untreated groups – and therefore that this is really an observation of natural history.”

Dr. Hill says that, at present, patients should be treated with thrombolysis before endovascular therapy if they are eligible, and these results do not change that recommendation. 

“The results of the ongoing trials comparing direct thrombectomy with thrombolysis plus thrombectomy will help to understand the potential clinical outcome relevance of this phenomenon,” he added.

The EXTEND trial was supported by grants from the Australian National Health and Medical Research Council of Australia and the Commonwealth Scientific and Industrial Research Organization Flagship Program. Dr. Yan reported no relevant financial relationships.

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

A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
 

The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that PFO closure significantly reduced the mean number of monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.

The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.

Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.

“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”

The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.

However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.

The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.

In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).

The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).  

For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
 

Better effect in patients with aura

Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.

In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).

“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.

In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.

“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
 

Many unanswered questions

But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.

They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.

But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.

“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.

Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”

He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.

“There are still many unanswered questions.

“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.

The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.

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

A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
 

The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that PFO closure significantly reduced the mean number of monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.

The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.

Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.

“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”

The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.

However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.

The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.

In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).

The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).  

For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
 

Better effect in patients with aura

Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.

In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).

“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.

In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.

“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
 

Many unanswered questions

But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.

They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.

But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.

“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.

Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”

He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.

“There are still many unanswered questions.

“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.

The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.

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

A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
 

The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that PFO closure significantly reduced the mean number of monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.

The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.

Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.

“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”

The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.

However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.

The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.

In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).

The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).  

For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
 

Better effect in patients with aura

Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.

In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).

“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.

In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.

“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
 

Many unanswered questions

But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.

They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.

But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.

“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.

Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”

He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.

“There are still many unanswered questions.

“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.

The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.

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

Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.

In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.

In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Md., stressed the importance of understanding what they saw, but also what they didn’t see.

“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.

“What we’re seeing here is not clinically detectable. ... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.

The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30%-40% of patients hospitalized with COVID-19 have elevated troponins, noted Dr. Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.

Dr. Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on Jan. 22, 2020.

The report is a follow-up to another just published by Dr. Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.

Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute MI, which Dr. Finn and colleagues define as an area of necrosis at least 1 cm² in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm², but <1 cm²).

“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Dr. Finn.

In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with 2 of 14 (14.2%) having epicardial coronary artery thrombi and 0 of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.

Further supporting the role of COVID-19–related hypercoagulability as the cause of myocardial injury in many patients, the investigators noted that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
 

COVID-19 vs. non–COVID-19 thrombi

Going one step further, Dr. Finn’s team compared cardiac microthrombi from their COVID-19–positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment elevation MI (STEMI).

The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19–negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.

“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Dr. Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
 

Anticoagulation, yes, but dose unclear

These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ont. But the details of how much anticoagulation, what kind, and for whom are still a moving target.

“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Dr. Weitz.

“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he said in an interview.

Recent top-line findings from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.

Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrollment.

However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.

Dr. Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”

It was notable, said Dr. Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes. “So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”

All three studies have paused enrollment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous coverage from this news organization.

The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Dr. Finn and Dr. Weitz reported no relevant conflicts of interest.

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

Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.

In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.

In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Md., stressed the importance of understanding what they saw, but also what they didn’t see.

“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.

“What we’re seeing here is not clinically detectable. ... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.

The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30%-40% of patients hospitalized with COVID-19 have elevated troponins, noted Dr. Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.

Dr. Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on Jan. 22, 2020.

The report is a follow-up to another just published by Dr. Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.

Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute MI, which Dr. Finn and colleagues define as an area of necrosis at least 1 cm² in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm², but <1 cm²).

“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Dr. Finn.

In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with 2 of 14 (14.2%) having epicardial coronary artery thrombi and 0 of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.

Further supporting the role of COVID-19–related hypercoagulability as the cause of myocardial injury in many patients, the investigators noted that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
 

COVID-19 vs. non–COVID-19 thrombi

Going one step further, Dr. Finn’s team compared cardiac microthrombi from their COVID-19–positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment elevation MI (STEMI).

The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19–negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.

