Cardiology

WEST PALM BEACH, FLA. – The incidence rate of many cardiovascular events is more than doubled in patients with multiple sclerosis (MS), compared with matched controls without MS, according to a study presented at ACTRIMS Forum 2020. The risk of a major adverse cardiac event (MACE) – that is, a first myocardial infarction, stroke, or cardiac arrest – is approximately twofold higher. Venous thromboembolism and peripheral vascular disease also occur at notably increased rates, reported Rebecca Persson, MPH, and colleagues at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Ms. Persson is an epidemiologist at the Boston Collaborative Drug Surveillance Program in Lexington, Mass.

Vascular comorbidities are more prevalent in patients with MS than in the general population, but few studies have reported on the incidence of cardiovascular disease after MS diagnosis. To describe rates of incident cardiovascular disease after MS diagnosis and compare them with rates in a matched population without MS, the researchers analyzed data from a U.S. Department of Defense database.

The study included a cohort of 6,406 patients with MS diagnosed and treated during Jan. 2004–Aug. 2017 who had at least one prescription for an MS disease-modifying treatment.

A cohort of 66,281 patients without MS were matched to the patients with MS 10:1 based on age, sex, geographic region, and cohort entry date. The researchers excluded patients with a history of cardiovascular disease or select comorbidities such as dyslipidemia, atrial fibrillation, or a disorder related to peripheral vascular disease. They also excluded patients with a history of treated hypertension or treated type 2 diabetes, defined as diagnosis and treatment within 90 days of each other.

Researchers considered a patient to have a cardiovascular disease outcome – including MI, stroke, cardiac arrest, heart failure, angina or unspecified ischemic heart disease, transient ischemic attack or unspecified cerebrovascular disease, venous thromboembolism, peripheral vascular disease, pericardial disease, bradycardia or heart block, or arrhythmia other than atrial fibrillation or atrial flutter – if the disease was recorded five or more times.

The researchers followed patients from cohort entry until study outcome (separate for each outcome), loss of eligibility, death, or end of data collection. Ms. Persson and colleagues calculated incidence rates (IRs) using the Byar method and incidence rate ratios (IRRs) using Poisson regression for each outcome.

The median age at MS diagnosis or at the matched date was 38 years, and 71% were female. The median duration of record after patients entered the cohort was 7.2 years for patients with MS and 5.3 years for patients without MS.

The IRs of all cardiovascular disease types, with the exception of bradycardia or heart block, were higher for patients with MS, compared with non-MS patients, the researchers reported. Many cardiovascular disease outcomes had IRRs greater than 2. “The incidence of MI was higher among MS patients than among non-MS patients,” the researchers said (IR, 12.4 vs. 5.9 per 10,000 person-years; IRR, 2.11).

“Risk of MACE and risk of stroke were higher among MS patients than among non-MS patients,” the researchers said. Relative risks also were higher among women than among men (2.47 vs. 1.55 for MACE, and 2.19 vs. 1.71 for stroke). When the investigators performed a sensitivity analysis to address the possibility that physicians might misdiagnosis MS symptoms as stroke, the rate of stroke was attenuated among patients with MS, but remained elevated relative to the rate among patients without MS (IRR, 1.63).

The IR of venous thromboembolism was more than 2 times higher among patients with MS than among non-MS patients (38.4 vs. 15.1 per 10,000 person-years; IRR, 2.54), as was the risk of peripheral vascular disease (14.9 vs. 6.0 per 10,000 person-years; IRR, 2.49). The relative risk of peripheral vascular disease was higher in women than men, and the risk in patients with MS increased after age 40 years.

The study was funded by a grant from Celgene, a subsidiary of Bristol-Myers Squibb. Four of Ms. Persson’s coauthors are employees of BMS, and one works for a company that has a business relationship with Celgene.

jremaly@mdedge.com

SOURCE: Persson R et al. ACTRIMS Forum 2020. Abstract P082.

WEST PALM BEACH, FLA. – The incidence rate of many cardiovascular events is more than doubled in patients with multiple sclerosis (MS), compared with matched controls without MS, according to a study presented at ACTRIMS Forum 2020. The risk of a major adverse cardiac event (MACE) – that is, a first myocardial infarction, stroke, or cardiac arrest – is approximately twofold higher. Venous thromboembolism and peripheral vascular disease also occur at notably increased rates, reported Rebecca Persson, MPH, and colleagues at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Ms. Persson is an epidemiologist at the Boston Collaborative Drug Surveillance Program in Lexington, Mass.

Vascular comorbidities are more prevalent in patients with MS than in the general population, but few studies have reported on the incidence of cardiovascular disease after MS diagnosis. To describe rates of incident cardiovascular disease after MS diagnosis and compare them with rates in a matched population without MS, the researchers analyzed data from a U.S. Department of Defense database.

