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Novel mitral valve device shows encouraging mortality data
NATIONAL HARBOR, MD. – In a pooled analysis of three trials conducted with the transcatheter Carillon Mitral Contour System for mitral valve repair, the 5-year survival is 56.2%, which is an encouraging outcome that justifies the ongoing multinational pivotal Carillon trial, according to the principal investigator of the analysis presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
In patients with functional mitral valve regurgitation (FMR), “the Carillon device shows extremely encouraging long-term mortality data from prospective controlled trials in comparison with guideline-directed medical therapy or with the COAPT results,” according to Janusz Lipiecki, MD, PhD, department of cardiology, University Hospital, Clermont-Ferrand, France.
The COAPT trial is an important benchmark, because it was the first large, randomized trial to show benefit for a percutaneous device in the treatment of heart failure patients with moderate to severe FMR (N Engl J Med. 2018;379:2307-18). The study associated the MitraClip with a nearly 40% reduction in all-cause mortality (29.1% vs. 46.1%) at 24 months, relative to guideline-directed medical therapy (GDMT).
The Carillon device, which is also delivered percutaneously, does not engage the valve leaflets to treat FMR. Rather, it is anchored in coronary sinus to reform the mitral annulus. This reduces FMR without damage to the mitral valve, thus preserving the potential for future valve repairs, according to Dr. Lipiecki, who reported that more than 1,100 devices have now been implanted, mostly in Europe.
The data so far are encouraging, said Dr. Lipiecki, who provided survival data in 74 patients followed for at least 5 years. Of these, 23 were drawn from the REDUCE FMR trial, which was blinded and sham controlled, and the remainder from the TITAN and TITAN II studies, which were prospective but not controlled.
In this series of 74 patients, there were no serious complications associated with the procedure, and all achieved a reduction in mitral regurgitation at 12 months, Dr. Lipiecki said. Furthermore, the reduction in FMR was associated with improvements in symptoms and “favorable remodeling” reflected in reduced left ventricular volume, he said.
In this series, the 5-year survival is 56%, which substantially exceeds what would be expected with GDMT, according to Dr. Lipiecki.
There were no baseline predictors of long-term survival, but improvements within the 6 months in functional heart class, 6-minute walk distance (6MWD), and mitral regurgitation were significantly associated with a greater likelihood of being alive at 5 years.
Although there is no comparable follow-up with other devices, including the MitraClip, Dr. Lipiecki did compare the 67.9% survival at 3 years in this series to that of the COAPT trial. He restricted the comparison to those treated for grade 3+ or 4+ mitral regurgitation. At 36 months, survival rates were 57.2% and 44.5% for those treated with MitraClip and GDMT, respectively.
“COAPT patients might not be comparable for a variety of reasons, including the anatomic restrictions important to the use of either of these devices,” Dr. Lipiecki acknowledged, but he said the long-term data with the Carillon device provide support for the pivotal Carillon trial now enrolling.
In this blinded trial, more than 350 patients at 75 sites are being randomized to placement of the Carillon device, which has been available in Europe since 2011, or a sham procedure. The trial is scheduled for completion in 2025.
NATIONAL HARBOR, MD. – In a pooled analysis of three trials conducted with the transcatheter Carillon Mitral Contour System for mitral valve repair, the 5-year survival is 56.2%, which is an encouraging outcome that justifies the ongoing multinational pivotal Carillon trial, according to the principal investigator of the analysis presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
In patients with functional mitral valve regurgitation (FMR), “the Carillon device shows extremely encouraging long-term mortality data from prospective controlled trials in comparison with guideline-directed medical therapy or with the COAPT results,” according to Janusz Lipiecki, MD, PhD, department of cardiology, University Hospital, Clermont-Ferrand, France.
The COAPT trial is an important benchmark, because it was the first large, randomized trial to show benefit for a percutaneous device in the treatment of heart failure patients with moderate to severe FMR (N Engl J Med. 2018;379:2307-18). The study associated the MitraClip with a nearly 40% reduction in all-cause mortality (29.1% vs. 46.1%) at 24 months, relative to guideline-directed medical therapy (GDMT).
The Carillon device, which is also delivered percutaneously, does not engage the valve leaflets to treat FMR. Rather, it is anchored in coronary sinus to reform the mitral annulus. This reduces FMR without damage to the mitral valve, thus preserving the potential for future valve repairs, according to Dr. Lipiecki, who reported that more than 1,100 devices have now been implanted, mostly in Europe.
The data so far are encouraging, said Dr. Lipiecki, who provided survival data in 74 patients followed for at least 5 years. Of these, 23 were drawn from the REDUCE FMR trial, which was blinded and sham controlled, and the remainder from the TITAN and TITAN II studies, which were prospective but not controlled.
In this series of 74 patients, there were no serious complications associated with the procedure, and all achieved a reduction in mitral regurgitation at 12 months, Dr. Lipiecki said. Furthermore, the reduction in FMR was associated with improvements in symptoms and “favorable remodeling” reflected in reduced left ventricular volume, he said.
In this series, the 5-year survival is 56%, which substantially exceeds what would be expected with GDMT, according to Dr. Lipiecki.
There were no baseline predictors of long-term survival, but improvements within the 6 months in functional heart class, 6-minute walk distance (6MWD), and mitral regurgitation were significantly associated with a greater likelihood of being alive at 5 years.
Although there is no comparable follow-up with other devices, including the MitraClip, Dr. Lipiecki did compare the 67.9% survival at 3 years in this series to that of the COAPT trial. He restricted the comparison to those treated for grade 3+ or 4+ mitral regurgitation. At 36 months, survival rates were 57.2% and 44.5% for those treated with MitraClip and GDMT, respectively.
“COAPT patients might not be comparable for a variety of reasons, including the anatomic restrictions important to the use of either of these devices,” Dr. Lipiecki acknowledged, but he said the long-term data with the Carillon device provide support for the pivotal Carillon trial now enrolling.
In this blinded trial, more than 350 patients at 75 sites are being randomized to placement of the Carillon device, which has been available in Europe since 2011, or a sham procedure. The trial is scheduled for completion in 2025.
NATIONAL HARBOR, MD. – In a pooled analysis of three trials conducted with the transcatheter Carillon Mitral Contour System for mitral valve repair, the 5-year survival is 56.2%, which is an encouraging outcome that justifies the ongoing multinational pivotal Carillon trial, according to the principal investigator of the analysis presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
In patients with functional mitral valve regurgitation (FMR), “the Carillon device shows extremely encouraging long-term mortality data from prospective controlled trials in comparison with guideline-directed medical therapy or with the COAPT results,” according to Janusz Lipiecki, MD, PhD, department of cardiology, University Hospital, Clermont-Ferrand, France.
The COAPT trial is an important benchmark, because it was the first large, randomized trial to show benefit for a percutaneous device in the treatment of heart failure patients with moderate to severe FMR (N Engl J Med. 2018;379:2307-18). The study associated the MitraClip with a nearly 40% reduction in all-cause mortality (29.1% vs. 46.1%) at 24 months, relative to guideline-directed medical therapy (GDMT).
The Carillon device, which is also delivered percutaneously, does not engage the valve leaflets to treat FMR. Rather, it is anchored in coronary sinus to reform the mitral annulus. This reduces FMR without damage to the mitral valve, thus preserving the potential for future valve repairs, according to Dr. Lipiecki, who reported that more than 1,100 devices have now been implanted, mostly in Europe.
The data so far are encouraging, said Dr. Lipiecki, who provided survival data in 74 patients followed for at least 5 years. Of these, 23 were drawn from the REDUCE FMR trial, which was blinded and sham controlled, and the remainder from the TITAN and TITAN II studies, which were prospective but not controlled.
In this series of 74 patients, there were no serious complications associated with the procedure, and all achieved a reduction in mitral regurgitation at 12 months, Dr. Lipiecki said. Furthermore, the reduction in FMR was associated with improvements in symptoms and “favorable remodeling” reflected in reduced left ventricular volume, he said.
In this series, the 5-year survival is 56%, which substantially exceeds what would be expected with GDMT, according to Dr. Lipiecki.
There were no baseline predictors of long-term survival, but improvements within the 6 months in functional heart class, 6-minute walk distance (6MWD), and mitral regurgitation were significantly associated with a greater likelihood of being alive at 5 years.
Although there is no comparable follow-up with other devices, including the MitraClip, Dr. Lipiecki did compare the 67.9% survival at 3 years in this series to that of the COAPT trial. He restricted the comparison to those treated for grade 3+ or 4+ mitral regurgitation. At 36 months, survival rates were 57.2% and 44.5% for those treated with MitraClip and GDMT, respectively.
“COAPT patients might not be comparable for a variety of reasons, including the anatomic restrictions important to the use of either of these devices,” Dr. Lipiecki acknowledged, but he said the long-term data with the Carillon device provide support for the pivotal Carillon trial now enrolling.
In this blinded trial, more than 350 patients at 75 sites are being randomized to placement of the Carillon device, which has been available in Europe since 2011, or a sham procedure. The trial is scheduled for completion in 2025.
REPORTING FROM CRT 2020
Anticoagulants may have advantage over aspirin for low-risk TAVR
NATIONAL HARBOR, MD. – Anticoagulation reduces the risk of leaflet thrombosis at 30 days relative to antiplatelet therapy in low-risk patients undergoing transcatheter aortic valve replacement (TAVR), according to a randomized feasibility study presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute..
At 30 days, oral anticoagulation with warfarin did not appear to be associated with any increased risk of adverse outcomes, including bleeding events, relative to aspirin, according to Toby Rogers, MD, PhD, the scientific lead for the Structural Heart Disease Program at MedStar Heart & Vascular Institute, Washington.
The rationale for this feasibility study, called LRT 2.0, was to evaluate whether anticoagulation after low-risk TAVR reduces the risk of early subclinical leaflet thrombosis, a potential threat to long-term valve survival.
“In the first LRT trial, HALT [hypoattenuated leaflet thickening] was observed in 13.5% of patients on antiplatelet therapy but only 4.8% of those on oral anticoagulation,” Dr. Rogers said.
The two strategies have not been adequately compared, particularly in low-risk patients, according to Dr. Rogers. He noted that current guidelines recommend dual-antiplatelet therapy after TAVR but the oral anticoagulant warfarin after surgical valve replacement, a situation he characterized as a “discrepancy.”
In the multicenter, randomized LRT 2.0 trial, 94 patients undergoing TAVR and meeting prespecified low-risk criteria, such as a Society of Thoracic Surgeons score of 3 or lower, were randomized to warfarin or to aspirin. The study called for an enrollment of 200 patients but was closed early when the Food and Drug Administration approved TAVR for low-risk patients in 2019, causing “enrollment to dry up over night.”
However, an additional registry cohort was included in a separate analysis. This registry cohort consisted of 30 patients who were evaluated for trial inclusion but were found to be inappropriate for randomization because they already had an indication for anticoagulation or had an elevated risk of bleeding. These low-risk TAVR patients were assigned to anticoagulation or antiplatelet therapy as appropriate.
When the randomized groups were compared, the incidence of HALT at 30 days on CT scan was 4.7% among those on warfarin and 16.3% (P = .07) among those taking aspirin. Dr. Rogers believes the near miss for statistical significance was a problem of power, a position supported by the pooled analysis of randomized and registry patients. With the added patients, the difference in HALT did reach significance (3.1% vs. 16.4%; P = .01).
The numerical differences in reduced leaflet motion and hypoattenuated motion favoring anticoagulation trended for significance in the randomized cohort (P = .12) but reached the cusp of significance in the pooled cohort (1.5% vs. 9.4%; P = .052) for both reduced leaflet motion and hypoattenuated motion).
There were no deaths recorded in any treatment arm, whether restricted to the randomized trial or within the pooled cohort. For the pooled cohort, there were more strokes in the aspirin arm (5.4% vs. 1.5%) but Dr. Rogers said that no conclusions could be drawn about relative risk because of the study size and small number of events.
For anticoagulation relative to antiplatelet therapy, respectively, the incidence of new-onset atrial fibrillation (1.5% vs. 1.8%), pacemaker implantation (11.8% vs. 7.1%), major bleeding (1.5% vs. 5.4%), and median length of stay (2.2 vs. 2.4 days) were all similar. The improvements in hemodynamics 30 days after TAVR were substantial and similar in the two groups, according to Dr. Rogers.
Emphasizing that this is a feasibility study, Dr. Rogers cautioned that these data do not necessarily demonstrate that anticoagulation is a better strategy than antiplatelet therapy in low-risk patients after TAVR, but they do associate anticoagulation with a reduced risk of early leaflet thrombosis.
“We fear leaflet thrombosis for the potential that it will negatively impact valve durability, which is particularly important in younger lower-risk patients who might outlive their first valve prosthesis,” Dr. Rogers said.
Panelists at the late-breaking clinical trial session expressed interest in this concept but generally agreed that longer follow-up is needed. This additional follow-up is important for monitoring effect on leaflet thrombosis as well as on the overall impact of these strategies on adverse events.
“We need to see CT scans at later time points because we do not know where this complication comes from. The trigger for leaflet thrombosis might still be there after 30 days,” said Andreas Baumbach, MD, professor of interventional cardiology at the University of Bristol (England). However, he agreed that this is an important line of research, because the potential risk of leaflet thrombosis is “a very important question for us.”
Dr. Rogers reported financial relationships with Edwards Lifesciences and Medtronic.
NATIONAL HARBOR, MD. – Anticoagulation reduces the risk of leaflet thrombosis at 30 days relative to antiplatelet therapy in low-risk patients undergoing transcatheter aortic valve replacement (TAVR), according to a randomized feasibility study presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute..
At 30 days, oral anticoagulation with warfarin did not appear to be associated with any increased risk of adverse outcomes, including bleeding events, relative to aspirin, according to Toby Rogers, MD, PhD, the scientific lead for the Structural Heart Disease Program at MedStar Heart & Vascular Institute, Washington.
The rationale for this feasibility study, called LRT 2.0, was to evaluate whether anticoagulation after low-risk TAVR reduces the risk of early subclinical leaflet thrombosis, a potential threat to long-term valve survival.
“In the first LRT trial, HALT [hypoattenuated leaflet thickening] was observed in 13.5% of patients on antiplatelet therapy but only 4.8% of those on oral anticoagulation,” Dr. Rogers said.
The two strategies have not been adequately compared, particularly in low-risk patients, according to Dr. Rogers. He noted that current guidelines recommend dual-antiplatelet therapy after TAVR but the oral anticoagulant warfarin after surgical valve replacement, a situation he characterized as a “discrepancy.”
In the multicenter, randomized LRT 2.0 trial, 94 patients undergoing TAVR and meeting prespecified low-risk criteria, such as a Society of Thoracic Surgeons score of 3 or lower, were randomized to warfarin or to aspirin. The study called for an enrollment of 200 patients but was closed early when the Food and Drug Administration approved TAVR for low-risk patients in 2019, causing “enrollment to dry up over night.”
However, an additional registry cohort was included in a separate analysis. This registry cohort consisted of 30 patients who were evaluated for trial inclusion but were found to be inappropriate for randomization because they already had an indication for anticoagulation or had an elevated risk of bleeding. These low-risk TAVR patients were assigned to anticoagulation or antiplatelet therapy as appropriate.
When the randomized groups were compared, the incidence of HALT at 30 days on CT scan was 4.7% among those on warfarin and 16.3% (P = .07) among those taking aspirin. Dr. Rogers believes the near miss for statistical significance was a problem of power, a position supported by the pooled analysis of randomized and registry patients. With the added patients, the difference in HALT did reach significance (3.1% vs. 16.4%; P = .01).
The numerical differences in reduced leaflet motion and hypoattenuated motion favoring anticoagulation trended for significance in the randomized cohort (P = .12) but reached the cusp of significance in the pooled cohort (1.5% vs. 9.4%; P = .052) for both reduced leaflet motion and hypoattenuated motion).
There were no deaths recorded in any treatment arm, whether restricted to the randomized trial or within the pooled cohort. For the pooled cohort, there were more strokes in the aspirin arm (5.4% vs. 1.5%) but Dr. Rogers said that no conclusions could be drawn about relative risk because of the study size and small number of events.
For anticoagulation relative to antiplatelet therapy, respectively, the incidence of new-onset atrial fibrillation (1.5% vs. 1.8%), pacemaker implantation (11.8% vs. 7.1%), major bleeding (1.5% vs. 5.4%), and median length of stay (2.2 vs. 2.4 days) were all similar. The improvements in hemodynamics 30 days after TAVR were substantial and similar in the two groups, according to Dr. Rogers.
Emphasizing that this is a feasibility study, Dr. Rogers cautioned that these data do not necessarily demonstrate that anticoagulation is a better strategy than antiplatelet therapy in low-risk patients after TAVR, but they do associate anticoagulation with a reduced risk of early leaflet thrombosis.
“We fear leaflet thrombosis for the potential that it will negatively impact valve durability, which is particularly important in younger lower-risk patients who might outlive their first valve prosthesis,” Dr. Rogers said.
Panelists at the late-breaking clinical trial session expressed interest in this concept but generally agreed that longer follow-up is needed. This additional follow-up is important for monitoring effect on leaflet thrombosis as well as on the overall impact of these strategies on adverse events.
“We need to see CT scans at later time points because we do not know where this complication comes from. The trigger for leaflet thrombosis might still be there after 30 days,” said Andreas Baumbach, MD, professor of interventional cardiology at the University of Bristol (England). However, he agreed that this is an important line of research, because the potential risk of leaflet thrombosis is “a very important question for us.”
Dr. Rogers reported financial relationships with Edwards Lifesciences and Medtronic.
NATIONAL HARBOR, MD. – Anticoagulation reduces the risk of leaflet thrombosis at 30 days relative to antiplatelet therapy in low-risk patients undergoing transcatheter aortic valve replacement (TAVR), according to a randomized feasibility study presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute..
At 30 days, oral anticoagulation with warfarin did not appear to be associated with any increased risk of adverse outcomes, including bleeding events, relative to aspirin, according to Toby Rogers, MD, PhD, the scientific lead for the Structural Heart Disease Program at MedStar Heart & Vascular Institute, Washington.