“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Dr. Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
 

Anticoagulation, yes, but dose unclear

These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ont. But the details of how much anticoagulation, what kind, and for whom are still a moving target.

“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Dr. Weitz.

“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he said in an interview.

Recent top-line findings from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.

Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrollment.

However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.

Dr. Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”

It was notable, said Dr. Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes. “So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”

All three studies have paused enrollment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous coverage from this news organization.

The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Dr. Finn and Dr. Weitz reported no relevant conflicts of interest.

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

Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.

In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.

In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Md., stressed the importance of understanding what they saw, but also what they didn’t see.

“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.

“What we’re seeing here is not clinically detectable. ... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.

The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30%-40% of patients hospitalized with COVID-19 have elevated troponins, noted Dr. Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.

Dr. Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on Jan. 22, 2020.

The report is a follow-up to another just published by Dr. Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.

Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute MI, which Dr. Finn and colleagues define as an area of necrosis at least 1 cm² in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm², but <1 cm²).

“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Dr. Finn.

In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with 2 of 14 (14.2%) having epicardial coronary artery thrombi and 0 of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.

Further supporting the role of COVID-19–related hypercoagulability as the cause of myocardial injury in many patients, the investigators noted that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
 

COVID-19 vs. non–COVID-19 thrombi

Going one step further, Dr. Finn’s team compared cardiac microthrombi from their COVID-19–positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment elevation MI (STEMI).

The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19–negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.

“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Dr. Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
 

Anticoagulation, yes, but dose unclear

These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ont. But the details of how much anticoagulation, what kind, and for whom are still a moving target.

“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Dr. Weitz.

“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he said in an interview.

Recent top-line findings from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.

Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrollment.

However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.

Dr. Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”

It was notable, said Dr. Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes. “So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”

All three studies have paused enrollment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous coverage from this news organization.

The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Dr. Finn and Dr. Weitz reported no relevant conflicts of interest.

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

Patients with an implantable cardioverter defibrillator (ICD) should be warned that some newer models of smartphones equipped with magnets, such as the iPhone 12, can disable their device, inhibiting its lifesaving functions, according to investigators who tested and confirmed this effect.

SL/Getty Images

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted which persisted for the duration of the test,” reported the investigating team led by Joshua C. Greenberg, MD, who is an electrophysiology fellow at Henry Ford Hospital, Detroit. The results were published in Heart Rhythm.

The American Heart Association has already cautioned that magnetic fields can inhibit the pulse generators for ICDs and pacemakers. On the AHA website, there is a list of devices and their potential for functional interference, but cell phones and other common devices are identified as posing a low risk.

The most recent iPhone and perhaps other advanced smartphones appear to be different. According to the authors of a study that tested the iPhone 12, this model has a circular array of magnets around a central charging coil. This array interacts with Apple’s proprietary MagSafe technology, which accelerates charging. The magnets also serve to orient the phone on the charger and enable other MagSafe accessories.

The authors of the new study were concerned that this array of magnets might be sufficiently strong to interfere with ICDs or other devices at risk. In a previously published study, the strength of a magnetic field sufficient to interfere with implantable cardiac devices was estimated to be at least 10 gauss.

Tests were performed on a patient wearing a Medtronic ICD.

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted,” according to the authors of the study. The functional loss of the ICS persisted for the duration of proximity. It was reproduced multiple times and with multiple phone positions.

Previous studies have provided evidence that earlier models do not share this risk. In a study testing the iPhone 6 and an Apple Watch in 148 patients with various types of implantable electronic devices, including pacemakers, cardioverter defibrillators, resynchronization defibrillators, and resynchronization pacemakers, only one instance of interference was observed in 1,352 tests.

With wand telemetry, iPhone-induced interferences could be detected with the iPhone 6 in 14% of the patients, but these did not appear to be clinically meaningful, and this type of interference could not be detected with the Apple Watch, according to the report. The single observed interaction, which was between an iPhone 6 and a dual-chamber pacemaker, suggested device-device interactions are uncommon.

More recently, a woman with a single-chamber Medtronic ICD who went to sleep wearing an Apple Watch was awoken by warning beeps from her cardiac device, according to a case report published online. The Apple watch became the prime suspect in causing the ICD warning when proximity of the watch reproduced the warning during clinical examination. However, the magnetic interference was ultimately found to be emanating from the wristband, not the watch.