The study included a cohort of 6,406 patients with MS diagnosed and treated during Jan. 2004–Aug. 2017 who had at least one prescription for an MS disease-modifying treatment.

A cohort of 66,281 patients without MS were matched to the patients with MS 10:1 based on age, sex, geographic region, and cohort entry date. The researchers excluded patients with a history of cardiovascular disease or select comorbidities such as dyslipidemia, atrial fibrillation, or a disorder related to peripheral vascular disease. They also excluded patients with a history of treated hypertension or treated type 2 diabetes, defined as diagnosis and treatment within 90 days of each other.

Researchers considered a patient to have a cardiovascular disease outcome – including MI, stroke, cardiac arrest, heart failure, angina or unspecified ischemic heart disease, transient ischemic attack or unspecified cerebrovascular disease, venous thromboembolism, peripheral vascular disease, pericardial disease, bradycardia or heart block, or arrhythmia other than atrial fibrillation or atrial flutter – if the disease was recorded five or more times.

The researchers followed patients from cohort entry until study outcome (separate for each outcome), loss of eligibility, death, or end of data collection. Ms. Persson and colleagues calculated incidence rates (IRs) using the Byar method and incidence rate ratios (IRRs) using Poisson regression for each outcome.

The median age at MS diagnosis or at the matched date was 38 years, and 71% were female. The median duration of record after patients entered the cohort was 7.2 years for patients with MS and 5.3 years for patients without MS.

The IRs of all cardiovascular disease types, with the exception of bradycardia or heart block, were higher for patients with MS, compared with non-MS patients, the researchers reported. Many cardiovascular disease outcomes had IRRs greater than 2. “The incidence of MI was higher among MS patients than among non-MS patients,” the researchers said (IR, 12.4 vs. 5.9 per 10,000 person-years; IRR, 2.11).

“Risk of MACE and risk of stroke were higher among MS patients than among non-MS patients,” the researchers said. Relative risks also were higher among women than among men (2.47 vs. 1.55 for MACE, and 2.19 vs. 1.71 for stroke). When the investigators performed a sensitivity analysis to address the possibility that physicians might misdiagnosis MS symptoms as stroke, the rate of stroke was attenuated among patients with MS, but remained elevated relative to the rate among patients without MS (IRR, 1.63).

The IR of venous thromboembolism was more than 2 times higher among patients with MS than among non-MS patients (38.4 vs. 15.1 per 10,000 person-years; IRR, 2.54), as was the risk of peripheral vascular disease (14.9 vs. 6.0 per 10,000 person-years; IRR, 2.49). The relative risk of peripheral vascular disease was higher in women than men, and the risk in patients with MS increased after age 40 years.

The study was funded by a grant from Celgene, a subsidiary of Bristol-Myers Squibb. Four of Ms. Persson’s coauthors are employees of BMS, and one works for a company that has a business relationship with Celgene.

jremaly@mdedge.com

SOURCE: Persson R et al. ACTRIMS Forum 2020. Abstract P082.

WEST PALM BEACH, FLA. – The incidence rate of many cardiovascular events is more than doubled in patients with multiple sclerosis (MS), compared with matched controls without MS, according to a study presented at ACTRIMS Forum 2020. The risk of a major adverse cardiac event (MACE) – that is, a first myocardial infarction, stroke, or cardiac arrest – is approximately twofold higher. Venous thromboembolism and peripheral vascular disease also occur at notably increased rates, reported Rebecca Persson, MPH, and colleagues at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Ms. Persson is an epidemiologist at the Boston Collaborative Drug Surveillance Program in Lexington, Mass.

Vascular comorbidities are more prevalent in patients with MS than in the general population, but few studies have reported on the incidence of cardiovascular disease after MS diagnosis. To describe rates of incident cardiovascular disease after MS diagnosis and compare them with rates in a matched population without MS, the researchers analyzed data from a U.S. Department of Defense database.

The study included a cohort of 6,406 patients with MS diagnosed and treated during Jan. 2004–Aug. 2017 who had at least one prescription for an MS disease-modifying treatment.

A cohort of 66,281 patients without MS were matched to the patients with MS 10:1 based on age, sex, geographic region, and cohort entry date. The researchers excluded patients with a history of cardiovascular disease or select comorbidities such as dyslipidemia, atrial fibrillation, or a disorder related to peripheral vascular disease. They also excluded patients with a history of treated hypertension or treated type 2 diabetes, defined as diagnosis and treatment within 90 days of each other.

Researchers considered a patient to have a cardiovascular disease outcome – including MI, stroke, cardiac arrest, heart failure, angina or unspecified ischemic heart disease, transient ischemic attack or unspecified cerebrovascular disease, venous thromboembolism, peripheral vascular disease, pericardial disease, bradycardia or heart block, or arrhythmia other than atrial fibrillation or atrial flutter – if the disease was recorded five or more times.