The rationale for this feasibility study, called LRT 2.0, was to evaluate whether anticoagulation after low-risk TAVR reduces the risk of early subclinical leaflet thrombosis, a potential threat to long-term valve survival.
“In the first LRT trial, HALT [hypoattenuated leaflet thickening] was observed in 13.5% of patients on antiplatelet therapy but only 4.8% of those on oral anticoagulation,” Dr. Rogers said.
The two strategies have not been adequately compared, particularly in low-risk patients, according to Dr. Rogers. He noted that current guidelines recommend dual-antiplatelet therapy after TAVR but the oral anticoagulant warfarin after surgical valve replacement, a situation he characterized as a “discrepancy.”
In the multicenter, randomized LRT 2.0 trial, 94 patients undergoing TAVR and meeting prespecified low-risk criteria, such as a Society of Thoracic Surgeons score of 3 or lower, were randomized to warfarin or to aspirin. The study called for an enrollment of 200 patients but was closed early when the Food and Drug Administration approved TAVR for low-risk patients in 2019, causing “enrollment to dry up over night.”
However, an additional registry cohort was included in a separate analysis. This registry cohort consisted of 30 patients who were evaluated for trial inclusion but were found to be inappropriate for randomization because they already had an indication for anticoagulation or had an elevated risk of bleeding. These low-risk TAVR patients were assigned to anticoagulation or antiplatelet therapy as appropriate.
When the randomized groups were compared, the incidence of HALT at 30 days on CT scan was 4.7% among those on warfarin and 16.3% (P = .07) among those taking aspirin. Dr. Rogers believes the near miss for statistical significance was a problem of power, a position supported by the pooled analysis of randomized and registry patients. With the added patients, the difference in HALT did reach significance (3.1% vs. 16.4%; P = .01).
The numerical differences in reduced leaflet motion and hypoattenuated motion favoring anticoagulation trended for significance in the randomized cohort (P = .12) but reached the cusp of significance in the pooled cohort (1.5% vs. 9.4%; P = .052) for both reduced leaflet motion and hypoattenuated motion).
There were no deaths recorded in any treatment arm, whether restricted to the randomized trial or within the pooled cohort. For the pooled cohort, there were more strokes in the aspirin arm (5.4% vs. 1.5%) but Dr. Rogers said that no conclusions could be drawn about relative risk because of the study size and small number of events.
For anticoagulation relative to antiplatelet therapy, respectively, the incidence of new-onset atrial fibrillation (1.5% vs. 1.8%), pacemaker implantation (11.8% vs. 7.1%), major bleeding (1.5% vs. 5.4%), and median length of stay (2.2 vs. 2.4 days) were all similar. The improvements in hemodynamics 30 days after TAVR were substantial and similar in the two groups, according to Dr. Rogers.
Emphasizing that this is a feasibility study, Dr. Rogers cautioned that these data do not necessarily demonstrate that anticoagulation is a better strategy than antiplatelet therapy in low-risk patients after TAVR, but they do associate anticoagulation with a reduced risk of early leaflet thrombosis.
“We fear leaflet thrombosis for the potential that it will negatively impact valve durability, which is particularly important in younger lower-risk patients who might outlive their first valve prosthesis,” Dr. Rogers said.
Panelists at the late-breaking clinical trial session expressed interest in this concept but generally agreed that longer follow-up is needed. This additional follow-up is important for monitoring effect on leaflet thrombosis as well as on the overall impact of these strategies on adverse events.
“We need to see CT scans at later time points because we do not know where this complication comes from. The trigger for leaflet thrombosis might still be there after 30 days,” said Andreas Baumbach, MD, professor of interventional cardiology at the University of Bristol (England). However, he agreed that this is an important line of research, because the potential risk of leaflet thrombosis is “a very important question for us.”
Dr. Rogers reported financial relationships with Edwards Lifesciences and Medtronic.
REPORTING FROM CRT 2020
AUGUSTUS: Apixaban surpassed warfarin despite prior stroke or thromboembolism
LOS ANGELES – The edge that the direct-acting oral anticoagulant apixaban (Eliquis) has over warfarin for safely preventing ischemic events in patients with atrial fibrillation and either a recent acute coronary syndrome event or a recent percutaneous coronary intervention held up even in patients with a history of stroke, transient ischemic attack, or thromboembolic event, according to a prespecified secondary analysis of data collected in the AUGUSTUS trial.
The treatment advantages of apixaban, compared with warfarin, seen in the overall AUGUSTUS results, first reported in March 2019, “were consistent” with the benefits seen in the subgroup of enrolled patients with a prior stroke, transient ischemic attack (TIA), or thromboembolic (TE) event, M. Cecilia Bahit, MD, said at the International Stroke Conference sponsored by the American Heart Association.
All patients in AUGUSTUS received a P2Y12 inhibitor antiplatelet drug, which was clopidogrel for more than 90% of patients. The two-by-two factorial design of AUGUSTUS also assessed the safety and efficacy of either adding or withholding aspirin from the two-drug regimen that all patients in the study received with a P2Y12 inhibitor plus an anticoagulant (apixaban or warfarin). The most notable finding of the aspirin versus placebo analysis was that patients without a prior stroke, TIA, or TE event had a “more profound” increase in their rate of major or clinically relevant minor bleeds when also treated with aspirin, compared with patients who received aspirin and had a history of stroke, TIA, or TE event, reported Dr. Bahit, a chief of cardiology and director of clinical research at the INECO Foundation in Rosario, Argentina.
In general, the findings of the secondary analysis that took into account stroke, TIA, or TE history “confirmed” the main AUGUSTUS findings, Dr. Bahit said; an antithrombotic regimen of apixaban plus clopidogrel (or other P2Y12 inhibitor) without aspirin was superior for both efficacy and safety, compared with the alternative regimens that either substituted warfarin for apixaban or that added aspirin.
AUGUSTUS enrolled 4,614 atrial fibrillation (AFib) patients who either had a recent acute coronary syndrome (ACS) event or had recently undergone percutaneous coronary intervention (PCI) at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the incidence of major or clinically relevant minor bleeds after 6 months, which was significantly lower in the subgroups that received apixaban instead of warfarin and in patients who received placebo instead of aspirin. The secondary endpoint of death or hospitalization after 6 months was also significantly lower in the apixaban-treated patients, compared with those on warfarin, while the aspirin and placebo subgroups showed no difference in the incidence of these events (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
The results reported by Dr. Bahit also highlighted both the high risk faced by patients with AFib who also have had an ACS event or PCI, as well as a prior stroke, TIA, or TE event, noted Larry B. Goldstein, MD, professor and chairman of neurology at the University of Kentucky, Lexington. “It’s difficult, because these patients had an ACS event or PCI, and you don’t want a coronary too close up, but do these patients really need a P2Y12 inhibitor plus an anticoagulant? Could these patients do as well on apixaban only? I would have liked to see that treatment arm in the study,” Dr. Goldstein commented in an interview.
“These are challenging patients because they often require anticoagulation for the AFib as well as antiplatelet agents” for the recent PCI or ACS event, commented Mitchell S.V. Elkind, MD, professor of neurology at Columbia University, New York. “The question has always been: How many blood thinners should these patients be on? Potentially they could be on three different agents [an anticoagulant and two antiplatelet drugs], and we know that all of those drugs together pretty dramatically increase the risk of bleeding. About 15% of the patients in the overall AUGUSTUS trial had either cerebrovascular disease or systemic thromboembolism, so this was a small subgroup of the overall trial, but the overall trial was large so it’s a significant number of patients who met this criteria. The results confirmed that even in a group of patients who may be considered at high risk because they have a prior history of cerebrovascular disease use of apixaban instead of warfarin seemed safer, and that those patients did not need to be on aspirin as well as their other antiplatelet agent. Patients with a history of stroke, in fact, had a lower risk of bleeding than the other patients in this trial, so one could argue that they should be on an agent like apixaban as well as an antiplatelet agent like clopidogrel without addition of aspirin,” he said in a recorded statement.
In addition to implications for using prescription drugs like apixaban and clopidogrel, the findings also send a message about the need for very aggressive implementation of lifestyle measures that can reduce cardiovascular disease risk in these patients, added Dr. Goldstein. The AUGUSTUS outcome analyses that subdivided the study population into those with a prior stroke, TIA, or TE event – 633 patients or about 14% of the 4,581 patients eligible for this analysis – and those who did not have this history showed the extremely high, incrementally elevated risk faced by patients with these prior events.
A history of stroke, TIA, or TE event linked with a jump in the 90-day rate of major or clinically relevant minor bleeds from 13% without this history to 17%, which is a 31% relative increase; it boosted the 90-day rate of death or hospitalization from 25% to 31%, a 24% relative increase; and it jacked up the rate of death or ischemic events from 6% to 9%, a 50% relative increase, Dr. Bahit reported.
These substantial increases “suggest we need to be very aggressive” in managing these high-risk patients who combine a background of AFib, a prior stroke, TIA, or TE events, and a recent ACS event or PCI, Dr. Goldstein observed. In these patients, he suggested that clinicians make sure to address smoking cessation, obesity, exercise, diet, and statin use, and get each of these to an optimal level to further cut risk. If all five of these basic interventions were successfully administered to a patient they could collectively cut the patient’s event risk by about 80%, he added.
AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer, the companies that jointly market apixaban. Dr. Bahit has received honoraria from Pfizer, and from CSL Behring and Merck. Dr. Elkind and Dr. Goldstein had no relevant disclosures.
SOURCE: Bahit MC et al. ISC 2020, Abstract LB22.
LOS ANGELES – The edge that the direct-acting oral anticoagulant apixaban (Eliquis) has over warfarin for safely preventing ischemic events in patients with atrial fibrillation and either a recent acute coronary syndrome event or a recent percutaneous coronary intervention held up even in patients with a history of stroke, transient ischemic attack, or thromboembolic event, according to a prespecified secondary analysis of data collected in the AUGUSTUS trial.
The treatment advantages of apixaban, compared with warfarin, seen in the overall AUGUSTUS results, first reported in March 2019, “were consistent” with the benefits seen in the subgroup of enrolled patients with a prior stroke, transient ischemic attack (TIA), or thromboembolic (TE) event, M. Cecilia Bahit, MD, said at the International Stroke Conference sponsored by the American Heart Association.
All patients in AUGUSTUS received a P2Y12 inhibitor antiplatelet drug, which was clopidogrel for more than 90% of patients. The two-by-two factorial design of AUGUSTUS also assessed the safety and efficacy of either adding or withholding aspirin from the two-drug regimen that all patients in the study received with a P2Y12 inhibitor plus an anticoagulant (apixaban or warfarin). The most notable finding of the aspirin versus placebo analysis was that patients without a prior stroke, TIA, or TE event had a “more profound” increase in their rate of major or clinically relevant minor bleeds when also treated with aspirin, compared with patients who received aspirin and had a history of stroke, TIA, or TE event, reported Dr. Bahit, a chief of cardiology and director of clinical research at the INECO Foundation in Rosario, Argentina.
In general, the findings of the secondary analysis that took into account stroke, TIA, or TE history “confirmed” the main AUGUSTUS findings, Dr. Bahit said; an antithrombotic regimen of apixaban plus clopidogrel (or other P2Y12 inhibitor) without aspirin was superior for both efficacy and safety, compared with the alternative regimens that either substituted warfarin for apixaban or that added aspirin.
AUGUSTUS enrolled 4,614 atrial fibrillation (AFib) patients who either had a recent acute coronary syndrome (ACS) event or had recently undergone percutaneous coronary intervention (PCI) at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the incidence of major or clinically relevant minor bleeds after 6 months, which was significantly lower in the subgroups that received apixaban instead of warfarin and in patients who received placebo instead of aspirin. The secondary endpoint of death or hospitalization after 6 months was also significantly lower in the apixaban-treated patients, compared with those on warfarin, while the aspirin and placebo subgroups showed no difference in the incidence of these events (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
The results reported by Dr. Bahit also highlighted both the high risk faced by patients with AFib who also have had an ACS event or PCI, as well as a prior stroke, TIA, or TE event, noted Larry B. Goldstein, MD, professor and chairman of neurology at the University of Kentucky, Lexington. “It’s difficult, because these patients had an ACS event or PCI, and you don’t want a coronary too close up, but do these patients really need a P2Y12 inhibitor plus an anticoagulant? Could these patients do as well on apixaban only? I would have liked to see that treatment arm in the study,” Dr. Goldstein commented in an interview.
“These are challenging patients because they often require anticoagulation for the AFib as well as antiplatelet agents” for the recent PCI or ACS event, commented Mitchell S.V. Elkind, MD, professor of neurology at Columbia University, New York. “The question has always been: How many blood thinners should these patients be on? Potentially they could be on three different agents [an anticoagulant and two antiplatelet drugs], and we know that all of those drugs together pretty dramatically increase the risk of bleeding. About 15% of the patients in the overall AUGUSTUS trial had either cerebrovascular disease or systemic thromboembolism, so this was a small subgroup of the overall trial, but the overall trial was large so it’s a significant number of patients who met this criteria. The results confirmed that even in a group of patients who may be considered at high risk because they have a prior history of cerebrovascular disease use of apixaban instead of warfarin seemed safer, and that those patients did not need to be on aspirin as well as their other antiplatelet agent. Patients with a history of stroke, in fact, had a lower risk of bleeding than the other patients in this trial, so one could argue that they should be on an agent like apixaban as well as an antiplatelet agent like clopidogrel without addition of aspirin,” he said in a recorded statement.
In addition to implications for using prescription drugs like apixaban and clopidogrel, the findings also send a message about the need for very aggressive implementation of lifestyle measures that can reduce cardiovascular disease risk in these patients, added Dr. Goldstein. The AUGUSTUS outcome analyses that subdivided the study population into those with a prior stroke, TIA, or TE event – 633 patients or about 14% of the 4,581 patients eligible for this analysis – and those who did not have this history showed the extremely high, incrementally elevated risk faced by patients with these prior events.
A history of stroke, TIA, or TE event linked with a jump in the 90-day rate of major or clinically relevant minor bleeds from 13% without this history to 17%, which is a 31% relative increase; it boosted the 90-day rate of death or hospitalization from 25% to 31%, a 24% relative increase; and it jacked up the rate of death or ischemic events from 6% to 9%, a 50% relative increase, Dr. Bahit reported.
These substantial increases “suggest we need to be very aggressive” in managing these high-risk patients who combine a background of AFib, a prior stroke, TIA, or TE events, and a recent ACS event or PCI, Dr. Goldstein observed. In these patients, he suggested that clinicians make sure to address smoking cessation, obesity, exercise, diet, and statin use, and get each of these to an optimal level to further cut risk. If all five of these basic interventions were successfully administered to a patient they could collectively cut the patient’s event risk by about 80%, he added.
AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer, the companies that jointly market apixaban. Dr. Bahit has received honoraria from Pfizer, and from CSL Behring and Merck. Dr. Elkind and Dr. Goldstein had no relevant disclosures.
SOURCE: Bahit MC et al. ISC 2020, Abstract LB22.
LOS ANGELES – The edge that the direct-acting oral anticoagulant apixaban (Eliquis) has over warfarin for safely preventing ischemic events in patients with atrial fibrillation and either a recent acute coronary syndrome event or a recent percutaneous coronary intervention held up even in patients with a history of stroke, transient ischemic attack, or thromboembolic event, according to a prespecified secondary analysis of data collected in the AUGUSTUS trial.
The treatment advantages of apixaban, compared with warfarin, seen in the overall AUGUSTUS results, first reported in March 2019, “were consistent” with the benefits seen in the subgroup of enrolled patients with a prior stroke, transient ischemic attack (TIA), or thromboembolic (TE) event, M. Cecilia Bahit, MD, said at the International Stroke Conference sponsored by the American Heart Association.
All patients in AUGUSTUS received a P2Y12 inhibitor antiplatelet drug, which was clopidogrel for more than 90% of patients. The two-by-two factorial design of AUGUSTUS also assessed the safety and efficacy of either adding or withholding aspirin from the two-drug regimen that all patients in the study received with a P2Y12 inhibitor plus an anticoagulant (apixaban or warfarin). The most notable finding of the aspirin versus placebo analysis was that patients without a prior stroke, TIA, or TE event had a “more profound” increase in their rate of major or clinically relevant minor bleeds when also treated with aspirin, compared with patients who received aspirin and had a history of stroke, TIA, or TE event, reported Dr. Bahit, a chief of cardiology and director of clinical research at the INECO Foundation in Rosario, Argentina.
In general, the findings of the secondary analysis that took into account stroke, TIA, or TE history “confirmed” the main AUGUSTUS findings, Dr. Bahit said; an antithrombotic regimen of apixaban plus clopidogrel (or other P2Y12 inhibitor) without aspirin was superior for both efficacy and safety, compared with the alternative regimens that either substituted warfarin for apixaban or that added aspirin.
AUGUSTUS enrolled 4,614 atrial fibrillation (AFib) patients who either had a recent acute coronary syndrome (ACS) event or had recently undergone percutaneous coronary intervention (PCI) at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the incidence of major or clinically relevant minor bleeds after 6 months, which was significantly lower in the subgroups that received apixaban instead of warfarin and in patients who received placebo instead of aspirin. The secondary endpoint of death or hospitalization after 6 months was also significantly lower in the apixaban-treated patients, compared with those on warfarin, while the aspirin and placebo subgroups showed no difference in the incidence of these events (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
The results reported by Dr. Bahit also highlighted both the high risk faced by patients with AFib who also have had an ACS event or PCI, as well as a prior stroke, TIA, or TE event, noted Larry B. Goldstein, MD, professor and chairman of neurology at the University of Kentucky, Lexington. “It’s difficult, because these patients had an ACS event or PCI, and you don’t want a coronary too close up, but do these patients really need a P2Y12 inhibitor plus an anticoagulant? Could these patients do as well on apixaban only? I would have liked to see that treatment arm in the study,” Dr. Goldstein commented in an interview.