This case prompted additional studies with Fitbit and other Apple Watch wristbands. Both wristbands contain magnets used to track heart rate. Both were found capable of deactivating ICDs at distances of approximately 2 cm. On the basis of these results, the authors concluded that patients should be counseled about the risk posed by wristbands used in fitness tracking, concluding that they should be kept at least 6 inches away from ICDs and not worn while sleeping.

On their website, Apple maintains a page that specifically warns about the potential for interactions between iPhone 12s and medical devices . Although there is an acknowledgment that the iPhone12 contains more magnets than prior iPhone models, it is stated that iPhone 12 models are “not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” Nevertheless, the Apple instructions advise keeping the iPhone and MagSafe accessories more than 6 inches away from medical devices.

Dr. Greenberg and coinvestigators concluded that the iPhone 12 does pose a greater risk to the dysfunction of ICDs and other medical devices because of the more powerful magnets. As a result, the study brings forward “an important public health issue concerning the newer generation iPhone 12.”

Well aware of this issue and this study, Bruce L. Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices, Cleveland Clinic, agreed. He said the focus should not be restricted to the iPhone 12 series but other wearable devices as alluded to in the study.

“Pacemakers and implantable defibrillators are designed to respond to magnets for important reasons, but magnets have many common uses,” he said. These can change the function of the implantable cardiac devise, but “it is temporary and only when placed in close proximity.”

The solution is simple. “Patients should be careful to avoid locating these objects near these devices,” Dr. Wilkoff said.

However, the first step is awareness. According to the study authors, devices with magnets powerful enough to impair function of implantable devices, such as the iPhone 12 “can potentially inhibit lifesaving therapy.”

Patients should be counseled and provided with practical steps, according to the authors. This includes keeping these devices out of pockets near implantable devices. They called for more noise from makers of smartphones and other devices with strong enough magnets to alter pacemaker and ICD function, and they advised physicians to draw awareness to this issue.

Dr. Greenberg reported no potential conflicts of interest.

Patients with an implantable cardioverter defibrillator (ICD) should be warned that some newer models of smartphones equipped with magnets, such as the iPhone 12, can disable their device, inhibiting its lifesaving functions, according to investigators who tested and confirmed this effect.

SL/Getty Images

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted which persisted for the duration of the test,” reported the investigating team led by Joshua C. Greenberg, MD, who is an electrophysiology fellow at Henry Ford Hospital, Detroit. The results were published in Heart Rhythm.

The American Heart Association has already cautioned that magnetic fields can inhibit the pulse generators for ICDs and pacemakers. On the AHA website, there is a list of devices and their potential for functional interference, but cell phones and other common devices are identified as posing a low risk.

The most recent iPhone and perhaps other advanced smartphones appear to be different. According to the authors of a study that tested the iPhone 12, this model has a circular array of magnets around a central charging coil. This array interacts with Apple’s proprietary MagSafe technology, which accelerates charging. The magnets also serve to orient the phone on the charger and enable other MagSafe accessories.

The authors of the new study were concerned that this array of magnets might be sufficiently strong to interfere with ICDs or other devices at risk. In a previously published study, the strength of a magnetic field sufficient to interfere with implantable cardiac devices was estimated to be at least 10 gauss.

Tests were performed on a patient wearing a Medtronic ICD.

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted,” according to the authors of the study. The functional loss of the ICS persisted for the duration of proximity. It was reproduced multiple times and with multiple phone positions.

Previous studies have provided evidence that earlier models do not share this risk. In a study testing the iPhone 6 and an Apple Watch in 148 patients with various types of implantable electronic devices, including pacemakers, cardioverter defibrillators, resynchronization defibrillators, and resynchronization pacemakers, only one instance of interference was observed in 1,352 tests.

With wand telemetry, iPhone-induced interferences could be detected with the iPhone 6 in 14% of the patients, but these did not appear to be clinically meaningful, and this type of interference could not be detected with the Apple Watch, according to the report. The single observed interaction, which was between an iPhone 6 and a dual-chamber pacemaker, suggested device-device interactions are uncommon.