The researchers followed patients from cohort entry until study outcome (separate for each outcome), loss of eligibility, death, or end of data collection. Ms. Persson and colleagues calculated incidence rates (IRs) using the Byar method and incidence rate ratios (IRRs) using Poisson regression for each outcome.

The median age at MS diagnosis or at the matched date was 38 years, and 71% were female. The median duration of record after patients entered the cohort was 7.2 years for patients with MS and 5.3 years for patients without MS.

The IRs of all cardiovascular disease types, with the exception of bradycardia or heart block, were higher for patients with MS, compared with non-MS patients, the researchers reported. Many cardiovascular disease outcomes had IRRs greater than 2. “The incidence of MI was higher among MS patients than among non-MS patients,” the researchers said (IR, 12.4 vs. 5.9 per 10,000 person-years; IRR, 2.11).

“Risk of MACE and risk of stroke were higher among MS patients than among non-MS patients,” the researchers said. Relative risks also were higher among women than among men (2.47 vs. 1.55 for MACE, and 2.19 vs. 1.71 for stroke). When the investigators performed a sensitivity analysis to address the possibility that physicians might misdiagnosis MS symptoms as stroke, the rate of stroke was attenuated among patients with MS, but remained elevated relative to the rate among patients without MS (IRR, 1.63).

The IR of venous thromboembolism was more than 2 times higher among patients with MS than among non-MS patients (38.4 vs. 15.1 per 10,000 person-years; IRR, 2.54), as was the risk of peripheral vascular disease (14.9 vs. 6.0 per 10,000 person-years; IRR, 2.49). The relative risk of peripheral vascular disease was higher in women than men, and the risk in patients with MS increased after age 40 years.

The study was funded by a grant from Celgene, a subsidiary of Bristol-Myers Squibb. Four of Ms. Persson’s coauthors are employees of BMS, and one works for a company that has a business relationship with Celgene.

jremaly@mdedge.com

SOURCE: Persson R et al. ACTRIMS Forum 2020. Abstract P082.

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.

Ted Bosworth/MDedge News

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.

Ted Bosworth/MDedge News

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.

Ted Bosworth/MDedge News

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.

LOS ANGELES – In a subanalysis of the TST (Treat Stroke to Target) trial, restricting analysis to only French participants followed for an average of 5 years demonstrated an even more robust potential to reduce recurrent stroke and other major cardiovascular events by treating patients to an LDL target of below 70 mg/dL. Treating LDL to a mean of 66 mg/dL versus 96 mg/dL was associated with a 26% relative risk reduction for the composite endpoint of ischemic stroke, MI, new symptoms requiring urgent coronary or carotid revascularization, and vascular death in an adjusted analysis.

“The results are similar to the main paper but even more spectacular, with no increase in hemorrhagic stroke whatsoever, and positive results on any stroke,” study investigator Pierre Amarenco, MD, professor and chair of the department of neurology and Stroke Centre, Bichat University Hospital, Paris, said.

Dr. Amarenco presented the findings as a late-breaking abstract at the International Stroke Conference sponsored by the American Heart Association. The trial was published simultaneously in the journal Stroke.

In the full TST trial population, risk was reduced by 22% with more-aggressive LDL-lowering treatment, compared with the more lax 90-110 mg/dL target.

The TST cohort included both French and Korean participants. Dr. Amarenco and colleagues focused on the French population in the current study because the group was larger (2,148 vs. 742 Korean participants) and had a longer follow-up, an average of 5.3 years compared to 2.0 years among Korean patients. The initial study had shown “very significant results in the French patients and no apparent effect in Korean patients,” he said. The longer duration of treatment in the French cohort could have contributed to the greater risk reduction, said Dr. Amarenco.

A 2017 European Atherosclerosis Society Consensus Panel statement noted that exposure time to lipid-lowering drugs correlates with outcomes. The European Stroke Organization and the American Heart Association/American Stroke Association guidelines each recommend intensive statin treatment to lower serum lipids following an ischemic stroke of atherosclerotic origin or after a transient ischemic attack (TIA). However, the current researchers noted that the recommendations do not specify specific target numbers.

“Therefore, there is uncertainty about the target levels of LDL cholesterol,” he said.
 

Aiming at different targets

To learn more, Dr. Amarenco and colleagues randomly assigned 1,073 of the French patients to a target LDL treatment group of 70 mg/dL and another 1,075 to a target range of 90-110 mg/dL. They enrolled participants at 61 sites in France. Mean age was 67 years. All participants had experienced an ischemic stroke within 3 months or a TIA within 15 days of baseline. They presented either with a modified Rankin Scale poststroke score of 0-3 or a TIA that included at least arm and leg motor deficit or speech disturbance that lasted more than 10 minutes.