“These are challenging patients because they often require anticoagulation for the AFib as well as antiplatelet agents” for the recent PCI or ACS event, commented Mitchell S.V. Elkind, MD, professor of neurology at Columbia University, New York. “The question has always been: How many blood thinners should these patients be on? Potentially they could be on three different agents [an anticoagulant and two antiplatelet drugs], and we know that all of those drugs together pretty dramatically increase the risk of bleeding. About 15% of the patients in the overall AUGUSTUS trial had either cerebrovascular disease or systemic thromboembolism, so this was a small subgroup of the overall trial, but the overall trial was large so it’s a significant number of patients who met this criteria. The results confirmed that even in a group of patients who may be considered at high risk because they have a prior history of cerebrovascular disease use of apixaban instead of warfarin seemed safer, and that those patients did not need to be on aspirin as well as their other antiplatelet agent. Patients with a history of stroke, in fact, had a lower risk of bleeding than the other patients in this trial, so one could argue that they should be on an agent like apixaban as well as an antiplatelet agent like clopidogrel without addition of aspirin,” he said in a recorded statement.
In addition to implications for using prescription drugs like apixaban and clopidogrel, the findings also send a message about the need for very aggressive implementation of lifestyle measures that can reduce cardiovascular disease risk in these patients, added Dr. Goldstein. The AUGUSTUS outcome analyses that subdivided the study population into those with a prior stroke, TIA, or TE event – 633 patients or about 14% of the 4,581 patients eligible for this analysis – and those who did not have this history showed the extremely high, incrementally elevated risk faced by patients with these prior events.
A history of stroke, TIA, or TE event linked with a jump in the 90-day rate of major or clinically relevant minor bleeds from 13% without this history to 17%, which is a 31% relative increase; it boosted the 90-day rate of death or hospitalization from 25% to 31%, a 24% relative increase; and it jacked up the rate of death or ischemic events from 6% to 9%, a 50% relative increase, Dr. Bahit reported.
These substantial increases “suggest we need to be very aggressive” in managing these high-risk patients who combine a background of AFib, a prior stroke, TIA, or TE events, and a recent ACS event or PCI, Dr. Goldstein observed. In these patients, he suggested that clinicians make sure to address smoking cessation, obesity, exercise, diet, and statin use, and get each of these to an optimal level to further cut risk. If all five of these basic interventions were successfully administered to a patient they could collectively cut the patient’s event risk by about 80%, he added.
AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer, the companies that jointly market apixaban. Dr. Bahit has received honoraria from Pfizer, and from CSL Behring and Merck. Dr. Elkind and Dr. Goldstein had no relevant disclosures.
SOURCE: Bahit MC et al. ISC 2020, Abstract LB22.
REPORTING FROM ISC 2020
Transradial access gains converts among U.S. interventional neurologists
LOS ANGELES –
“It’s growing dramatically in U.S. practice. It may be hype, but there is big excitement. We are still in an assessment mode, but the adoption rate has been high,” Raul G. Nogueira, MD, said in an interview during the International Stroke Conference sponsored by the American Heart Association. “The big advantage [of transradial catheterization entry] is elimination of groin complications, some of which can be pretty bad. Is it safe for the brain? It’s probably okay, but that needs more study,” said Dr. Nogueira, professor of neurology at Emory University and director of the Neurovascular Service at the Grady Marcus Stroke and Neuroscience Center in Atlanta.
His uncertainty stems from the more difficult route taken to advance a catheter from the wrist into brain vessels, a maneuver that requires significant manipulation of the catheter tip, unlike the path from the right radial artery into the heart’s arteries, a “straight shot,” he explained. To reach the brain’s vasculature, the tip must execute a spin “that may scrape small emboli from the arch or arteries, so we need to look at this a little more carefully.” Ideally in a prospective, randomized study, he said. “We need to see whether the burden of [magnetic resonance] lesions is any higher when you go through the radial [artery].”
Some of the first-reported, large-scale U.S. experiences using a radial-artery approach for various neurovascular procedures, including a few thrombectomy cases, came in a series of 1,272 patients treated at any of four U.S. centers during July 2018 to June 2019, a period when the neurovascular staffs at all four centers transitioned from primarily using femoral-artery access to using radial access as their default mode. During the 12-month transition period, overall use of radial access at all four centers rose from roughly a quarter of all neurovascular interventions during July to September 2018 to closer to 80% by April to June 2019, Eyad Almallouhi, MD, reported at the conference.
During the entire 12 months, the operators ran up a 94% rate of successfully completed procedures using radial access, a rate that rose from about 88% during the first quarter to roughly 95% success during the fourth quarter tracked, said Dr. Almallouhi, a neurologist at the Medical University of South Carolina in Charleston. The rate of crossover from what began as a transradial procedure but switched to transfemoral was just under 6% overall, with a nearly 14% crossover rate during the first quarter that then dropped to around 5% for the rest of the transition year. Crossovers for interventional procedures throughout the study year occurred at a 12% rate, while crossovers for diagnostic procedures occurred at a 5% clip throughout the entire year.
None of the transradial patients had a major access-site complication, and minor complications occurred in less than 2% of the patients, including 11 with a forearm hematoma, 6 with forearm pain, and 5 with oozing at their access site. The absence of any major access-site complications among the transradial-access patients in this series contrasts with a recent report of a 1.7% rate of major complications secondary to femoral-artery access for mechanical thrombectomy in a combined analysis of data from seven published studies that included 660 thrombectomy procedures (Am J Neuroradiol. 2019 Feb. doi: 10.3174/ajnr.A6423). The other three centers that participated in the study Dr. Almallouhi presented were the University of Miami, Thomas Jefferson University in Philadelphia, and the University of Pittsburgh.
Of the 1,272 total procedures studied, 83% were diagnostic procedures, which had an overall 95% success rate, and 17% were interventional procedures, which had a success rate of 89%. The interventional transradial procedures included 62 primary coilings of aneurysms, 44 stent-assisted aneurysm coilings, 40 patients who underwent a flow diversion, 21 balloon-assisted aneurysm coilings, and 24 patients who underwent stroke thrombectomy.
The size of the devices commonly used for thrombectomy are often too large to allow for radial-artery access, noted Dr. Nogueira. For urgent interventions like thrombectomy “we use balloon-guided catheters that are large-bore and don’t fit well in the radial,” he said, although thrombectomy via the radial artery without a balloon-guided catheter is possible for clots located in the basilar artery. Last year, researchers in Germany reported using a balloon-guided catheter to perform mechanical thrombectomy via the radial artery (Interv Neuroradiol. 2019 Oct 1;25[5]:508-10). But it’s a different story for elective, diagnostic procedures. “I have moved most of these to transradial,” Dr. Nogueira said. He and his coauthors summarized the case for transradial access for cerebral angiography in a recent review; in addition to enhanced safety they cited other advantages including improved patient satisfaction and reduced cost because of a shorter length of stay (Interv Cardiol Clin. 2020 Jan;9[1]:75-86).
Despite his enthusiasm and the enthusiasm of other neurointerventionalists for the transradial approach, other stroke neurologists have been more cautious and slower to shift away from the femoral approach. “Our experience has been that for most cases it’s a bit more challenging to access the cervical vessels from the radial artery than from the traditional femoral approach. For arches with complex anatomy, however, the transradial approach can be of benefit in some cases, depending on the angles that need to be traversed,” commented Jeremy Payne, MD, director of the Banner Center for Neurovascular Medicine and medical director of the Banner—University Medical Center Phoenix Comprehensive Stroke Program. Dr. Payne highlighted that, while he is not an interventionalist himself, he and his interventional staff have regularly discussed the transradial option.
“In the cardiology literature the radial approach has been very successful, with better overall safety than the traditional femoral approach. Largely this seems to do with the anatomy of the aortic arch. It’s simply a more direct approach to the coronaries via the right radial artery; getting the wire into the correct vessel is significantly more difficult the more acute the angle it has to traverse,” such as when the target is an intracerebral vessel, Dr. Payne said in an interview.
“Our experience in the past 6 months has been about 25% transradial for some of our procedures, mainly diagnostic angiograms. We don’t find any difference in safety, however, as our transfemoral procedures are already very safe. One of the benefits of a transradial approach has been that a closure device may not be needed, with fewer vascular complications at the access site, such as fistula formation. We use ultrasound for access, and have not seen a difference in those approaches at all so far. One might argue that using ultrasound to establish access would slow us down, but so far our fastest case start-to-recanalization time in an acute stroke this year was 6 minutes, so speed does not appear to be a limiting issue. Another concern overall for transradial access is the potential limitation in the tools we may be able to deploy, given the smaller size of the vessel. It is reassuring [in the report from Dr. Almallouhi] that a variety of cases were successfully completed via this approach. However, fewer than 2% of their cases [24 patients] were apparently emergent, acute strokes, lending no specific support to that context. I do not expect that to change based on this paper,” Dr. Payne concluded.
“It is not clear to me that transradial neurointervention will change much. We have excellent safety data for the femoral approach, a proven track record of efficacy, and for most patients it seems to afford a somewhat wider range of tools that can be deployed, with simpler anatomy for accessing the cervical vessels in most arches. It is reassuring that the results reported by Dr. Almallouhi did not suggest negative outcomes, and as such I suspect the transradial approach at least gives us an additional option in a minority of patients. We have seen in the past 5-10 years an explosion of tools for the endovascular treatment of stroke; transradial access represents another potential strategy that appears so far to be safe,” Dr. Payne said.
Drs. Nogueira, Almallouhi, and Payne had no relevant disclosures.
SOURCE: Almallouhi E et al. Stroke. 2020 Feb;51(suppl 1):A64.
LOS ANGELES –
“It’s growing dramatically in U.S. practice. It may be hype, but there is big excitement. We are still in an assessment mode, but the adoption rate has been high,” Raul G. Nogueira, MD, said in an interview during the International Stroke Conference sponsored by the American Heart Association. “The big advantage [of transradial catheterization entry] is elimination of groin complications, some of which can be pretty bad. Is it safe for the brain? It’s probably okay, but that needs more study,” said Dr. Nogueira, professor of neurology at Emory University and director of the Neurovascular Service at the Grady Marcus Stroke and Neuroscience Center in Atlanta.
His uncertainty stems from the more difficult route taken to advance a catheter from the wrist into brain vessels, a maneuver that requires significant manipulation of the catheter tip, unlike the path from the right radial artery into the heart’s arteries, a “straight shot,” he explained. To reach the brain’s vasculature, the tip must execute a spin “that may scrape small emboli from the arch or arteries, so we need to look at this a little more carefully.” Ideally in a prospective, randomized study, he said. “We need to see whether the burden of [magnetic resonance] lesions is any higher when you go through the radial [artery].”
Some of the first-reported, large-scale U.S. experiences using a radial-artery approach for various neurovascular procedures, including a few thrombectomy cases, came in a series of 1,272 patients treated at any of four U.S. centers during July 2018 to June 2019, a period when the neurovascular staffs at all four centers transitioned from primarily using femoral-artery access to using radial access as their default mode. During the 12-month transition period, overall use of radial access at all four centers rose from roughly a quarter of all neurovascular interventions during July to September 2018 to closer to 80% by April to June 2019, Eyad Almallouhi, MD, reported at the conference.
During the entire 12 months, the operators ran up a 94% rate of successfully completed procedures using radial access, a rate that rose from about 88% during the first quarter to roughly 95% success during the fourth quarter tracked, said Dr. Almallouhi, a neurologist at the Medical University of South Carolina in Charleston. The rate of crossover from what began as a transradial procedure but switched to transfemoral was just under 6% overall, with a nearly 14% crossover rate during the first quarter that then dropped to around 5% for the rest of the transition year. Crossovers for interventional procedures throughout the study year occurred at a 12% rate, while crossovers for diagnostic procedures occurred at a 5% clip throughout the entire year.
None of the transradial patients had a major access-site complication, and minor complications occurred in less than 2% of the patients, including 11 with a forearm hematoma, 6 with forearm pain, and 5 with oozing at their access site. The absence of any major access-site complications among the transradial-access patients in this series contrasts with a recent report of a 1.7% rate of major complications secondary to femoral-artery access for mechanical thrombectomy in a combined analysis of data from seven published studies that included 660 thrombectomy procedures (Am J Neuroradiol. 2019 Feb. doi: 10.3174/ajnr.A6423). The other three centers that participated in the study Dr. Almallouhi presented were the University of Miami, Thomas Jefferson University in Philadelphia, and the University of Pittsburgh.
Of the 1,272 total procedures studied, 83% were diagnostic procedures, which had an overall 95% success rate, and 17% were interventional procedures, which had a success rate of 89%. The interventional transradial procedures included 62 primary coilings of aneurysms, 44 stent-assisted aneurysm coilings, 40 patients who underwent a flow diversion, 21 balloon-assisted aneurysm coilings, and 24 patients who underwent stroke thrombectomy.
The size of the devices commonly used for thrombectomy are often too large to allow for radial-artery access, noted Dr. Nogueira. For urgent interventions like thrombectomy “we use balloon-guided catheters that are large-bore and don’t fit well in the radial,” he said, although thrombectomy via the radial artery without a balloon-guided catheter is possible for clots located in the basilar artery. Last year, researchers in Germany reported using a balloon-guided catheter to perform mechanical thrombectomy via the radial artery (Interv Neuroradiol. 2019 Oct 1;25[5]:508-10). But it’s a different story for elective, diagnostic procedures. “I have moved most of these to transradial,” Dr. Nogueira said. He and his coauthors summarized the case for transradial access for cerebral angiography in a recent review; in addition to enhanced safety they cited other advantages including improved patient satisfaction and reduced cost because of a shorter length of stay (Interv Cardiol Clin. 2020 Jan;9[1]:75-86).
Despite his enthusiasm and the enthusiasm of other neurointerventionalists for the transradial approach, other stroke neurologists have been more cautious and slower to shift away from the femoral approach. “Our experience has been that for most cases it’s a bit more challenging to access the cervical vessels from the radial artery than from the traditional femoral approach. For arches with complex anatomy, however, the transradial approach can be of benefit in some cases, depending on the angles that need to be traversed,” commented Jeremy Payne, MD, director of the Banner Center for Neurovascular Medicine and medical director of the Banner—University Medical Center Phoenix Comprehensive Stroke Program. Dr. Payne highlighted that, while he is not an interventionalist himself, he and his interventional staff have regularly discussed the transradial option.
“In the cardiology literature the radial approach has been very successful, with better overall safety than the traditional femoral approach. Largely this seems to do with the anatomy of the aortic arch. It’s simply a more direct approach to the coronaries via the right radial artery; getting the wire into the correct vessel is significantly more difficult the more acute the angle it has to traverse,” such as when the target is an intracerebral vessel, Dr. Payne said in an interview.
“Our experience in the past 6 months has been about 25% transradial for some of our procedures, mainly diagnostic angiograms. We don’t find any difference in safety, however, as our transfemoral procedures are already very safe. One of the benefits of a transradial approach has been that a closure device may not be needed, with fewer vascular complications at the access site, such as fistula formation. We use ultrasound for access, and have not seen a difference in those approaches at all so far. One might argue that using ultrasound to establish access would slow us down, but so far our fastest case start-to-recanalization time in an acute stroke this year was 6 minutes, so speed does not appear to be a limiting issue. Another concern overall for transradial access is the potential limitation in the tools we may be able to deploy, given the smaller size of the vessel. It is reassuring [in the report from Dr. Almallouhi] that a variety of cases were successfully completed via this approach. However, fewer than 2% of their cases [24 patients] were apparently emergent, acute strokes, lending no specific support to that context. I do not expect that to change based on this paper,” Dr. Payne concluded.
“It is not clear to me that transradial neurointervention will change much. We have excellent safety data for the femoral approach, a proven track record of efficacy, and for most patients it seems to afford a somewhat wider range of tools that can be deployed, with simpler anatomy for accessing the cervical vessels in most arches. It is reassuring that the results reported by Dr. Almallouhi did not suggest negative outcomes, and as such I suspect the transradial approach at least gives us an additional option in a minority of patients. We have seen in the past 5-10 years an explosion of tools for the endovascular treatment of stroke; transradial access represents another potential strategy that appears so far to be safe,” Dr. Payne said.
Drs. Nogueira, Almallouhi, and Payne had no relevant disclosures.
SOURCE: Almallouhi E et al. Stroke. 2020 Feb;51(suppl 1):A64.
LOS ANGELES –
“It’s growing dramatically in U.S. practice. It may be hype, but there is big excitement. We are still in an assessment mode, but the adoption rate has been high,” Raul G. Nogueira, MD, said in an interview during the International Stroke Conference sponsored by the American Heart Association. “The big advantage [of transradial catheterization entry] is elimination of groin complications, some of which can be pretty bad. Is it safe for the brain? It’s probably okay, but that needs more study,” said Dr. Nogueira, professor of neurology at Emory University and director of the Neurovascular Service at the Grady Marcus Stroke and Neuroscience Center in Atlanta.
His uncertainty stems from the more difficult route taken to advance a catheter from the wrist into brain vessels, a maneuver that requires significant manipulation of the catheter tip, unlike the path from the right radial artery into the heart’s arteries, a “straight shot,” he explained. To reach the brain’s vasculature, the tip must execute a spin “that may scrape small emboli from the arch or arteries, so we need to look at this a little more carefully.” Ideally in a prospective, randomized study, he said. “We need to see whether the burden of [magnetic resonance] lesions is any higher when you go through the radial [artery].”
Some of the first-reported, large-scale U.S. experiences using a radial-artery approach for various neurovascular procedures, including a few thrombectomy cases, came in a series of 1,272 patients treated at any of four U.S. centers during July 2018 to June 2019, a period when the neurovascular staffs at all four centers transitioned from primarily using femoral-artery access to using radial access as their default mode. During the 12-month transition period, overall use of radial access at all four centers rose from roughly a quarter of all neurovascular interventions during July to September 2018 to closer to 80% by April to June 2019, Eyad Almallouhi, MD, reported at the conference.
During the entire 12 months, the operators ran up a 94% rate of successfully completed procedures using radial access, a rate that rose from about 88% during the first quarter to roughly 95% success during the fourth quarter tracked, said Dr. Almallouhi, a neurologist at the Medical University of South Carolina in Charleston. The rate of crossover from what began as a transradial procedure but switched to transfemoral was just under 6% overall, with a nearly 14% crossover rate during the first quarter that then dropped to around 5% for the rest of the transition year. Crossovers for interventional procedures throughout the study year occurred at a 12% rate, while crossovers for diagnostic procedures occurred at a 5% clip throughout the entire year.