More recently, a woman with a single-chamber Medtronic ICD who went to sleep wearing an Apple Watch was awoken by warning beeps from her cardiac device, according to a case report published online. The Apple watch became the prime suspect in causing the ICD warning when proximity of the watch reproduced the warning during clinical examination. However, the magnetic interference was ultimately found to be emanating from the wristband, not the watch.

This case prompted additional studies with Fitbit and other Apple Watch wristbands. Both wristbands contain magnets used to track heart rate. Both were found capable of deactivating ICDs at distances of approximately 2 cm. On the basis of these results, the authors concluded that patients should be counseled about the risk posed by wristbands used in fitness tracking, concluding that they should be kept at least 6 inches away from ICDs and not worn while sleeping.

On their website, Apple maintains a page that specifically warns about the potential for interactions between iPhone 12s and medical devices . Although there is an acknowledgment that the iPhone12 contains more magnets than prior iPhone models, it is stated that iPhone 12 models are “not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” Nevertheless, the Apple instructions advise keeping the iPhone and MagSafe accessories more than 6 inches away from medical devices.

Dr. Greenberg and coinvestigators concluded that the iPhone 12 does pose a greater risk to the dysfunction of ICDs and other medical devices because of the more powerful magnets. As a result, the study brings forward “an important public health issue concerning the newer generation iPhone 12.”

Well aware of this issue and this study, Bruce L. Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices, Cleveland Clinic, agreed. He said the focus should not be restricted to the iPhone 12 series but other wearable devices as alluded to in the study.

“Pacemakers and implantable defibrillators are designed to respond to magnets for important reasons, but magnets have many common uses,” he said. These can change the function of the implantable cardiac devise, but “it is temporary and only when placed in close proximity.”

The solution is simple. “Patients should be careful to avoid locating these objects near these devices,” Dr. Wilkoff said.

However, the first step is awareness. According to the study authors, devices with magnets powerful enough to impair function of implantable devices, such as the iPhone 12 “can potentially inhibit lifesaving therapy.”

Patients should be counseled and provided with practical steps, according to the authors. This includes keeping these devices out of pockets near implantable devices. They called for more noise from makers of smartphones and other devices with strong enough magnets to alter pacemaker and ICD function, and they advised physicians to draw awareness to this issue.

Dr. Greenberg reported no potential conflicts of interest.

Patients with an implantable cardioverter defibrillator (ICD) should be warned that some newer models of smartphones equipped with magnets, such as the iPhone 12, can disable their device, inhibiting its lifesaving functions, according to investigators who tested and confirmed this effect.

SL/Getty Images

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted which persisted for the duration of the test,” reported the investigating team led by Joshua C. Greenberg, MD, who is an electrophysiology fellow at Henry Ford Hospital, Detroit. The results were published in Heart Rhythm.

The American Heart Association has already cautioned that magnetic fields can inhibit the pulse generators for ICDs and pacemakers. On the AHA website, there is a list of devices and their potential for functional interference, but cell phones and other common devices are identified as posing a low risk.

The most recent iPhone and perhaps other advanced smartphones appear to be different. According to the authors of a study that tested the iPhone 12, this model has a circular array of magnets around a central charging coil. This array interacts with Apple’s proprietary MagSafe technology, which accelerates charging. The magnets also serve to orient the phone on the charger and enable other MagSafe accessories.

The authors of the new study were concerned that this array of magnets might be sufficiently strong to interfere with ICDs or other devices at risk. In a previously published study, the strength of a magnetic field sufficient to interfere with implantable cardiac devices was estimated to be at least 10 gauss.

Tests were performed on a patient wearing a Medtronic ICD.

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted,” according to the authors of the study. The functional loss of the ICS persisted for the duration of proximity. It was reproduced multiple times and with multiple phone positions.

Previous studies have provided evidence that earlier models do not share this risk. In a study testing the iPhone 6 and an Apple Watch in 148 patients with various types of implantable electronic devices, including pacemakers, cardioverter defibrillators, resynchronization defibrillators, and resynchronization pacemakers, only one instance of interference was observed in 1,352 tests.