None of the transradial patients had a major access-site complication, and minor complications occurred in less than 2% of the patients, including 11 with a forearm hematoma, 6 with forearm pain, and 5 with oozing at their access site. The absence of any major access-site complications among the transradial-access patients in this series contrasts with a recent report of a 1.7% rate of major complications secondary to femoral-artery access for mechanical thrombectomy in a combined analysis of data from seven published studies that included 660 thrombectomy procedures (Am J Neuroradiol. 2019 Feb. doi: 10.3174/ajnr.A6423). The other three centers that participated in the study Dr. Almallouhi presented were the University of Miami, Thomas Jefferson University in Philadelphia, and the University of Pittsburgh.
Of the 1,272 total procedures studied, 83% were diagnostic procedures, which had an overall 95% success rate, and 17% were interventional procedures, which had a success rate of 89%. The interventional transradial procedures included 62 primary coilings of aneurysms, 44 stent-assisted aneurysm coilings, 40 patients who underwent a flow diversion, 21 balloon-assisted aneurysm coilings, and 24 patients who underwent stroke thrombectomy.
The size of the devices commonly used for thrombectomy are often too large to allow for radial-artery access, noted Dr. Nogueira. For urgent interventions like thrombectomy “we use balloon-guided catheters that are large-bore and don’t fit well in the radial,” he said, although thrombectomy via the radial artery without a balloon-guided catheter is possible for clots located in the basilar artery. Last year, researchers in Germany reported using a balloon-guided catheter to perform mechanical thrombectomy via the radial artery (Interv Neuroradiol. 2019 Oct 1;25[5]:508-10). But it’s a different story for elective, diagnostic procedures. “I have moved most of these to transradial,” Dr. Nogueira said. He and his coauthors summarized the case for transradial access for cerebral angiography in a recent review; in addition to enhanced safety they cited other advantages including improved patient satisfaction and reduced cost because of a shorter length of stay (Interv Cardiol Clin. 2020 Jan;9[1]:75-86).
Despite his enthusiasm and the enthusiasm of other neurointerventionalists for the transradial approach, other stroke neurologists have been more cautious and slower to shift away from the femoral approach. “Our experience has been that for most cases it’s a bit more challenging to access the cervical vessels from the radial artery than from the traditional femoral approach. For arches with complex anatomy, however, the transradial approach can be of benefit in some cases, depending on the angles that need to be traversed,” commented Jeremy Payne, MD, director of the Banner Center for Neurovascular Medicine and medical director of the Banner—University Medical Center Phoenix Comprehensive Stroke Program. Dr. Payne highlighted that, while he is not an interventionalist himself, he and his interventional staff have regularly discussed the transradial option.
“In the cardiology literature the radial approach has been very successful, with better overall safety than the traditional femoral approach. Largely this seems to do with the anatomy of the aortic arch. It’s simply a more direct approach to the coronaries via the right radial artery; getting the wire into the correct vessel is significantly more difficult the more acute the angle it has to traverse,” such as when the target is an intracerebral vessel, Dr. Payne said in an interview.
“Our experience in the past 6 months has been about 25% transradial for some of our procedures, mainly diagnostic angiograms. We don’t find any difference in safety, however, as our transfemoral procedures are already very safe. One of the benefits of a transradial approach has been that a closure device may not be needed, with fewer vascular complications at the access site, such as fistula formation. We use ultrasound for access, and have not seen a difference in those approaches at all so far. One might argue that using ultrasound to establish access would slow us down, but so far our fastest case start-to-recanalization time in an acute stroke this year was 6 minutes, so speed does not appear to be a limiting issue. Another concern overall for transradial access is the potential limitation in the tools we may be able to deploy, given the smaller size of the vessel. It is reassuring [in the report from Dr. Almallouhi] that a variety of cases were successfully completed via this approach. However, fewer than 2% of their cases [24 patients] were apparently emergent, acute strokes, lending no specific support to that context. I do not expect that to change based on this paper,” Dr. Payne concluded.
“It is not clear to me that transradial neurointervention will change much. We have excellent safety data for the femoral approach, a proven track record of efficacy, and for most patients it seems to afford a somewhat wider range of tools that can be deployed, with simpler anatomy for accessing the cervical vessels in most arches. It is reassuring that the results reported by Dr. Almallouhi did not suggest negative outcomes, and as such I suspect the transradial approach at least gives us an additional option in a minority of patients. We have seen in the past 5-10 years an explosion of tools for the endovascular treatment of stroke; transradial access represents another potential strategy that appears so far to be safe,” Dr. Payne said.
Drs. Nogueira, Almallouhi, and Payne had no relevant disclosures.
SOURCE: Almallouhi E et al. Stroke. 2020 Feb;51(suppl 1):A64.
REPORTING FROM ISC 2020
Mortality sevenfold higher post TAVR with severe kidney injury
NATIONAL HARBOR, MD. – Acute kidney injury (AKI), a potentially modifiable risk factor in some cases, predicts increased mortality within the first year after transcatheter aortic valve transplantation (TAVR), according to an analysis of a U.S. registry presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
“After adjustment, there are higher rates of all-cause mortality regardless of the severity of AKI,” reported Howard M. Julien, MD, of the University of Pennsylvania, Philadelphia.
Relative to the absence of AKI (stage 0), the hazard ratio for death at 1 year was more than threefold greater (HR, 3.26), even for those with stage 1 AKI. When unadjusted for covariates, it remained more than twice as high (HR, 2.67; P less than .001), Dr. Julien reported.
For stage 3 AKI, the unadjusted risk was more than nine times higher and remained roughly seven times greater after adjustment (HR, 7.04; P less than .001). Stage 2 AKI was linked with an adjusted risk of about the same magnitude.
Drawn from the National Cardiovascular TAVR Registry, which is maintained jointly by the Society of Thoracic Surgeons and the American College of Cardiology, data were analyzed on more than 100,000 TAVRs performed during 2012-2018. A subset of TAVRs performed between January 2016 and June 2018 served as a source of trends in what Dr. Julien described as the “modern era” of this procedure.
The incidence of AKI overall was about 10%, but rates were higher at the earliest time point in the analysis and fell modestly over the study period for all three stages. In a logistic regression analysis, the factors associated with the greatest odds ratio of developing AKI in patients following TAVR were conversion to open heart surgery (OR, 10.84, P less than .001), nonfemoral access (OR, 2.33; P less than .001), anemia (OR, 1.90; P less than .001), general versus moderate sedation (OR, 1.62; P less than .001), diabetes (OR, 1.61; P less than .001), and cardiogenic shock within 24 hours (OR, 1.60; P less than .023).
Other factors with a significant but lower relative risk association with AKI included a high contrast volume (OR, 1.004; P less than .001), use of a self-expanding valve (HR, 1.22; P = .009), severe lung disease (OR, 1.21; P = .043) and prior peripheral artery disease (HR, 1.20; P = .043).
“The message from these data is that there appears to be a cluster of patients who are unstable at the time of their procedure and are more likely to develop the most severe forms of AKI,” Dr. Julien reported.
The higher rate of AKI in patients who have diabetes is “not surprising,” but several of the factors associated with AKI are potentially modifiable. This includes choices in regard to sedation and arterial access. The value of modifying the amount of contrast is less clear, because the volume of contrast was no longer significant after an adjustment with multivariate analysis.
In fact, all of these factors require validation. Dr. Julien warned that neither the cause of AKI nor its temporal relationship to TAVR could be consistently determined from the registry data. In addition, retrospective analyses always include the potential for unrecognized residual confounders.
Still, these data are useful for drawing attention to the fact that AKI is a common complication of TAVR and one that is associated with adverse outcomes, including reduced survival at 1 year.
“The factors taken from these data might be useful to help identify patients who are at risk of the most severe forms of AKI and, hopefully, lead to prevention strategies that take these characteristics into consideration,” Dr. Julien said.
Dr. Julien reported no potential financial conflicts of interest.
NATIONAL HARBOR, MD. – Acute kidney injury (AKI), a potentially modifiable risk factor in some cases, predicts increased mortality within the first year after transcatheter aortic valve transplantation (TAVR), according to an analysis of a U.S. registry presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
“After adjustment, there are higher rates of all-cause mortality regardless of the severity of AKI,” reported Howard M. Julien, MD, of the University of Pennsylvania, Philadelphia.
Relative to the absence of AKI (stage 0), the hazard ratio for death at 1 year was more than threefold greater (HR, 3.26), even for those with stage 1 AKI. When unadjusted for covariates, it remained more than twice as high (HR, 2.67; P less than .001), Dr. Julien reported.
For stage 3 AKI, the unadjusted risk was more than nine times higher and remained roughly seven times greater after adjustment (HR, 7.04; P less than .001). Stage 2 AKI was linked with an adjusted risk of about the same magnitude.
Drawn from the National Cardiovascular TAVR Registry, which is maintained jointly by the Society of Thoracic Surgeons and the American College of Cardiology, data were analyzed on more than 100,000 TAVRs performed during 2012-2018. A subset of TAVRs performed between January 2016 and June 2018 served as a source of trends in what Dr. Julien described as the “modern era” of this procedure.
The incidence of AKI overall was about 10%, but rates were higher at the earliest time point in the analysis and fell modestly over the study period for all three stages. In a logistic regression analysis, the factors associated with the greatest odds ratio of developing AKI in patients following TAVR were conversion to open heart surgery (OR, 10.84, P less than .001), nonfemoral access (OR, 2.33; P less than .001), anemia (OR, 1.90; P less than .001), general versus moderate sedation (OR, 1.62; P less than .001), diabetes (OR, 1.61; P less than .001), and cardiogenic shock within 24 hours (OR, 1.60; P less than .023).
Other factors with a significant but lower relative risk association with AKI included a high contrast volume (OR, 1.004; P less than .001), use of a self-expanding valve (HR, 1.22; P = .009), severe lung disease (OR, 1.21; P = .043) and prior peripheral artery disease (HR, 1.20; P = .043).
“The message from these data is that there appears to be a cluster of patients who are unstable at the time of their procedure and are more likely to develop the most severe forms of AKI,” Dr. Julien reported.
The higher rate of AKI in patients who have diabetes is “not surprising,” but several of the factors associated with AKI are potentially modifiable. This includes choices in regard to sedation and arterial access. The value of modifying the amount of contrast is less clear, because the volume of contrast was no longer significant after an adjustment with multivariate analysis.
In fact, all of these factors require validation. Dr. Julien warned that neither the cause of AKI nor its temporal relationship to TAVR could be consistently determined from the registry data. In addition, retrospective analyses always include the potential for unrecognized residual confounders.
Still, these data are useful for drawing attention to the fact that AKI is a common complication of TAVR and one that is associated with adverse outcomes, including reduced survival at 1 year.
“The factors taken from these data might be useful to help identify patients who are at risk of the most severe forms of AKI and, hopefully, lead to prevention strategies that take these characteristics into consideration,” Dr. Julien said.
Dr. Julien reported no potential financial conflicts of interest.
NATIONAL HARBOR, MD. – Acute kidney injury (AKI), a potentially modifiable risk factor in some cases, predicts increased mortality within the first year after transcatheter aortic valve transplantation (TAVR), according to an analysis of a U.S. registry presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
“After adjustment, there are higher rates of all-cause mortality regardless of the severity of AKI,” reported Howard M. Julien, MD, of the University of Pennsylvania, Philadelphia.
Relative to the absence of AKI (stage 0), the hazard ratio for death at 1 year was more than threefold greater (HR, 3.26), even for those with stage 1 AKI. When unadjusted for covariates, it remained more than twice as high (HR, 2.67; P less than .001), Dr. Julien reported.
For stage 3 AKI, the unadjusted risk was more than nine times higher and remained roughly seven times greater after adjustment (HR, 7.04; P less than .001). Stage 2 AKI was linked with an adjusted risk of about the same magnitude.
Drawn from the National Cardiovascular TAVR Registry, which is maintained jointly by the Society of Thoracic Surgeons and the American College of Cardiology, data were analyzed on more than 100,000 TAVRs performed during 2012-2018. A subset of TAVRs performed between January 2016 and June 2018 served as a source of trends in what Dr. Julien described as the “modern era” of this procedure.
The incidence of AKI overall was about 10%, but rates were higher at the earliest time point in the analysis and fell modestly over the study period for all three stages. In a logistic regression analysis, the factors associated with the greatest odds ratio of developing AKI in patients following TAVR were conversion to open heart surgery (OR, 10.84, P less than .001), nonfemoral access (OR, 2.33; P less than .001), anemia (OR, 1.90; P less than .001), general versus moderate sedation (OR, 1.62; P less than .001), diabetes (OR, 1.61; P less than .001), and cardiogenic shock within 24 hours (OR, 1.60; P less than .023).
Other factors with a significant but lower relative risk association with AKI included a high contrast volume (OR, 1.004; P less than .001), use of a self-expanding valve (HR, 1.22; P = .009), severe lung disease (OR, 1.21; P = .043) and prior peripheral artery disease (HR, 1.20; P = .043).
“The message from these data is that there appears to be a cluster of patients who are unstable at the time of their procedure and are more likely to develop the most severe forms of AKI,” Dr. Julien reported.
The higher rate of AKI in patients who have diabetes is “not surprising,” but several of the factors associated with AKI are potentially modifiable. This includes choices in regard to sedation and arterial access. The value of modifying the amount of contrast is less clear, because the volume of contrast was no longer significant after an adjustment with multivariate analysis.
In fact, all of these factors require validation. Dr. Julien warned that neither the cause of AKI nor its temporal relationship to TAVR could be consistently determined from the registry data. In addition, retrospective analyses always include the potential for unrecognized residual confounders.
Still, these data are useful for drawing attention to the fact that AKI is a common complication of TAVR and one that is associated with adverse outcomes, including reduced survival at 1 year.
“The factors taken from these data might be useful to help identify patients who are at risk of the most severe forms of AKI and, hopefully, lead to prevention strategies that take these characteristics into consideration,” Dr. Julien said.
Dr. Julien reported no potential financial conflicts of interest.
REPORTING FROM CRT 2020
After PCI, stopping antiplatelet therapy for surgery appears safe
NATIONAL HARBOR, MD. – Following a percutaneous intervention with a second-generation drug-eluting stent, a judicious interruption of antiplatelet therapy for noncardiac surgery does not increase risk of net adverse clinical events, according to a large dataset presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
Drawn from a multicenter registry in South Korea, it is likely that those in whom antiplatelet therapy was stopped during the perioperative period were at a lower relative risk, but the data remain reassuring, according to Jung-Sun Kim, MD, PhD, professor of medicine at Yonsei University, Seoul, South Korea.
In the registry of patients with a second-generation drug-eluting stent (DES) undergoing noncardiac surgery, “antiplatelet therapy was discontinued in almost half of the patients,” Dr. Kim reported. When these patients were compared with those who did not discontinue antiplatelet therapy, the data, called an “exploratory analysis,” suggested “no increased risk” of a composite of major adverse cardiac events (MACE) or major bleeding.
The retrospective analysis involved 3,582 percutaneous intervention (PCI) patients who had received a second-generation DES and subsequently underwent noncardiac surgery. In 1,750 of these patients, antiplatelet therapy was temporarily discontinued. The remaining 1,832 remained on some form of antiplatelet treatment, whether aspirin, a P2Y12 inhibitor, or dual-antiplatelet therapy.
There were no significant differences in crude rates between groups in rates at 30 days of a composite endpoint of MACE, major bleeding as defined by the International Society on Thrombosis and Haemostasis, or net adverse clinical events (NACE), a composite of adverse events that included MACE and major bleeding.
Relative risks for antiplatelet discontinuation remained generally low even after multiple stratifications performed to explore different variables, including the types of antiplatelet therapy being taken at the time of discontinuation, the types of noncardiac surgery performed, and the duration of discontinuation.
Of these variables, the interval of discontinuation appeared to be most relevant. Antiplatelet discontinuation of 3 days or less appeared to be associated with a higher risk of bleeding, although the difference did not reach significance. Discontinuations of 9 days or more were associated with increased risk of MACE, and this difference did reach statistical significance (hazard ratio, 3.38; 95% confidence interval, 1.36-8.38).
“Discontinuation of antiplatelet therapy for a period of 4-8 days appears to be optimal,” Dr. Kim said.
In general, risk of MACE, major bleeding, or NACE could not be linked to type of surgery, with the exception of intra-abdominal surgery. For this procedure, there appeared to be a lower risk of MACE in those who discontinued relative to those who remained on antiplatelet therapy, Dr. Kim reported.
Importantly, because of the fact that the decision to stop antiplatelet treatment was made by treating physicians, the characteristics of those who discontinued or remained on antiplatelet therapy differed meaningfully. Specifically, those in the discontinuation group were younger and were less likely to have additional risks for thrombotic events such as diabetes or chronic kidney disease. In those who discontinued antiplatelets, the average time since PCI was 23 months versus 16 months in the continuation group.
In addition, “more of the patients underwent higher-risk surgeries in the discontinuation group,” Dr. Kim added.
Relative rates of MACE and NACE remained similar even after risk adjustment, but Dr. Kim advised that the data should be “interpreted cautiously” because of the retrospective nature of the analysis.
A panel of experts invited to comment on the presentation agreed. These data were considered reassuring for clinicians considering an interruption of antiplatelet therapy following PCI with a second-generation DES, but there was uncertainty about their value for defining which patients are the best candidates.
The decision to discontinue antiplatelet drugs for noncardiac surgery is an important and common dilemma, but these data might be best characterized as “a testament to Korean cardiologists making good decisions,” said David J. Moliterno, MD, chairman of the department of medicine at University of Kentucky Health Care, Lexington.
Dr. Kim reported no potential financial conflicts of interest.
NATIONAL HARBOR, MD. – Following a percutaneous intervention with a second-generation drug-eluting stent, a judicious interruption of antiplatelet therapy for noncardiac surgery does not increase risk of net adverse clinical events, according to a large dataset presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
Drawn from a multicenter registry in South Korea, it is likely that those in whom antiplatelet therapy was stopped during the perioperative period were at a lower relative risk, but the data remain reassuring, according to Jung-Sun Kim, MD, PhD, professor of medicine at Yonsei University, Seoul, South Korea.