With wand telemetry, iPhone-induced interferences could be detected with the iPhone 6 in 14% of the patients, but these did not appear to be clinically meaningful, and this type of interference could not be detected with the Apple Watch, according to the report. The single observed interaction, which was between an iPhone 6 and a dual-chamber pacemaker, suggested device-device interactions are uncommon.

More recently, a woman with a single-chamber Medtronic ICD who went to sleep wearing an Apple Watch was awoken by warning beeps from her cardiac device, according to a case report published online. The Apple watch became the prime suspect in causing the ICD warning when proximity of the watch reproduced the warning during clinical examination. However, the magnetic interference was ultimately found to be emanating from the wristband, not the watch.

This case prompted additional studies with Fitbit and other Apple Watch wristbands. Both wristbands contain magnets used to track heart rate. Both were found capable of deactivating ICDs at distances of approximately 2 cm. On the basis of these results, the authors concluded that patients should be counseled about the risk posed by wristbands used in fitness tracking, concluding that they should be kept at least 6 inches away from ICDs and not worn while sleeping.

On their website, Apple maintains a page that specifically warns about the potential for interactions between iPhone 12s and medical devices . Although there is an acknowledgment that the iPhone12 contains more magnets than prior iPhone models, it is stated that iPhone 12 models are “not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” Nevertheless, the Apple instructions advise keeping the iPhone and MagSafe accessories more than 6 inches away from medical devices.

Dr. Greenberg and coinvestigators concluded that the iPhone 12 does pose a greater risk to the dysfunction of ICDs and other medical devices because of the more powerful magnets. As a result, the study brings forward “an important public health issue concerning the newer generation iPhone 12.”

Well aware of this issue and this study, Bruce L. Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices, Cleveland Clinic, agreed. He said the focus should not be restricted to the iPhone 12 series but other wearable devices as alluded to in the study.

“Pacemakers and implantable defibrillators are designed to respond to magnets for important reasons, but magnets have many common uses,” he said. These can change the function of the implantable cardiac devise, but “it is temporary and only when placed in close proximity.”

The solution is simple. “Patients should be careful to avoid locating these objects near these devices,” Dr. Wilkoff said.

However, the first step is awareness. According to the study authors, devices with magnets powerful enough to impair function of implantable devices, such as the iPhone 12 “can potentially inhibit lifesaving therapy.”

Patients should be counseled and provided with practical steps, according to the authors. This includes keeping these devices out of pockets near implantable devices. They called for more noise from makers of smartphones and other devices with strong enough magnets to alter pacemaker and ICD function, and they advised physicians to draw awareness to this issue.

Dr. Greenberg reported no potential conflicts of interest.

Full-dose anticoagulation was superior to low, prophylactic doses in reducing the need for vital organ support such as ventilation in moderately ill patients hospitalized for COVID-19, according to a report released Jan. 22 by the National Institutes of Health (NIH).

“This is a major advance for patients hospitalized with COVID. Full dose of anticoagulation in these non-ICU patients improved outcomes and there’s a trend toward a reduction in mortality,” Judith Hochman, MD, director of the Cardiovascular Clinical Research Center at NYU Langone Medical Center, New York, said in an interview.

“We have treatments that are improving outcomes but not as many that reduce mortality, so we’re hopeful when the full dataset comes in that will be confirmed,” she said.

The observation of increased rates of blood clots and inflammation among COVID-19 patients, which can lead to complications such as lung failure, heart attack, and stroke, has given rise to various anticoagulant treatment protocols and a need for randomized data on routinely administering increased doses of anticoagulation to hospitalized patients.

Today’s top-line findings come from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – examining the safety and efficacy of full-dose anticoagulation to treat moderately ill or critically ill adults hospitalized with COVID-19 compared with a lower dose typically used to prevent blood clots in hospitalized patients.

In December 2020, all three trials paused enrollment of the critically ill subgroup after results showed that full-dose anticoagulation started in the intensive care unit (ICU) was not beneficial and may have been harmful in some patients.

Moderately ill patients with COVID-19, defined as those who did not require ICU care or organ support, made up 80% of participants at enrollment in the three trials, Dr. Hochman said.