In the registry of patients with a second-generation drug-eluting stent (DES) undergoing noncardiac surgery, “antiplatelet therapy was discontinued in almost half of the patients,” Dr. Kim reported. When these patients were compared with those who did not discontinue antiplatelet therapy, the data, called an “exploratory analysis,” suggested “no increased risk” of a composite of major adverse cardiac events (MACE) or major bleeding.
The retrospective analysis involved 3,582 percutaneous intervention (PCI) patients who had received a second-generation DES and subsequently underwent noncardiac surgery. In 1,750 of these patients, antiplatelet therapy was temporarily discontinued. The remaining 1,832 remained on some form of antiplatelet treatment, whether aspirin, a P2Y12 inhibitor, or dual-antiplatelet therapy.
There were no significant differences in crude rates between groups in rates at 30 days of a composite endpoint of MACE, major bleeding as defined by the International Society on Thrombosis and Haemostasis, or net adverse clinical events (NACE), a composite of adverse events that included MACE and major bleeding.
Relative risks for antiplatelet discontinuation remained generally low even after multiple stratifications performed to explore different variables, including the types of antiplatelet therapy being taken at the time of discontinuation, the types of noncardiac surgery performed, and the duration of discontinuation.
Of these variables, the interval of discontinuation appeared to be most relevant. Antiplatelet discontinuation of 3 days or less appeared to be associated with a higher risk of bleeding, although the difference did not reach significance. Discontinuations of 9 days or more were associated with increased risk of MACE, and this difference did reach statistical significance (hazard ratio, 3.38; 95% confidence interval, 1.36-8.38).
“Discontinuation of antiplatelet therapy for a period of 4-8 days appears to be optimal,” Dr. Kim said.
In general, risk of MACE, major bleeding, or NACE could not be linked to type of surgery, with the exception of intra-abdominal surgery. For this procedure, there appeared to be a lower risk of MACE in those who discontinued relative to those who remained on antiplatelet therapy, Dr. Kim reported.
Importantly, because of the fact that the decision to stop antiplatelet treatment was made by treating physicians, the characteristics of those who discontinued or remained on antiplatelet therapy differed meaningfully. Specifically, those in the discontinuation group were younger and were less likely to have additional risks for thrombotic events such as diabetes or chronic kidney disease. In those who discontinued antiplatelets, the average time since PCI was 23 months versus 16 months in the continuation group.
In addition, “more of the patients underwent higher-risk surgeries in the discontinuation group,” Dr. Kim added.
Relative rates of MACE and NACE remained similar even after risk adjustment, but Dr. Kim advised that the data should be “interpreted cautiously” because of the retrospective nature of the analysis.
A panel of experts invited to comment on the presentation agreed. These data were considered reassuring for clinicians considering an interruption of antiplatelet therapy following PCI with a second-generation DES, but there was uncertainty about their value for defining which patients are the best candidates.
The decision to discontinue antiplatelet drugs for noncardiac surgery is an important and common dilemma, but these data might be best characterized as “a testament to Korean cardiologists making good decisions,” said David J. Moliterno, MD, chairman of the department of medicine at University of Kentucky Health Care, Lexington.
Dr. Kim reported no potential financial conflicts of interest.
NATIONAL HARBOR, MD. – Following a percutaneous intervention with a second-generation drug-eluting stent, a judicious interruption of antiplatelet therapy for noncardiac surgery does not increase risk of net adverse clinical events, according to a large dataset presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
Drawn from a multicenter registry in South Korea, it is likely that those in whom antiplatelet therapy was stopped during the perioperative period were at a lower relative risk, but the data remain reassuring, according to Jung-Sun Kim, MD, PhD, professor of medicine at Yonsei University, Seoul, South Korea.
In the registry of patients with a second-generation drug-eluting stent (DES) undergoing noncardiac surgery, “antiplatelet therapy was discontinued in almost half of the patients,” Dr. Kim reported. When these patients were compared with those who did not discontinue antiplatelet therapy, the data, called an “exploratory analysis,” suggested “no increased risk” of a composite of major adverse cardiac events (MACE) or major bleeding.
The retrospective analysis involved 3,582 percutaneous intervention (PCI) patients who had received a second-generation DES and subsequently underwent noncardiac surgery. In 1,750 of these patients, antiplatelet therapy was temporarily discontinued. The remaining 1,832 remained on some form of antiplatelet treatment, whether aspirin, a P2Y12 inhibitor, or dual-antiplatelet therapy.
There were no significant differences in crude rates between groups in rates at 30 days of a composite endpoint of MACE, major bleeding as defined by the International Society on Thrombosis and Haemostasis, or net adverse clinical events (NACE), a composite of adverse events that included MACE and major bleeding.
Relative risks for antiplatelet discontinuation remained generally low even after multiple stratifications performed to explore different variables, including the types of antiplatelet therapy being taken at the time of discontinuation, the types of noncardiac surgery performed, and the duration of discontinuation.
Of these variables, the interval of discontinuation appeared to be most relevant. Antiplatelet discontinuation of 3 days or less appeared to be associated with a higher risk of bleeding, although the difference did not reach significance. Discontinuations of 9 days or more were associated with increased risk of MACE, and this difference did reach statistical significance (hazard ratio, 3.38; 95% confidence interval, 1.36-8.38).
“Discontinuation of antiplatelet therapy for a period of 4-8 days appears to be optimal,” Dr. Kim said.
In general, risk of MACE, major bleeding, or NACE could not be linked to type of surgery, with the exception of intra-abdominal surgery. For this procedure, there appeared to be a lower risk of MACE in those who discontinued relative to those who remained on antiplatelet therapy, Dr. Kim reported.
Importantly, because of the fact that the decision to stop antiplatelet treatment was made by treating physicians, the characteristics of those who discontinued or remained on antiplatelet therapy differed meaningfully. Specifically, those in the discontinuation group were younger and were less likely to have additional risks for thrombotic events such as diabetes or chronic kidney disease. In those who discontinued antiplatelets, the average time since PCI was 23 months versus 16 months in the continuation group.
In addition, “more of the patients underwent higher-risk surgeries in the discontinuation group,” Dr. Kim added.
Relative rates of MACE and NACE remained similar even after risk adjustment, but Dr. Kim advised that the data should be “interpreted cautiously” because of the retrospective nature of the analysis.
A panel of experts invited to comment on the presentation agreed. These data were considered reassuring for clinicians considering an interruption of antiplatelet therapy following PCI with a second-generation DES, but there was uncertainty about their value for defining which patients are the best candidates.
The decision to discontinue antiplatelet drugs for noncardiac surgery is an important and common dilemma, but these data might be best characterized as “a testament to Korean cardiologists making good decisions,” said David J. Moliterno, MD, chairman of the department of medicine at University of Kentucky Health Care, Lexington.
Dr. Kim reported no potential financial conflicts of interest.
REPORTING FROM CRT 2020
FDA promises rigorous review of new renal denervation trials
NATIONAL HARBOR, MD. – Just a month before results from the first of several new pivotal trials with a renal denervation device are to be presented, a Food and Drug Administration medical officer speaking at CRT 2020 sponsored by MedStar Heart & Vascular Institute explained which data will most attract the scrutiny of regulators.
“The FDA is very interested in these devices. We recognize that there is a clinical need, but a reasonable benefit-to-risk relationship has to be established,” said Meir Shinnar, MD, PhD, who works in the division of cardiac devices in the FDA’s Office of Device Evaluation.
The field of renal denervation is expected to heat up again if the results of the SPYRAL HTN OFF MED pivotal trial, planned as a late-breaking presentation at the annual meeting of the American College of Cardiology in March 2020, are positive. However, long-term safety will remain a concern, and positive results will not diminish the rigor with which the relative safety and efficacy of other devices in late stages of clinical testing are evaluated.
“The safety profile is unique to the device design and the procedural technique,” Dr. Shinnar said. For example, vascular injury from the energy employed for denervation, whether radiofrequency or another modality, is an important theoretical risk. A minor initial injury might have no immediate consequences but pose major risks if it leads to altered kidney function over time.
“Most of the follow-up data we have now [with renal denervation devices] is about 1-3 years, but I think long-term safety requires a minimum of 5 years of safety data,” Dr. Shinnar said. “We do not expect all that data to be available at the time of approval, but postmarketing studies will be needed.”
Almost 6 years after the SYMPLICITY HTN-3 trial failed to show a significant reduction in blood pressure among patients with resistant hypertension treated with renal denervation rather than a sham procedure (N Engl J Med 2014;370:1393-401), this treatment is again considered promising. The surprising SYMPLICITY HTN-3 result led to several revisions in technique based on the suspicion that denervation was inadequate.
However, the basic principles remain unchanged. For renal denervation, SPYRAL HTN OFF MED, like the SYMPLICITY HTN 3 study, is employing the Symplicity (Medtronic) device, which has been approved in 50 countries but not in the United States, Canada, or Japan.
SPYRAL HTN OFF MED is designed to provide a very straightforward test of efficacy. Unlike SYMPLICITY HTN-3, which permitted patients to remain on their antihypertensive medications, patients in SPYRAL HTN OFF MED will be tested in the absence of drug therapy (a trial with adjunctive antihypertensive drugs, SPYRAL HTN ON MED, is ongoing). This is a design feature that is relevant to regulatory evaluation.
Although not speaking about the SPYRAL HTN OFF MED trial specifically, Dr. Shinnar noted that “the bar is considered to be higher for a first-line indication than when a device is used as an adjunctive to drug therapy.”
Whether used with or without medications, devices are not likely to receive approval without showing a durable benefit. Dr. Shinnar, citing the surgical studies in which blood pressure control was lost 1-2 years after denervation, said 12 months is now considered a “preferred” length of follow-up to confirm efficacy.
If renal denervation moves forward as a result of the new wave of phase 3 trials, there will still be many unanswered questions, according to Dr. Shinnar, who noted that the FDA convened an advisory committee in December 2018 to gather expert opinion about meaningful safety as well as efficacy endpoints for this modality. One will be determining which populations, defined by age, gender, or phenotype, most benefit.
It also remains unclear whether the first approval will create a standard to which subsequent devices should be compared, according to Dr. Shinnar. Although the FDA recognizes blood pressure reductions as an acceptable endpoint, he believes that documentation of the impact on clinical events will be sought in postmarketing analyses.
“All of the denervation modalities involve class 3 devices that require significant data,” Dr. Shinnar cautioned.
Even if the SPYRAL HTN OFF MED trial is positive on the basis of efficacy, it does not guarantee regulatory approval. Dr. Shinnar described a multifaceted approach to defining an acceptable risk-to-benefit ratio from approved devices, and warned that several points regarding the evaluation of renal denervation devices by the FDA are still being debated internally.
Dr. Shinnar reported no potential financial conflicts of interest.
NATIONAL HARBOR, MD. – Just a month before results from the first of several new pivotal trials with a renal denervation device are to be presented, a Food and Drug Administration medical officer speaking at CRT 2020 sponsored by MedStar Heart & Vascular Institute explained which data will most attract the scrutiny of regulators.
“The FDA is very interested in these devices. We recognize that there is a clinical need, but a reasonable benefit-to-risk relationship has to be established,” said Meir Shinnar, MD, PhD, who works in the division of cardiac devices in the FDA’s Office of Device Evaluation.
The field of renal denervation is expected to heat up again if the results of the SPYRAL HTN OFF MED pivotal trial, planned as a late-breaking presentation at the annual meeting of the American College of Cardiology in March 2020, are positive. However, long-term safety will remain a concern, and positive results will not diminish the rigor with which the relative safety and efficacy of other devices in late stages of clinical testing are evaluated.
“The safety profile is unique to the device design and the procedural technique,” Dr. Shinnar said. For example, vascular injury from the energy employed for denervation, whether radiofrequency or another modality, is an important theoretical risk. A minor initial injury might have no immediate consequences but pose major risks if it leads to altered kidney function over time.
“Most of the follow-up data we have now [with renal denervation devices] is about 1-3 years, but I think long-term safety requires a minimum of 5 years of safety data,” Dr. Shinnar said. “We do not expect all that data to be available at the time of approval, but postmarketing studies will be needed.”
Almost 6 years after the SYMPLICITY HTN-3 trial failed to show a significant reduction in blood pressure among patients with resistant hypertension treated with renal denervation rather than a sham procedure (N Engl J Med 2014;370:1393-401), this treatment is again considered promising. The surprising SYMPLICITY HTN-3 result led to several revisions in technique based on the suspicion that denervation was inadequate.
However, the basic principles remain unchanged. For renal denervation, SPYRAL HTN OFF MED, like the SYMPLICITY HTN 3 study, is employing the Symplicity (Medtronic) device, which has been approved in 50 countries but not in the United States, Canada, or Japan.
SPYRAL HTN OFF MED is designed to provide a very straightforward test of efficacy. Unlike SYMPLICITY HTN-3, which permitted patients to remain on their antihypertensive medications, patients in SPYRAL HTN OFF MED will be tested in the absence of drug therapy (a trial with adjunctive antihypertensive drugs, SPYRAL HTN ON MED, is ongoing). This is a design feature that is relevant to regulatory evaluation.
Although not speaking about the SPYRAL HTN OFF MED trial specifically, Dr. Shinnar noted that “the bar is considered to be higher for a first-line indication than when a device is used as an adjunctive to drug therapy.”
Whether used with or without medications, devices are not likely to receive approval without showing a durable benefit. Dr. Shinnar, citing the surgical studies in which blood pressure control was lost 1-2 years after denervation, said 12 months is now considered a “preferred” length of follow-up to confirm efficacy.
If renal denervation moves forward as a result of the new wave of phase 3 trials, there will still be many unanswered questions, according to Dr. Shinnar, who noted that the FDA convened an advisory committee in December 2018 to gather expert opinion about meaningful safety as well as efficacy endpoints for this modality. One will be determining which populations, defined by age, gender, or phenotype, most benefit.
It also remains unclear whether the first approval will create a standard to which subsequent devices should be compared, according to Dr. Shinnar. Although the FDA recognizes blood pressure reductions as an acceptable endpoint, he believes that documentation of the impact on clinical events will be sought in postmarketing analyses.
“All of the denervation modalities involve class 3 devices that require significant data,” Dr. Shinnar cautioned.
Even if the SPYRAL HTN OFF MED trial is positive on the basis of efficacy, it does not guarantee regulatory approval. Dr. Shinnar described a multifaceted approach to defining an acceptable risk-to-benefit ratio from approved devices, and warned that several points regarding the evaluation of renal denervation devices by the FDA are still being debated internally.
Dr. Shinnar reported no potential financial conflicts of interest.
NATIONAL HARBOR, MD. – Just a month before results from the first of several new pivotal trials with a renal denervation device are to be presented, a Food and Drug Administration medical officer speaking at CRT 2020 sponsored by MedStar Heart & Vascular Institute explained which data will most attract the scrutiny of regulators.
“The FDA is very interested in these devices. We recognize that there is a clinical need, but a reasonable benefit-to-risk relationship has to be established,” said Meir Shinnar, MD, PhD, who works in the division of cardiac devices in the FDA’s Office of Device Evaluation.
The field of renal denervation is expected to heat up again if the results of the SPYRAL HTN OFF MED pivotal trial, planned as a late-breaking presentation at the annual meeting of the American College of Cardiology in March 2020, are positive. However, long-term safety will remain a concern, and positive results will not diminish the rigor with which the relative safety and efficacy of other devices in late stages of clinical testing are evaluated.
“The safety profile is unique to the device design and the procedural technique,” Dr. Shinnar said. For example, vascular injury from the energy employed for denervation, whether radiofrequency or another modality, is an important theoretical risk. A minor initial injury might have no immediate consequences but pose major risks if it leads to altered kidney function over time.
“Most of the follow-up data we have now [with renal denervation devices] is about 1-3 years, but I think long-term safety requires a minimum of 5 years of safety data,” Dr. Shinnar said. “We do not expect all that data to be available at the time of approval, but postmarketing studies will be needed.”
Almost 6 years after the SYMPLICITY HTN-3 trial failed to show a significant reduction in blood pressure among patients with resistant hypertension treated with renal denervation rather than a sham procedure (N Engl J Med 2014;370:1393-401), this treatment is again considered promising. The surprising SYMPLICITY HTN-3 result led to several revisions in technique based on the suspicion that denervation was inadequate.
However, the basic principles remain unchanged. For renal denervation, SPYRAL HTN OFF MED, like the SYMPLICITY HTN 3 study, is employing the Symplicity (Medtronic) device, which has been approved in 50 countries but not in the United States, Canada, or Japan.
SPYRAL HTN OFF MED is designed to provide a very straightforward test of efficacy. Unlike SYMPLICITY HTN-3, which permitted patients to remain on their antihypertensive medications, patients in SPYRAL HTN OFF MED will be tested in the absence of drug therapy (a trial with adjunctive antihypertensive drugs, SPYRAL HTN ON MED, is ongoing). This is a design feature that is relevant to regulatory evaluation.
Although not speaking about the SPYRAL HTN OFF MED trial specifically, Dr. Shinnar noted that “the bar is considered to be higher for a first-line indication than when a device is used as an adjunctive to drug therapy.”
Whether used with or without medications, devices are not likely to receive approval without showing a durable benefit. Dr. Shinnar, citing the surgical studies in which blood pressure control was lost 1-2 years after denervation, said 12 months is now considered a “preferred” length of follow-up to confirm efficacy.
If renal denervation moves forward as a result of the new wave of phase 3 trials, there will still be many unanswered questions, according to Dr. Shinnar, who noted that the FDA convened an advisory committee in December 2018 to gather expert opinion about meaningful safety as well as efficacy endpoints for this modality. One will be determining which populations, defined by age, gender, or phenotype, most benefit.
It also remains unclear whether the first approval will create a standard to which subsequent devices should be compared, according to Dr. Shinnar. Although the FDA recognizes blood pressure reductions as an acceptable endpoint, he believes that documentation of the impact on clinical events will be sought in postmarketing analyses.
“All of the denervation modalities involve class 3 devices that require significant data,” Dr. Shinnar cautioned.
Even if the SPYRAL HTN OFF MED trial is positive on the basis of efficacy, it does not guarantee regulatory approval. Dr. Shinnar described a multifaceted approach to defining an acceptable risk-to-benefit ratio from approved devices, and warned that several points regarding the evaluation of renal denervation devices by the FDA are still being debated internally.
Dr. Shinnar reported no potential financial conflicts of interest.
EXPERT ANALYSIS FROM CRT 2020
BASILAR: Endovascular treatment improves outcomes in BAO stroke
LOS ANGELES – Endovascular therapy significantly improved functional outcomes and reduced mortality at 90 days, compared with standard thrombolysis alone, new evidence from a large, prospective registry study suggests.
Participants who received both interventions were almost five times more likely to be able to walk independently at 90 days compared with those who received thrombolysis alone.
Despite multiple trials supporting the potential benefits of endovascular therapy for anterior stroke, little prospective research addresses outcomes associated with an ischemic stroke caused by a posterior basilar artery occlusion (BAO).
“Basilar artery occlusion is the ‘orphan’ of the large vessel occlusions,” Raul Gomes Nogueira, MD, PhD, said here at a late-breaking abstract session at the International Stroke Conference sponsored by the American Heart Association.
“They account for about 5% of the large vessel occlusions – but have the most dismal prognosis.” Severe disability and mortality rates associated with BAO, for example, reach an estimated 68% to 78%, he said.
The results, from the EVT for Acute Basilar Artery Occlusion Study (BASILAR), were also simultaneously published in JAMA Neurology.
Prior studies in this patient population are generally single-center, retrospective studies and “the numbers tend to be small,” said Nogueira, who is affiliated with the Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine in Atlanta, Georgia.
Nogueira and colleagues studied 829 consecutive adults who presented with an acute, symptomatic BAO. They examined a nationwide prospective registry study of people with radiologically confirmed BAO in 47 comprehensive stroke centers across 15 provinces in China.
The median age was 65 years and 74% were men. A total 182 participants received thrombolysis therapy within 6 hours of estimated BAO onset. The 647 people in the dual intervention group also received endovascular therapy within 24 hours.
Standard medical treatment included intravenous rt-PA or urokinase, antiplatelet drugs and systematic anticoagulation alone or in combination. Endovascular therapy included mechanical thrombectomy with stent retrievers and/or thromboaspiration, balloon angioplasty, stenting, intra-arterial thrombolysis, or a combination of these interventions.
Interestingly, participants were not randomly assigned, in part because of the favorable outcomes associated with endovascular therapy. “The high number of patients who received [the dual intervention] may suggest the existence of a lack of equipoise among participating centers,” the researchers note.
Key Efficacy Endpoints
A significantly higher proportion of people in the dual treatment group achieved the primary outcome, functional improvement at 90 days, at 32%, compared with 9.3% in the thrombolysis-only group. This endpoint was defined as a modified Rankin Scale (mRS) score of 3 or less, which reflects an ability to walk independently. The difference was statistically significant (P < .001).
The absolute difference between groups was 22.7% (95% confidence interval, 17.1%-28.2%) with an adjusted odds ratio of 4.70 (95% CI, 2.53-8.75; P < .001) in favor of dual intervention.
The number needed to treat for one additional patient to be able to walk unassisted was 4.4.
Other outcomes, including differences in National Institutes of Health Stroke Scale scores from baseline to 5 to 7 days or discharge, as well as propensity score matching and subgroup analyses, likewise supported the superiority of using both interventions.
Safety Outcomes
Nogueira and colleagues also assessed safety. They found that symptomatic intracerebral hemorrhage (ICH) occurred in 45 patients, or 7.1% of the endovascular treatment group. In contrast, only one patient, or 0.5%, of the standard medical treatment alone cohort experienced an ICH. This difference was statistically significant (P < .001).
Mortality at 90 days was significantly lower in the endovascular therapy plus medical therapy group, 46.2%, compared with 71.4% in the standard medical treatment alone group (P < .001).
The absolute difference in mortality was 25.2% (95% CI, 17.6%-2.8%) favoring dual treatment, with an adjusted odds ratio of 2.93 (95% CI, 1.95-4.40; P < .001).
Rates of other serious adverse events during the 90-day follow-up period were similar in the two study groups, Nogueira said.
He acknowledged that the nonrandomized design was a limitation of the registry study, adding that “sometimes in life it’s important to acknowledge the best of what can be done. It’s very hard when you have access to thrombectomy to randomize people.”
However, other researchers have attempted or are enrolling people with BAO into trials that randomly assign them to endovascular therapy and standard medical treatment or medical treatment alone.
The BEST trial in China, for example, randomly assigned 131 patients to these groups but was stopped early in September 2017. “The BEST trial was terminated prematurely because of loss of equipoise that led to a high crossover rate and drop in valid recruitment,” the current researchers note.
“The other two trials…are facing the challenge of whether they will achieve their inclusion target,” they add, “because a growing number of stroke centers are unwilling to randomize patients to standard medical treatment alone after the many positive results of trials for endovascular treatment in patients with anterior-circulation stroke.”
The BAOCHE trial from China, for example, is ongoing with approximately 110 patients enrolled so far.
Investigators for the Basilar Artery International Cooperation Study (BASICS) in the Netherlands just completed enrollment of their 300th and final patient in December 2019.
“We are hopeful BASICS trial will shed additional light,” Nogueira said. The results are expected to be presented at the European Stroke Organization Conference in Vienna in May 2020.
More Guidance From MRI?
“With the advent of the stent retrievers and successful recanalization, we know there can be better outcomes for patients. And we know the morbidity and mortality of the basilar artery occlusions are so poor that we tend to want to be aggressive in these cases,” session comoderator Shlee S. Song, MD, director of the Comprehensive Stroke Center and associate professor of neurology at Cedars-Sinai Medical Center in Los Angeles, California, told Medscape Medical News when asked to comment on the study.
“I agree that we’ve lost equipoise in this cohort – that we really cannot do a randomized trial anymore. You know if you don’t do anything, 90% of the time there will be a poor outcome,” she added.
This is an important study for showing how BAO patients fare after endovascular treatment, Song said.
One unanswered question from the study is if any of the centers in China used magnetic resonance imaging to help determine the most appropriate candidates for endovascular treatment of these posterior circulation strokes, which is a common practice in the United States, she said.
The study was supported by the National Science Fund for Distinguished Young Scholars, Chongqing Major Disease Prevention and Control Technology Research Project, Army Medical University Clinical Medical Research Talent Training Program, and Major Clinical Innovation Technology Project of the Second Affiliated Hospital of the Army Military Medical University. Sing had no relevant disclosures. Nogueira’s financial disclosures include working as a consultant for Stryker Neurovascular; as a principal investigator on the Imperative trial and the PROST trial; as a steering committee member for Biogen for the CHARM trial; as an advisory board member for Cerenovus/Neuravi, Phenox, Anaconda, Genentech, Biogen, Prolong Pharmaceuticals and Brainomix; and as an advisory board member with stock options for Viz.ai, Corindus Vascular Robotics, Vesalio, Ceretrieve, Astrocyte Pharmaceuticals, and Cerebrotech.
This article first appeared on Medscape.com.
SOURCE: Nogueira RG et al. ISC 2020. Late-breaking abstract 17.
LOS ANGELES – Endovascular therapy significantly improved functional outcomes and reduced mortality at 90 days, compared with standard thrombolysis alone, new evidence from a large, prospective registry study suggests.
Participants who received both interventions were almost five times more likely to be able to walk independently at 90 days compared with those who received thrombolysis alone.
Despite multiple trials supporting the potential benefits of endovascular therapy for anterior stroke, little prospective research addresses outcomes associated with an ischemic stroke caused by a posterior basilar artery occlusion (BAO).
“Basilar artery occlusion is the ‘orphan’ of the large vessel occlusions,” Raul Gomes Nogueira, MD, PhD, said here at a late-breaking abstract session at the International Stroke Conference sponsored by the American Heart Association.
“They account for about 5% of the large vessel occlusions – but have the most dismal prognosis.” Severe disability and mortality rates associated with BAO, for example, reach an estimated 68% to 78%, he said.
The results, from the EVT for Acute Basilar Artery Occlusion Study (BASILAR), were also simultaneously published in JAMA Neurology.
Prior studies in this patient population are generally single-center, retrospective studies and “the numbers tend to be small,” said Nogueira, who is affiliated with the Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine in Atlanta, Georgia.
Nogueira and colleagues studied 829 consecutive adults who presented with an acute, symptomatic BAO. They examined a nationwide prospective registry study of people with radiologically confirmed BAO in 47 comprehensive stroke centers across 15 provinces in China.
The median age was 65 years and 74% were men. A total 182 participants received thrombolysis therapy within 6 hours of estimated BAO onset. The 647 people in the dual intervention group also received endovascular therapy within 24 hours.
Standard medical treatment included intravenous rt-PA or urokinase, antiplatelet drugs and systematic anticoagulation alone or in combination. Endovascular therapy included mechanical thrombectomy with stent retrievers and/or thromboaspiration, balloon angioplasty, stenting, intra-arterial thrombolysis, or a combination of these interventions.
Interestingly, participants were not randomly assigned, in part because of the favorable outcomes associated with endovascular therapy. “The high number of patients who received [the dual intervention] may suggest the existence of a lack of equipoise among participating centers,” the researchers note.
Key Efficacy Endpoints
A significantly higher proportion of people in the dual treatment group achieved the primary outcome, functional improvement at 90 days, at 32%, compared with 9.3% in the thrombolysis-only group. This endpoint was defined as a modified Rankin Scale (mRS) score of 3 or less, which reflects an ability to walk independently. The difference was statistically significant (P < .001).
The absolute difference between groups was 22.7% (95% confidence interval, 17.1%-28.2%) with an adjusted odds ratio of 4.70 (95% CI, 2.53-8.75; P < .001) in favor of dual intervention.
The number needed to treat for one additional patient to be able to walk unassisted was 4.4.
Other outcomes, including differences in National Institutes of Health Stroke Scale scores from baseline to 5 to 7 days or discharge, as well as propensity score matching and subgroup analyses, likewise supported the superiority of using both interventions.
Safety Outcomes
Nogueira and colleagues also assessed safety. They found that symptomatic intracerebral hemorrhage (ICH) occurred in 45 patients, or 7.1% of the endovascular treatment group. In contrast, only one patient, or 0.5%, of the standard medical treatment alone cohort experienced an ICH. This difference was statistically significant (P < .001).
Mortality at 90 days was significantly lower in the endovascular therapy plus medical therapy group, 46.2%, compared with 71.4% in the standard medical treatment alone group (P < .001).
The absolute difference in mortality was 25.2% (95% CI, 17.6%-2.8%) favoring dual treatment, with an adjusted odds ratio of 2.93 (95% CI, 1.95-4.40; P < .001).
Rates of other serious adverse events during the 90-day follow-up period were similar in the two study groups, Nogueira said.
He acknowledged that the nonrandomized design was a limitation of the registry study, adding that “sometimes in life it’s important to acknowledge the best of what can be done. It’s very hard when you have access to thrombectomy to randomize people.”
However, other researchers have attempted or are enrolling people with BAO into trials that randomly assign them to endovascular therapy and standard medical treatment or medical treatment alone.
The BEST trial in China, for example, randomly assigned 131 patients to these groups but was stopped early in September 2017. “The BEST trial was terminated prematurely because of loss of equipoise that led to a high crossover rate and drop in valid recruitment,” the current researchers note.
“The other two trials…are facing the challenge of whether they will achieve their inclusion target,” they add, “because a growing number of stroke centers are unwilling to randomize patients to standard medical treatment alone after the many positive results of trials for endovascular treatment in patients with anterior-circulation stroke.”
The BAOCHE trial from China, for example, is ongoing with approximately 110 patients enrolled so far.
Investigators for the Basilar Artery International Cooperation Study (BASICS) in the Netherlands just completed enrollment of their 300th and final patient in December 2019.
“We are hopeful BASICS trial will shed additional light,” Nogueira said. The results are expected to be presented at the European Stroke Organization Conference in Vienna in May 2020.
More Guidance From MRI?
“With the advent of the stent retrievers and successful recanalization, we know there can be better outcomes for patients. And we know the morbidity and mortality of the basilar artery occlusions are so poor that we tend to want to be aggressive in these cases,” session comoderator Shlee S. Song, MD, director of the Comprehensive Stroke Center and associate professor of neurology at Cedars-Sinai Medical Center in Los Angeles, California, told Medscape Medical News when asked to comment on the study.
“I agree that we’ve lost equipoise in this cohort – that we really cannot do a randomized trial anymore. You know if you don’t do anything, 90% of the time there will be a poor outcome,” she added.
This is an important study for showing how BAO patients fare after endovascular treatment, Song said.
One unanswered question from the study is if any of the centers in China used magnetic resonance imaging to help determine the most appropriate candidates for endovascular treatment of these posterior circulation strokes, which is a common practice in the United States, she said.
The study was supported by the National Science Fund for Distinguished Young Scholars, Chongqing Major Disease Prevention and Control Technology Research Project, Army Medical University Clinical Medical Research Talent Training Program, and Major Clinical Innovation Technology Project of the Second Affiliated Hospital of the Army Military Medical University. Sing had no relevant disclosures. Nogueira’s financial disclosures include working as a consultant for Stryker Neurovascular; as a principal investigator on the Imperative trial and the PROST trial; as a steering committee member for Biogen for the CHARM trial; as an advisory board member for Cerenovus/Neuravi, Phenox, Anaconda, Genentech, Biogen, Prolong Pharmaceuticals and Brainomix; and as an advisory board member with stock options for Viz.ai, Corindus Vascular Robotics, Vesalio, Ceretrieve, Astrocyte Pharmaceuticals, and Cerebrotech.
This article first appeared on Medscape.com.
SOURCE: Nogueira RG et al. ISC 2020. Late-breaking abstract 17.
LOS ANGELES – Endovascular therapy significantly improved functional outcomes and reduced mortality at 90 days, compared with standard thrombolysis alone, new evidence from a large, prospective registry study suggests.
Participants who received both interventions were almost five times more likely to be able to walk independently at 90 days compared with those who received thrombolysis alone.
Despite multiple trials supporting the potential benefits of endovascular therapy for anterior stroke, little prospective research addresses outcomes associated with an ischemic stroke caused by a posterior basilar artery occlusion (BAO).
“Basilar artery occlusion is the ‘orphan’ of the large vessel occlusions,” Raul Gomes Nogueira, MD, PhD, said here at a late-breaking abstract session at the International Stroke Conference sponsored by the American Heart Association.
“They account for about 5% of the large vessel occlusions – but have the most dismal prognosis.” Severe disability and mortality rates associated with BAO, for example, reach an estimated 68% to 78%, he said.
The results, from the EVT for Acute Basilar Artery Occlusion Study (BASILAR), were also simultaneously published in JAMA Neurology.
Prior studies in this patient population are generally single-center, retrospective studies and “the numbers tend to be small,” said Nogueira, who is affiliated with the Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine in Atlanta, Georgia.
Nogueira and colleagues studied 829 consecutive adults who presented with an acute, symptomatic BAO. They examined a nationwide prospective registry study of people with radiologically confirmed BAO in 47 comprehensive stroke centers across 15 provinces in China.
The median age was 65 years and 74% were men. A total 182 participants received thrombolysis therapy within 6 hours of estimated BAO onset. The 647 people in the dual intervention group also received endovascular therapy within 24 hours.
Standard medical treatment included intravenous rt-PA or urokinase, antiplatelet drugs and systematic anticoagulation alone or in combination. Endovascular therapy included mechanical thrombectomy with stent retrievers and/or thromboaspiration, balloon angioplasty, stenting, intra-arterial thrombolysis, or a combination of these interventions.
Interestingly, participants were not randomly assigned, in part because of the favorable outcomes associated with endovascular therapy. “The high number of patients who received [the dual intervention] may suggest the existence of a lack of equipoise among participating centers,” the researchers note.
Key Efficacy Endpoints
A significantly higher proportion of people in the dual treatment group achieved the primary outcome, functional improvement at 90 days, at 32%, compared with 9.3% in the thrombolysis-only group. This endpoint was defined as a modified Rankin Scale (mRS) score of 3 or less, which reflects an ability to walk independently. The difference was statistically significant (P < .001).
The absolute difference between groups was 22.7% (95% confidence interval, 17.1%-28.2%) with an adjusted odds ratio of 4.70 (95% CI, 2.53-8.75; P < .001) in favor of dual intervention.
The number needed to treat for one additional patient to be able to walk unassisted was 4.4.
Other outcomes, including differences in National Institutes of Health Stroke Scale scores from baseline to 5 to 7 days or discharge, as well as propensity score matching and subgroup analyses, likewise supported the superiority of using both interventions.
Safety Outcomes
Nogueira and colleagues also assessed safety. They found that symptomatic intracerebral hemorrhage (ICH) occurred in 45 patients, or 7.1% of the endovascular treatment group. In contrast, only one patient, or 0.5%, of the standard medical treatment alone cohort experienced an ICH. This difference was statistically significant (P < .001).
Mortality at 90 days was significantly lower in the endovascular therapy plus medical therapy group, 46.2%, compared with 71.4% in the standard medical treatment alone group (P < .001).
The absolute difference in mortality was 25.2% (95% CI, 17.6%-2.8%) favoring dual treatment, with an adjusted odds ratio of 2.93 (95% CI, 1.95-4.40; P < .001).
Rates of other serious adverse events during the 90-day follow-up period were similar in the two study groups, Nogueira said.
He acknowledged that the nonrandomized design was a limitation of the registry study, adding that “sometimes in life it’s important to acknowledge the best of what can be done. It’s very hard when you have access to thrombectomy to randomize people.”
However, other researchers have attempted or are enrolling people with BAO into trials that randomly assign them to endovascular therapy and standard medical treatment or medical treatment alone.
The BEST trial in China, for example, randomly assigned 131 patients to these groups but was stopped early in September 2017. “The BEST trial was terminated prematurely because of loss of equipoise that led to a high crossover rate and drop in valid recruitment,” the current researchers note.
“The other two trials…are facing the challenge of whether they will achieve their inclusion target,” they add, “because a growing number of stroke centers are unwilling to randomize patients to standard medical treatment alone after the many positive results of trials for endovascular treatment in patients with anterior-circulation stroke.”
The BAOCHE trial from China, for example, is ongoing with approximately 110 patients enrolled so far.
Investigators for the Basilar Artery International Cooperation Study (BASICS) in the Netherlands just completed enrollment of their 300th and final patient in December 2019.