Among more than 1,000 moderately ill patients reviewed as of the data cut with the data safety monitoring board, full doses of low molecular weight or unfractionated heparin were superior to low prophylactic doses for the primary endpoint of need for ventilation or other organ supportive interventions at 21 days after randomization.

This met the predefined threshold for 99% probability of superiority and recruitment was stopped, Dr. Hochman reported. “Obviously safety figured into this decision. The risk/benefit ratio was very clear.”

The results do not pertain to patients with a previous indication for anticoagulation, who were excluded from the trials.

Data from an additional 1,000 patients will be reviewed and the data published sometime in the next 2-3 months, she said.

With large numbers of COVID-19 patients requiring hospitalization, the outcomes could help reduce the overload on intensive care units around the world, the NIH noted.

The results also highlight the critical role of timing in the course of COVID-19.

“We believe that full anticoagulation is effective early in the disease course,” Dr. Hochman said. “Based on the results so far from these three platform trials, those that were very, very sick at the time of enrollment really didn’t benefit and we needed to have caught them at an earlier stage.

“It’s possible that the people in the ICU are just different and the minute they get sick they need the ICU; so we haven’t clearly demonstrated this time course and when to intervene, but that’s the implication of the findings.”

The question of even earlier treatment is being examined in the partner ACTIV-4B trial, which is enrolling patients with COVID-19 illness not requiring hospitalization and randomizing them to the direct oral anticoagulant apixaban or aspirin or placebo.

“It’s a very important trial and we really want to get the message out that patients should volunteer for it,” said Dr. Hochman, principal investigator of the ACTIV-4 trial.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.

The REMAP-CAP, ACTIV-4, and ATTACC study platforms span five continents in more than 300 hospitals and are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (United Kingdom), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

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

Full-dose anticoagulation was superior to low, prophylactic doses in reducing the need for vital organ support such as ventilation in moderately ill patients hospitalized for COVID-19, according to a report released Jan. 22 by the National Institutes of Health (NIH).

“This is a major advance for patients hospitalized with COVID. Full dose of anticoagulation in these non-ICU patients improved outcomes and there’s a trend toward a reduction in mortality,” Judith Hochman, MD, director of the Cardiovascular Clinical Research Center at NYU Langone Medical Center, New York, said in an interview.

“We have treatments that are improving outcomes but not as many that reduce mortality, so we’re hopeful when the full dataset comes in that will be confirmed,” she said.

The observation of increased rates of blood clots and inflammation among COVID-19 patients, which can lead to complications such as lung failure, heart attack, and stroke, has given rise to various anticoagulant treatment protocols and a need for randomized data on routinely administering increased doses of anticoagulation to hospitalized patients.

Today’s top-line findings come from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – examining the safety and efficacy of full-dose anticoagulation to treat moderately ill or critically ill adults hospitalized with COVID-19 compared with a lower dose typically used to prevent blood clots in hospitalized patients.

In December 2020, all three trials paused enrollment of the critically ill subgroup after results showed that full-dose anticoagulation started in the intensive care unit (ICU) was not beneficial and may have been harmful in some patients.

Moderately ill patients with COVID-19, defined as those who did not require ICU care or organ support, made up 80% of participants at enrollment in the three trials, Dr. Hochman said.

Among more than 1,000 moderately ill patients reviewed as of the data cut with the data safety monitoring board, full doses of low molecular weight or unfractionated heparin were superior to low prophylactic doses for the primary endpoint of need for ventilation or other organ supportive interventions at 21 days after randomization.

This met the predefined threshold for 99% probability of superiority and recruitment was stopped, Dr. Hochman reported. “Obviously safety figured into this decision. The risk/benefit ratio was very clear.”

The results do not pertain to patients with a previous indication for anticoagulation, who were excluded from the trials.

Data from an additional 1,000 patients will be reviewed and the data published sometime in the next 2-3 months, she said.

With large numbers of COVID-19 patients requiring hospitalization, the outcomes could help reduce the overload on intensive care units around the world, the NIH noted.

The results also highlight the critical role of timing in the course of COVID-19.