“We are hopeful BASICS trial will shed additional light,” Nogueira said. The results are expected to be presented at the European Stroke Organization Conference in Vienna in May 2020.
More Guidance From MRI?
“With the advent of the stent retrievers and successful recanalization, we know there can be better outcomes for patients. And we know the morbidity and mortality of the basilar artery occlusions are so poor that we tend to want to be aggressive in these cases,” session comoderator Shlee S. Song, MD, director of the Comprehensive Stroke Center and associate professor of neurology at Cedars-Sinai Medical Center in Los Angeles, California, told Medscape Medical News when asked to comment on the study.
“I agree that we’ve lost equipoise in this cohort – that we really cannot do a randomized trial anymore. You know if you don’t do anything, 90% of the time there will be a poor outcome,” she added.
This is an important study for showing how BAO patients fare after endovascular treatment, Song said.
One unanswered question from the study is if any of the centers in China used magnetic resonance imaging to help determine the most appropriate candidates for endovascular treatment of these posterior circulation strokes, which is a common practice in the United States, she said.
The study was supported by the National Science Fund for Distinguished Young Scholars, Chongqing Major Disease Prevention and Control Technology Research Project, Army Medical University Clinical Medical Research Talent Training Program, and Major Clinical Innovation Technology Project of the Second Affiliated Hospital of the Army Military Medical University. Sing had no relevant disclosures. Nogueira’s financial disclosures include working as a consultant for Stryker Neurovascular; as a principal investigator on the Imperative trial and the PROST trial; as a steering committee member for Biogen for the CHARM trial; as an advisory board member for Cerenovus/Neuravi, Phenox, Anaconda, Genentech, Biogen, Prolong Pharmaceuticals and Brainomix; and as an advisory board member with stock options for Viz.ai, Corindus Vascular Robotics, Vesalio, Ceretrieve, Astrocyte Pharmaceuticals, and Cerebrotech.
This article first appeared on Medscape.com.
SOURCE: Nogueira RG et al. ISC 2020. Late-breaking abstract 17.
REPORTING FROM ISC 2020
Key to denervation response for hypertension may be in carotid body
NATIONAL HARBOR, MD. – Of characteristics that might predict which patients with resistant hypertension will respond to carotid body ablation, the relative activity of the carotid body organ itself might be critical for moving this technology forward, an investigator on a first-in-man study suggests.
The study, first presented in 2018 at the European Society of Cardiology congress, showed carotid body ablation resulted in significant but modest reductions in blood pressure in patients with resistant hypertension.
For many reasons, the carotid body is an attractive target for sustained or indefinite control of resistant hypertension, but median systolic blood pressure reductions following ultrasound ablation were highly variable in the first-in-man study, according to Felix Mahfoud, MD, of Saarland University Hospital in Homburg, Germany, a coinvestigator on the study who discussed the findings at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
Of several strategies being pursued to separate those most likely to gain a major benefit, simply measuring carotid body activity is now emerging as particularly promising.
“Patients with a high degree of carotid body activity had a significantly larger fall in blood pressure versus all other methods of grouping patients,” Dr. Mahfoud reported.
The carotid body is a “grain-size” organ of about 2 mm in size that sits on the carotid bifurcation. It communicates directly with the brain to alter sympathetic activity in response to changing levels of such physiologic variable as oxygen, carbon dioxide, and pH, according to Dr. Mahfoud.
In a 2016 proof-of-principle study conducted in resistant hypertension patients, surgical resection of the carotid body was associated with a median 18–mm Hg reduction in systolic blood pressure (SBP) on 24-hour ambulatory monitoring that was sustained through 24 months (Narkiewicz K et al. JACC Basic Transl Sci. 2016;29:313-24).
Subsequently, ultrasound ablation of the carotid body was by way of a transcatheter approach. Dr. Mahfoud’s unpublished first-in-man study, conducted in 2018 enrolled 38 patients with resistant hypertension. The median reductions from baseline of 7-8 mm Hg at 1, 3, and 6 months were significant (P less than .01), but the benefit was disappointingly modest.
However, the variability was large. Some patients achieved SBP reductions of up to 20 mm Hg at 6 months, prompting additional analyses to understand if the best responders could be identified. When compared to the mean reduction of 7 mm Hg at 6 months, this represented a 13–mm Hg additional reduction. There are now several potential approaches being considered.
In addition to carotid body activity, which is readily measured and has substantial potential to serve as a routine selection criterion, isolated systolic hypertension (ISH) was also found to be a discriminator for response. For those with ISH, which Dr. Mahfoud noted is also characterized as “stiff arteries,” SBP reductions at 6 months were negligible, but in those without ISH, the median reduction from baseline was 11 mm Hg.
Further investigations are now planned to evaluate potential predictors of response, according to Dr. Mahfoud. He believes carotid body ablation might have advantages over alternatives, including other experimental therapies, in at least some patients.
To deliver ultrasound ablation in the first-in-man study, a propriety catheter (Cibiem transvenous system) was advanced through the jugular vein guided with intravascular ultrasound. When the carotid body was reached, two to three ultrasound ablations of 8-12 seconds each were applied. The procedure time was 20-30 minutes.
Initially, an arterial approach to the carotid body was used. However, after a transient ischemic attack early in the series, the approach was switched to the jugular vein. There have been no serious subsequent procedural-related complications since.
Although the median SBP reductions were modest, they were not insignificant in a population selected for severe resistant hypertension. The median SBP at entry was 180 mm Hg in patients taking a median of 4.5 antihypertensive drugs, according to Dr. Mahfoud.
In other words, this approach still retains promise for selected patients if larger studies demonstrate that response can be predicted, and the data continue to support tolerability.
A venous approach to the carotid body with intravascular ultrasound guidance and therapeutic ultrasound appears “to offer a safe and effective treatment option in resistant hypertension,” according to Dr. Mahfoud. “A companion diagnostic test is being developed to determine whether patients are likely to respond to this therapy.”
Dr. Mahfoud reports financial relationships with Medtronic, St. Jude, and ReCor.
This article was updated to clarify the study details and correct misspellings of the presenter's name.
SOURCE: CRT 2020.
NATIONAL HARBOR, MD. – Of characteristics that might predict which patients with resistant hypertension will respond to carotid body ablation, the relative activity of the carotid body organ itself might be critical for moving this technology forward, an investigator on a first-in-man study suggests.
The study, first presented in 2018 at the European Society of Cardiology congress, showed carotid body ablation resulted in significant but modest reductions in blood pressure in patients with resistant hypertension.
For many reasons, the carotid body is an attractive target for sustained or indefinite control of resistant hypertension, but median systolic blood pressure reductions following ultrasound ablation were highly variable in the first-in-man study, according to Felix Mahfoud, MD, of Saarland University Hospital in Homburg, Germany, a coinvestigator on the study who discussed the findings at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
Of several strategies being pursued to separate those most likely to gain a major benefit, simply measuring carotid body activity is now emerging as particularly promising.
“Patients with a high degree of carotid body activity had a significantly larger fall in blood pressure versus all other methods of grouping patients,” Dr. Mahfoud reported.
The carotid body is a “grain-size” organ of about 2 mm in size that sits on the carotid bifurcation. It communicates directly with the brain to alter sympathetic activity in response to changing levels of such physiologic variable as oxygen, carbon dioxide, and pH, according to Dr. Mahfoud.
In a 2016 proof-of-principle study conducted in resistant hypertension patients, surgical resection of the carotid body was associated with a median 18–mm Hg reduction in systolic blood pressure (SBP) on 24-hour ambulatory monitoring that was sustained through 24 months (Narkiewicz K et al. JACC Basic Transl Sci. 2016;29:313-24).
Subsequently, ultrasound ablation of the carotid body was by way of a transcatheter approach. Dr. Mahfoud’s unpublished first-in-man study, conducted in 2018 enrolled 38 patients with resistant hypertension. The median reductions from baseline of 7-8 mm Hg at 1, 3, and 6 months were significant (P less than .01), but the benefit was disappointingly modest.
However, the variability was large. Some patients achieved SBP reductions of up to 20 mm Hg at 6 months, prompting additional analyses to understand if the best responders could be identified. When compared to the mean reduction of 7 mm Hg at 6 months, this represented a 13–mm Hg additional reduction. There are now several potential approaches being considered.
In addition to carotid body activity, which is readily measured and has substantial potential to serve as a routine selection criterion, isolated systolic hypertension (ISH) was also found to be a discriminator for response. For those with ISH, which Dr. Mahfoud noted is also characterized as “stiff arteries,” SBP reductions at 6 months were negligible, but in those without ISH, the median reduction from baseline was 11 mm Hg.
Further investigations are now planned to evaluate potential predictors of response, according to Dr. Mahfoud. He believes carotid body ablation might have advantages over alternatives, including other experimental therapies, in at least some patients.
To deliver ultrasound ablation in the first-in-man study, a propriety catheter (Cibiem transvenous system) was advanced through the jugular vein guided with intravascular ultrasound. When the carotid body was reached, two to three ultrasound ablations of 8-12 seconds each were applied. The procedure time was 20-30 minutes.
Initially, an arterial approach to the carotid body was used. However, after a transient ischemic attack early in the series, the approach was switched to the jugular vein. There have been no serious subsequent procedural-related complications since.
Although the median SBP reductions were modest, they were not insignificant in a population selected for severe resistant hypertension. The median SBP at entry was 180 mm Hg in patients taking a median of 4.5 antihypertensive drugs, according to Dr. Mahfoud.
In other words, this approach still retains promise for selected patients if larger studies demonstrate that response can be predicted, and the data continue to support tolerability.
A venous approach to the carotid body with intravascular ultrasound guidance and therapeutic ultrasound appears “to offer a safe and effective treatment option in resistant hypertension,” according to Dr. Mahfoud. “A companion diagnostic test is being developed to determine whether patients are likely to respond to this therapy.”
Dr. Mahfoud reports financial relationships with Medtronic, St. Jude, and ReCor.
This article was updated to clarify the study details and correct misspellings of the presenter's name.
SOURCE: CRT 2020.
NATIONAL HARBOR, MD. – Of characteristics that might predict which patients with resistant hypertension will respond to carotid body ablation, the relative activity of the carotid body organ itself might be critical for moving this technology forward, an investigator on a first-in-man study suggests.
The study, first presented in 2018 at the European Society of Cardiology congress, showed carotid body ablation resulted in significant but modest reductions in blood pressure in patients with resistant hypertension.
For many reasons, the carotid body is an attractive target for sustained or indefinite control of resistant hypertension, but median systolic blood pressure reductions following ultrasound ablation were highly variable in the first-in-man study, according to Felix Mahfoud, MD, of Saarland University Hospital in Homburg, Germany, a coinvestigator on the study who discussed the findings at CRT 2020 sponsored by MedStar Heart & Vascular Institute.
Of several strategies being pursued to separate those most likely to gain a major benefit, simply measuring carotid body activity is now emerging as particularly promising.
“Patients with a high degree of carotid body activity had a significantly larger fall in blood pressure versus all other methods of grouping patients,” Dr. Mahfoud reported.
The carotid body is a “grain-size” organ of about 2 mm in size that sits on the carotid bifurcation. It communicates directly with the brain to alter sympathetic activity in response to changing levels of such physiologic variable as oxygen, carbon dioxide, and pH, according to Dr. Mahfoud.
In a 2016 proof-of-principle study conducted in resistant hypertension patients, surgical resection of the carotid body was associated with a median 18–mm Hg reduction in systolic blood pressure (SBP) on 24-hour ambulatory monitoring that was sustained through 24 months (Narkiewicz K et al. JACC Basic Transl Sci. 2016;29:313-24).
Subsequently, ultrasound ablation of the carotid body was by way of a transcatheter approach. Dr. Mahfoud’s unpublished first-in-man study, conducted in 2018 enrolled 38 patients with resistant hypertension. The median reductions from baseline of 7-8 mm Hg at 1, 3, and 6 months were significant (P less than .01), but the benefit was disappointingly modest.
However, the variability was large. Some patients achieved SBP reductions of up to 20 mm Hg at 6 months, prompting additional analyses to understand if the best responders could be identified. When compared to the mean reduction of 7 mm Hg at 6 months, this represented a 13–mm Hg additional reduction. There are now several potential approaches being considered.
In addition to carotid body activity, which is readily measured and has substantial potential to serve as a routine selection criterion, isolated systolic hypertension (ISH) was also found to be a discriminator for response. For those with ISH, which Dr. Mahfoud noted is also characterized as “stiff arteries,” SBP reductions at 6 months were negligible, but in those without ISH, the median reduction from baseline was 11 mm Hg.
Further investigations are now planned to evaluate potential predictors of response, according to Dr. Mahfoud. He believes carotid body ablation might have advantages over alternatives, including other experimental therapies, in at least some patients.
To deliver ultrasound ablation in the first-in-man study, a propriety catheter (Cibiem transvenous system) was advanced through the jugular vein guided with intravascular ultrasound. When the carotid body was reached, two to three ultrasound ablations of 8-12 seconds each were applied. The procedure time was 20-30 minutes.
Initially, an arterial approach to the carotid body was used. However, after a transient ischemic attack early in the series, the approach was switched to the jugular vein. There have been no serious subsequent procedural-related complications since.
Although the median SBP reductions were modest, they were not insignificant in a population selected for severe resistant hypertension. The median SBP at entry was 180 mm Hg in patients taking a median of 4.5 antihypertensive drugs, according to Dr. Mahfoud.
In other words, this approach still retains promise for selected patients if larger studies demonstrate that response can be predicted, and the data continue to support tolerability.
A venous approach to the carotid body with intravascular ultrasound guidance and therapeutic ultrasound appears “to offer a safe and effective treatment option in resistant hypertension,” according to Dr. Mahfoud. “A companion diagnostic test is being developed to determine whether patients are likely to respond to this therapy.”
Dr. Mahfoud reports financial relationships with Medtronic, St. Jude, and ReCor.
This article was updated to clarify the study details and correct misspellings of the presenter's name.
SOURCE: CRT 2020.
REPORTING FROM CRT 2020
First clinical evidence of neuroprotection in acute stroke?
LOS ANGELES – A new potential neuroprotectant agent has been found to be beneficial for patients with acute ischemic stroke undergoing endovascular thrombectomy in a large placebo-controlled trial, but only for those patients who did not also receive thrombolysis.
There was no difference between groups on the primary outcome in the main analysis of the trial, lead author Michael Hill, MD, reported.
However, “In our study, we found a dramatic interaction of nerinetide with alteplase. There was a large benefit of nerinetide in patients not given thrombolysis, but in patients who received alteplase, this benefit was completely obliterated,” Dr. Hill said in an interview.
“In patients not treated with thrombolysis, we found a large effect size with a 9.5% absolute improvement in patients having an independent outcome (modified Rankin Score [mRS] 0-2) and a number need to treat of 10 to 11,” he said. “We also found a mortality benefit and a reduction in the size of strokes, with all other secondary outcomes going in the right direction.
“The drug works really well in patients who do not get thrombolysis, but it doesn’t work at all in patients who have had thrombolysis. The thrombolytic appears to break the peptide down so it is inactive,” he added.
“This is the first evidence that neuroprotection is possible in human stroke. This has never been shown before,” Dr. Hill noted. “Many previous clinical trials of potential neuroprotectants have been negative. We think this is a major breakthrough. This is pretty exciting stuff with really tantalizing results.”
Dr. Hill, professor of neurology at the University of Calgary (Alta.), presented results of the ESCAPE-NA1 trial on Feb. 20 at the International Stroke Conference (ISC) 2020. The trial was also simultaneously published online (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30258-0).
Endogenous nitric oxide
The new agent – known as NA1 or nerinetide – is a 20-amino-acid peptide with a novel mechanism of action; it inhibits signaling that leads to neuronal excitotoxicity. “It reduces endogenous nitric oxide generated inside the cell during ischemia, which is one of the main biochemical processes contributing to cell death,” Dr. Hill explained. In a primate model of ischemia reperfusion that was published in Nature in 2012, it was highly protective, he added.
The drug is given just once at the time of thrombectomy. It is short lived in the blood but detectable in the brain for up to 24 hours, he said.
The trial included 1,105 patients who had experienced acute ischemic stroke due to large-vessel occlusion within a 12-hour treatment window and for whom imaging results suitable for thrombectomy were available. The patients were randomly assigned to receive either intravenous nerinetide in a single dose of 2.6 mg/kg or saline placebo at the time of thrombectomy.
Patients were stratified by intravenous alteplase treatment and by declared endovascular device choice.
The primary outcome was a favorable functional outcome 90 days after randomization, defined as an mRS score of 0-2. In the main analysis of the whole population, this favorable outcome was achieved for 61.4% of the group that received nerinetide and for 59.2% of the placebo group, a nonsignificant difference. Secondary outcomes were also similar between the two groups.
But an exploratory analysis showed evidence that nerinetide’s treatment effect was modified by alteplase treatment. Among the patients who did not receive alteplase, use of nerinetide was associated with improved outcomes, whereas no benefit was found in the alteplase stratum. The difference in absolute risk slightly but not significantly favored placebo.
In the stratum that did not receive alteplase (40% of the trial population), the favorable mRS outcome was achieved by 59.3% of patients who received nerinetide, compared with 49.8% of those given placebo – a significant difference (adjusted risk ratio, 1.18; 95% confidence interval, 1.01-1.38).
There was also a 7.5% absolute risk reduction in mortality at 90 days post treatment with nerinetide for the patients who did not receive thrombolysis. This resulted in an approximate halving of the hazard of death (adjusted hazard ratio, 0.56).
In addition, infarct size was reduced in those patients who received nerinetide but not thrombolysis.
Among the patients who received alteplase, the proportion of patients who achieved an mRS of 0-2 was similar between groups, as were median infarct volumes.
The observed treatment effect modification by alteplase was supported by reductions in peak plasma nerinetide concentrations in the alteplase stratum, the researchers reported.
They said that the combination of the clinical results in the no-thrombolytic stratum and subsequent tests documenting that nerinetide is broken down by plasmin (which is generated by alteplase) “provide evidence that the clinical observation of effect modification is not a chance finding.” But they added: “This novel observation will require additional confirmation, and we cannot draw a definitive conclusion on treatment effect in this study.”