“We believe that full anticoagulation is effective early in the disease course,” Dr. Hochman said. “Based on the results so far from these three platform trials, those that were very, very sick at the time of enrollment really didn’t benefit and we needed to have caught them at an earlier stage.

“It’s possible that the people in the ICU are just different and the minute they get sick they need the ICU; so we haven’t clearly demonstrated this time course and when to intervene, but that’s the implication of the findings.”

The question of even earlier treatment is being examined in the partner ACTIV-4B trial, which is enrolling patients with COVID-19 illness not requiring hospitalization and randomizing them to the direct oral anticoagulant apixaban or aspirin or placebo.

“It’s a very important trial and we really want to get the message out that patients should volunteer for it,” said Dr. Hochman, principal investigator of the ACTIV-4 trial.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.

The REMAP-CAP, ACTIV-4, and ATTACC study platforms span five continents in more than 300 hospitals and are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (United Kingdom), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

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

Full-dose anticoagulation was superior to low, prophylactic doses in reducing the need for vital organ support such as ventilation in moderately ill patients hospitalized for COVID-19, according to a report released Jan. 22 by the National Institutes of Health (NIH).

“This is a major advance for patients hospitalized with COVID. Full dose of anticoagulation in these non-ICU patients improved outcomes and there’s a trend toward a reduction in mortality,” Judith Hochman, MD, director of the Cardiovascular Clinical Research Center at NYU Langone Medical Center, New York, said in an interview.

“We have treatments that are improving outcomes but not as many that reduce mortality, so we’re hopeful when the full dataset comes in that will be confirmed,” she said.

The observation of increased rates of blood clots and inflammation among COVID-19 patients, which can lead to complications such as lung failure, heart attack, and stroke, has given rise to various anticoagulant treatment protocols and a need for randomized data on routinely administering increased doses of anticoagulation to hospitalized patients.

Today’s top-line findings come from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – examining the safety and efficacy of full-dose anticoagulation to treat moderately ill or critically ill adults hospitalized with COVID-19 compared with a lower dose typically used to prevent blood clots in hospitalized patients.

In December 2020, all three trials paused enrollment of the critically ill subgroup after results showed that full-dose anticoagulation started in the intensive care unit (ICU) was not beneficial and may have been harmful in some patients.

Moderately ill patients with COVID-19, defined as those who did not require ICU care or organ support, made up 80% of participants at enrollment in the three trials, Dr. Hochman said.

Among more than 1,000 moderately ill patients reviewed as of the data cut with the data safety monitoring board, full doses of low molecular weight or unfractionated heparin were superior to low prophylactic doses for the primary endpoint of need for ventilation or other organ supportive interventions at 21 days after randomization.

This met the predefined threshold for 99% probability of superiority and recruitment was stopped, Dr. Hochman reported. “Obviously safety figured into this decision. The risk/benefit ratio was very clear.”

The results do not pertain to patients with a previous indication for anticoagulation, who were excluded from the trials.

Data from an additional 1,000 patients will be reviewed and the data published sometime in the next 2-3 months, she said.

With large numbers of COVID-19 patients requiring hospitalization, the outcomes could help reduce the overload on intensive care units around the world, the NIH noted.

The results also highlight the critical role of timing in the course of COVID-19.

“We believe that full anticoagulation is effective early in the disease course,” Dr. Hochman said. “Based on the results so far from these three platform trials, those that were very, very sick at the time of enrollment really didn’t benefit and we needed to have caught them at an earlier stage.

“It’s possible that the people in the ICU are just different and the minute they get sick they need the ICU; so we haven’t clearly demonstrated this time course and when to intervene, but that’s the implication of the findings.”

The question of even earlier treatment is being examined in the partner ACTIV-4B trial, which is enrolling patients with COVID-19 illness not requiring hospitalization and randomizing them to the direct oral anticoagulant apixaban or aspirin or placebo.

“It’s a very important trial and we really want to get the message out that patients should volunteer for it,” said Dr. Hochman, principal investigator of the ACTIV-4 trial.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.

The REMAP-CAP, ACTIV-4, and ATTACC study platforms span five continents in more than 300 hospitals and are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (United Kingdom), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

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