“Shaking up the field”
There is still more work to do, Dr. Hill said. “We don’t fully understand the pharmacology, and we will certainly have to do another trial, but we believe this agent is going to shake the field up. This is a totally new drug, and we have to think carefully about where it could fit in.”
“The obvious first group is those patients who do not receive thrombolysis. This is a large group, as most patients do not present in time for thrombolysis. Then we can work on the biochemistry and see if we can develop a version of nerinetide that is resistant to breakdown by thrombolysis,” he said.
Another possibility would be to withhold thrombolysis and give nerinetide instead. “It may be that thrombolysis is not needed if patients are receiving thrombectomy – this is being suggested now in initial studies,” Hill stated.
They also chose a very select group of patients – those undergoing thrombectomy, who represent only 10% to 15% of stroke patients. “We have to work out how to expand that population,” he said.
Hill noted that there have been many examples in the past of potential neuroprotectant agents that have worked in animal models of ischemia-reperfusion but that failed in humans with acute stroke.
“Until recently, we have not had a reliable ischemia-reperfusion model in humans, but now with endovascular therapy, we have a situation where the blood flow is reliably restored, which is an ideal situation to test new neuroprotectant agents. That may be another factor that has contributed to our positive findings,” he said.
In an accompanying comment in The Lancet, Graeme J. Hankey, MD, of the University of Western Australia, Perth, noted that although endovascular thrombectomy after use of intravenous alteplase improves reperfusion and clinical outcomes for a fifth of patients with ischemic stroke caused by large-artery occlusion, half of patients do not recover an independent lifestyle. Cytoprotection aims to augment the resilience of neurons, neurovascular units, and white matter during ischemia until perfusion is restored (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30316-0).
Dr. Hankey also pointed out that numerous cytoprotection strategies have been reported to reduce brain infarction in preclinical models of ischemic stroke but have not been found to improve clinical outcomes in clinical trials involving patients with ischemic stroke.
The advent of thrombectomy provides an opportunity to reassess cytoprotection as an adjunctive therapy for patients with types of temporary brain ischemia that align more closely with successful preclinical models of ischemia, cytoprotection, and reperfusion, he added.
On the results of the current study and the benefit in the no-thrombolysis group, Dr. Hankey stated: “Although this result might be a chance finding or confounded by the indication for alteplase, complementary pharmacokinetic data in a small number of patients treated with nerinetide showed that alteplase lowered plasma concentrations of nerinetide, probably by converting plasminogen to plasmin, which cleaves peptide bonds not only in fibrin but also in the eicosapeptide nerinetide.”
He said the ESCAPE-NA1 trial “informs the study of cytoprotection as an adjunct therapy to reperfusion in acute ischemic stroke” and suggested that researchers who have reported encouraging results of other cytoprotective therapies for ischemic stroke should test their compounds for interactions with concurrent thrombolytic therapies.
The ESCAPE-NA1 trial was sponsored by NoNO, the company developing nerinetide. Dr. Hill has received grants from NoNO for the conduct of the study, is named on a U.S. patent for systems and methods for assisting in decision making and triaging for acute stroke patients, and owns stock in Calgary Scientific. Other coauthors are employees of NoNO or have stock options in the company. Dr. Hankey has received personal honoraria from the American Heart Association, AC Immune, Bayer, Bristol-Myers Squibb, and Medscape outside the area of work that he commented on.
This article first appeared on Medscape.com.
LOS ANGELES – A new potential neuroprotectant agent has been found to be beneficial for patients with acute ischemic stroke undergoing endovascular thrombectomy in a large placebo-controlled trial, but only for those patients who did not also receive thrombolysis.
There was no difference between groups on the primary outcome in the main analysis of the trial, lead author Michael Hill, MD, reported.
However, “In our study, we found a dramatic interaction of nerinetide with alteplase. There was a large benefit of nerinetide in patients not given thrombolysis, but in patients who received alteplase, this benefit was completely obliterated,” Dr. Hill said in an interview.
“In patients not treated with thrombolysis, we found a large effect size with a 9.5% absolute improvement in patients having an independent outcome (modified Rankin Score [mRS] 0-2) and a number need to treat of 10 to 11,” he said. “We also found a mortality benefit and a reduction in the size of strokes, with all other secondary outcomes going in the right direction.
“The drug works really well in patients who do not get thrombolysis, but it doesn’t work at all in patients who have had thrombolysis. The thrombolytic appears to break the peptide down so it is inactive,” he added.
“This is the first evidence that neuroprotection is possible in human stroke. This has never been shown before,” Dr. Hill noted. “Many previous clinical trials of potential neuroprotectants have been negative. We think this is a major breakthrough. This is pretty exciting stuff with really tantalizing results.”
Dr. Hill, professor of neurology at the University of Calgary (Alta.), presented results of the ESCAPE-NA1 trial on Feb. 20 at the International Stroke Conference (ISC) 2020. The trial was also simultaneously published online (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30258-0).
Endogenous nitric oxide
The new agent – known as NA1 or nerinetide – is a 20-amino-acid peptide with a novel mechanism of action; it inhibits signaling that leads to neuronal excitotoxicity. “It reduces endogenous nitric oxide generated inside the cell during ischemia, which is one of the main biochemical processes contributing to cell death,” Dr. Hill explained. In a primate model of ischemia reperfusion that was published in Nature in 2012, it was highly protective, he added.
The drug is given just once at the time of thrombectomy. It is short lived in the blood but detectable in the brain for up to 24 hours, he said.
The trial included 1,105 patients who had experienced acute ischemic stroke due to large-vessel occlusion within a 12-hour treatment window and for whom imaging results suitable for thrombectomy were available. The patients were randomly assigned to receive either intravenous nerinetide in a single dose of 2.6 mg/kg or saline placebo at the time of thrombectomy.
Patients were stratified by intravenous alteplase treatment and by declared endovascular device choice.
The primary outcome was a favorable functional outcome 90 days after randomization, defined as an mRS score of 0-2. In the main analysis of the whole population, this favorable outcome was achieved for 61.4% of the group that received nerinetide and for 59.2% of the placebo group, a nonsignificant difference. Secondary outcomes were also similar between the two groups.
But an exploratory analysis showed evidence that nerinetide’s treatment effect was modified by alteplase treatment. Among the patients who did not receive alteplase, use of nerinetide was associated with improved outcomes, whereas no benefit was found in the alteplase stratum. The difference in absolute risk slightly but not significantly favored placebo.
In the stratum that did not receive alteplase (40% of the trial population), the favorable mRS outcome was achieved by 59.3% of patients who received nerinetide, compared with 49.8% of those given placebo – a significant difference (adjusted risk ratio, 1.18; 95% confidence interval, 1.01-1.38).
There was also a 7.5% absolute risk reduction in mortality at 90 days post treatment with nerinetide for the patients who did not receive thrombolysis. This resulted in an approximate halving of the hazard of death (adjusted hazard ratio, 0.56).
In addition, infarct size was reduced in those patients who received nerinetide but not thrombolysis.
Among the patients who received alteplase, the proportion of patients who achieved an mRS of 0-2 was similar between groups, as were median infarct volumes.
The observed treatment effect modification by alteplase was supported by reductions in peak plasma nerinetide concentrations in the alteplase stratum, the researchers reported.
They said that the combination of the clinical results in the no-thrombolytic stratum and subsequent tests documenting that nerinetide is broken down by plasmin (which is generated by alteplase) “provide evidence that the clinical observation of effect modification is not a chance finding.” But they added: “This novel observation will require additional confirmation, and we cannot draw a definitive conclusion on treatment effect in this study.”
“Shaking up the field”
There is still more work to do, Dr. Hill said. “We don’t fully understand the pharmacology, and we will certainly have to do another trial, but we believe this agent is going to shake the field up. This is a totally new drug, and we have to think carefully about where it could fit in.”
“The obvious first group is those patients who do not receive thrombolysis. This is a large group, as most patients do not present in time for thrombolysis. Then we can work on the biochemistry and see if we can develop a version of nerinetide that is resistant to breakdown by thrombolysis,” he said.
Another possibility would be to withhold thrombolysis and give nerinetide instead. “It may be that thrombolysis is not needed if patients are receiving thrombectomy – this is being suggested now in initial studies,” Hill stated.
They also chose a very select group of patients – those undergoing thrombectomy, who represent only 10% to 15% of stroke patients. “We have to work out how to expand that population,” he said.
Hill noted that there have been many examples in the past of potential neuroprotectant agents that have worked in animal models of ischemia-reperfusion but that failed in humans with acute stroke.
“Until recently, we have not had a reliable ischemia-reperfusion model in humans, but now with endovascular therapy, we have a situation where the blood flow is reliably restored, which is an ideal situation to test new neuroprotectant agents. That may be another factor that has contributed to our positive findings,” he said.
In an accompanying comment in The Lancet, Graeme J. Hankey, MD, of the University of Western Australia, Perth, noted that although endovascular thrombectomy after use of intravenous alteplase improves reperfusion and clinical outcomes for a fifth of patients with ischemic stroke caused by large-artery occlusion, half of patients do not recover an independent lifestyle. Cytoprotection aims to augment the resilience of neurons, neurovascular units, and white matter during ischemia until perfusion is restored (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30316-0).
Dr. Hankey also pointed out that numerous cytoprotection strategies have been reported to reduce brain infarction in preclinical models of ischemic stroke but have not been found to improve clinical outcomes in clinical trials involving patients with ischemic stroke.
The advent of thrombectomy provides an opportunity to reassess cytoprotection as an adjunctive therapy for patients with types of temporary brain ischemia that align more closely with successful preclinical models of ischemia, cytoprotection, and reperfusion, he added.
On the results of the current study and the benefit in the no-thrombolysis group, Dr. Hankey stated: “Although this result might be a chance finding or confounded by the indication for alteplase, complementary pharmacokinetic data in a small number of patients treated with nerinetide showed that alteplase lowered plasma concentrations of nerinetide, probably by converting plasminogen to plasmin, which cleaves peptide bonds not only in fibrin but also in the eicosapeptide nerinetide.”
He said the ESCAPE-NA1 trial “informs the study of cytoprotection as an adjunct therapy to reperfusion in acute ischemic stroke” and suggested that researchers who have reported encouraging results of other cytoprotective therapies for ischemic stroke should test their compounds for interactions with concurrent thrombolytic therapies.
The ESCAPE-NA1 trial was sponsored by NoNO, the company developing nerinetide. Dr. Hill has received grants from NoNO for the conduct of the study, is named on a U.S. patent for systems and methods for assisting in decision making and triaging for acute stroke patients, and owns stock in Calgary Scientific. Other coauthors are employees of NoNO or have stock options in the company. Dr. Hankey has received personal honoraria from the American Heart Association, AC Immune, Bayer, Bristol-Myers Squibb, and Medscape outside the area of work that he commented on.
This article first appeared on Medscape.com.
LOS ANGELES – A new potential neuroprotectant agent has been found to be beneficial for patients with acute ischemic stroke undergoing endovascular thrombectomy in a large placebo-controlled trial, but only for those patients who did not also receive thrombolysis.
There was no difference between groups on the primary outcome in the main analysis of the trial, lead author Michael Hill, MD, reported.
However, “In our study, we found a dramatic interaction of nerinetide with alteplase. There was a large benefit of nerinetide in patients not given thrombolysis, but in patients who received alteplase, this benefit was completely obliterated,” Dr. Hill said in an interview.
“In patients not treated with thrombolysis, we found a large effect size with a 9.5% absolute improvement in patients having an independent outcome (modified Rankin Score [mRS] 0-2) and a number need to treat of 10 to 11,” he said. “We also found a mortality benefit and a reduction in the size of strokes, with all other secondary outcomes going in the right direction.
“The drug works really well in patients who do not get thrombolysis, but it doesn’t work at all in patients who have had thrombolysis. The thrombolytic appears to break the peptide down so it is inactive,” he added.
“This is the first evidence that neuroprotection is possible in human stroke. This has never been shown before,” Dr. Hill noted. “Many previous clinical trials of potential neuroprotectants have been negative. We think this is a major breakthrough. This is pretty exciting stuff with really tantalizing results.”
Dr. Hill, professor of neurology at the University of Calgary (Alta.), presented results of the ESCAPE-NA1 trial on Feb. 20 at the International Stroke Conference (ISC) 2020. The trial was also simultaneously published online (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30258-0).
Endogenous nitric oxide
The new agent – known as NA1 or nerinetide – is a 20-amino-acid peptide with a novel mechanism of action; it inhibits signaling that leads to neuronal excitotoxicity. “It reduces endogenous nitric oxide generated inside the cell during ischemia, which is one of the main biochemical processes contributing to cell death,” Dr. Hill explained. In a primate model of ischemia reperfusion that was published in Nature in 2012, it was highly protective, he added.
The drug is given just once at the time of thrombectomy. It is short lived in the blood but detectable in the brain for up to 24 hours, he said.
The trial included 1,105 patients who had experienced acute ischemic stroke due to large-vessel occlusion within a 12-hour treatment window and for whom imaging results suitable for thrombectomy were available. The patients were randomly assigned to receive either intravenous nerinetide in a single dose of 2.6 mg/kg or saline placebo at the time of thrombectomy.
Patients were stratified by intravenous alteplase treatment and by declared endovascular device choice.
The primary outcome was a favorable functional outcome 90 days after randomization, defined as an mRS score of 0-2. In the main analysis of the whole population, this favorable outcome was achieved for 61.4% of the group that received nerinetide and for 59.2% of the placebo group, a nonsignificant difference. Secondary outcomes were also similar between the two groups.
But an exploratory analysis showed evidence that nerinetide’s treatment effect was modified by alteplase treatment. Among the patients who did not receive alteplase, use of nerinetide was associated with improved outcomes, whereas no benefit was found in the alteplase stratum. The difference in absolute risk slightly but not significantly favored placebo.
In the stratum that did not receive alteplase (40% of the trial population), the favorable mRS outcome was achieved by 59.3% of patients who received nerinetide, compared with 49.8% of those given placebo – a significant difference (adjusted risk ratio, 1.18; 95% confidence interval, 1.01-1.38).
There was also a 7.5% absolute risk reduction in mortality at 90 days post treatment with nerinetide for the patients who did not receive thrombolysis. This resulted in an approximate halving of the hazard of death (adjusted hazard ratio, 0.56).
In addition, infarct size was reduced in those patients who received nerinetide but not thrombolysis.
Among the patients who received alteplase, the proportion of patients who achieved an mRS of 0-2 was similar between groups, as were median infarct volumes.
The observed treatment effect modification by alteplase was supported by reductions in peak plasma nerinetide concentrations in the alteplase stratum, the researchers reported.
They said that the combination of the clinical results in the no-thrombolytic stratum and subsequent tests documenting that nerinetide is broken down by plasmin (which is generated by alteplase) “provide evidence that the clinical observation of effect modification is not a chance finding.” But they added: “This novel observation will require additional confirmation, and we cannot draw a definitive conclusion on treatment effect in this study.”
“Shaking up the field”
There is still more work to do, Dr. Hill said. “We don’t fully understand the pharmacology, and we will certainly have to do another trial, but we believe this agent is going to shake the field up. This is a totally new drug, and we have to think carefully about where it could fit in.”
“The obvious first group is those patients who do not receive thrombolysis. This is a large group, as most patients do not present in time for thrombolysis. Then we can work on the biochemistry and see if we can develop a version of nerinetide that is resistant to breakdown by thrombolysis,” he said.
Another possibility would be to withhold thrombolysis and give nerinetide instead. “It may be that thrombolysis is not needed if patients are receiving thrombectomy – this is being suggested now in initial studies,” Hill stated.
They also chose a very select group of patients – those undergoing thrombectomy, who represent only 10% to 15% of stroke patients. “We have to work out how to expand that population,” he said.
Hill noted that there have been many examples in the past of potential neuroprotectant agents that have worked in animal models of ischemia-reperfusion but that failed in humans with acute stroke.
“Until recently, we have not had a reliable ischemia-reperfusion model in humans, but now with endovascular therapy, we have a situation where the blood flow is reliably restored, which is an ideal situation to test new neuroprotectant agents. That may be another factor that has contributed to our positive findings,” he said.
In an accompanying comment in The Lancet, Graeme J. Hankey, MD, of the University of Western Australia, Perth, noted that although endovascular thrombectomy after use of intravenous alteplase improves reperfusion and clinical outcomes for a fifth of patients with ischemic stroke caused by large-artery occlusion, half of patients do not recover an independent lifestyle. Cytoprotection aims to augment the resilience of neurons, neurovascular units, and white matter during ischemia until perfusion is restored (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30316-0).
Dr. Hankey also pointed out that numerous cytoprotection strategies have been reported to reduce brain infarction in preclinical models of ischemic stroke but have not been found to improve clinical outcomes in clinical trials involving patients with ischemic stroke.
The advent of thrombectomy provides an opportunity to reassess cytoprotection as an adjunctive therapy for patients with types of temporary brain ischemia that align more closely with successful preclinical models of ischemia, cytoprotection, and reperfusion, he added.
On the results of the current study and the benefit in the no-thrombolysis group, Dr. Hankey stated: “Although this result might be a chance finding or confounded by the indication for alteplase, complementary pharmacokinetic data in a small number of patients treated with nerinetide showed that alteplase lowered plasma concentrations of nerinetide, probably by converting plasminogen to plasmin, which cleaves peptide bonds not only in fibrin but also in the eicosapeptide nerinetide.”
He said the ESCAPE-NA1 trial “informs the study of cytoprotection as an adjunct therapy to reperfusion in acute ischemic stroke” and suggested that researchers who have reported encouraging results of other cytoprotective therapies for ischemic stroke should test their compounds for interactions with concurrent thrombolytic therapies.
The ESCAPE-NA1 trial was sponsored by NoNO, the company developing nerinetide. Dr. Hill has received grants from NoNO for the conduct of the study, is named on a U.S. patent for systems and methods for assisting in decision making and triaging for acute stroke patients, and owns stock in Calgary Scientific. Other coauthors are employees of NoNO or have stock options in the company. Dr. Hankey has received personal honoraria from the American Heart Association, AC Immune, Bayer, Bristol-Myers Squibb, and Medscape outside the area of work that he commented on.
This article first appeared on Medscape.com.