Investigators could use any type and any dose of statin to reach the respective targets. Statins could be prescribed as monotherapy or in combination with ezetimibe (Zetia) or other agents. The baseline mean LDL cholesterol level was 137 mg/dL in the lower target group and 138 mg/dL in the higher target group, respectively (3.5 mmol/L in both groups). Dr. Amarenco and colleagues measured LDL cholesterol levels at 3 weeks postrandomization and then every 6 months.

A smaller proportion of the lower LDL cholesterol target group experienced the adverse composite outcome, 9.6%, compared with 12.9% of the higher LDL cholesterol target group. This translated to a hazard ratio of 0.73 (95% confidence interval, 0.57-0.94; P = .015). The absolute risk reduction was 3.3% with a number needed to treat of 30.

An analysis adjusted for covariates showed a hazard ratio of 0.74 (95% CI, 0.57-0.95; P = .019).

Cerebral infarction and acute cerebral artery revascularization were reduced by 27% (HR, 0.73; 95% CI, 0.54-0.99; P = .046). Cerebral infarction or intracranial hemorrhage (all strokes) were reduced by 28% (HR, 0.72; 95% CI, 0.54-0.98; P = .023). In this case, there was an absolute risk reduction of 2.9% and a number needed to treat of 34.

In contrast, MI or urgent coronary revascularization following new symptoms were not significantly reduced (HR, 0.66; 95% CI, 0.67-1.20; P = .18). The investigators also reported nonsignificant results regarding vascular death (HR, 0.76; 95% CI, 0.44-1.32; P = .32] and all deaths (HR, 1.0; 95% CI, 0.74-1.35; P = .99).

Dr. Amarenco and colleagues also tracked adverse events. They found intracranial hemorrhage occurred in 13 (1.2%) patients assigned an LDL cholesterol below 70 mg/dL and in 11 (1%) patients assigned an LDL cholesterol of 100 ± 10 mg/dL. In this analysis, the hazard ratio was 1.17 (95% CI, 0.53-2.62; P = .70), and the absolute difference was 0.2%.

The investigators also reported that 10.3% of the lower LDL target group vs 13.6% of the higher LDL target group experienced either the primary outcome or intracranial hemorrhage. This translated to a 25% relative risk reduction (HR, 0.75; 95% CI, 0.58-0.96; P = .021), an absolute risk reduction of 3.3% and a number needed to treat of 30.
 

Avoiding one in four events

Assessing the French participants in the TST trial showed that targeting LDL below 70 mg/dL for more than 5 years avoided more than one in four subsequent major cardiovascular events among adults who experienced a recent ischemic stroke or TIA.

Furthermore, more intense LDL lowering also avoided more than one in four recurrent cerebral infarctions or urgent carotid revascularizations following a TIA, as well as one in four recurrent cerebral infarctions or hemorrhages (all strokes), compared with the higher LDL target.

“This was obtained without increasing the risk of intracranial hemorrhage with a number needed to treat of 30,” the researchers noted. “In the context of all randomized clinical trials with statin and other lipid-lowering drugs, there is no reason to think that Asian patients do not benefit from statin treatment and from a lower target LDL cholesterol,” the researchers added.

Therefore, they plan to continue assessing the 742 Korean participants until they reach a median of 5 years of follow-up.

Clinically validating results

“My feeling is that these data are highly supportive of a practice that many of us have been using for years without this level of evidence,” Mitchell S.V. Elkind, MD, said when asked to comment on the study.

Prior secondary analyses of studies, including research into patients with intracranial atherosclerosis, demonstrated benefit from treating to this lower LDL cholesterol target. “These studies were suggestive enough that many of us were treating patients aggressively with statins,” added Dr. Elkind, professor of neurology and epidemiology and chief of the division of neurology clinical outcomes research and population sciences at Columbia University in New York.

“But this really confirms that [fact] with clinical trial evidence,” said Dr. Elkind, “and I think will be very useful to us as clinicians.”

The results could be used to counsel patients about the potential benefits of statin therapy or to motivate primary care providers to treat patients more aggressively, said Dr. Elkind, who will begin his term as president of the American Heart Association/American Stroke Association in July.

This study was supported by a grant from the French Ministry of Health and from SOS-Attaque Cérébrale Association, with unrestricted grants from Pfizer, AstraZeneca, and Merck for French sites and from Pfizer for South Korean sites.

Dr. Amarenco receives research grant support and consulting fees from Pfizer, Merck, and AstraZeneca. Elkind had has disclosed no relevant financial relationships.

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

SOURCE: Amarenko P et al. ISC 2020. Late-breaking abstract 9.

LOS ANGELES – In a subanalysis of the TST (Treat Stroke to Target) trial, restricting analysis to only French participants followed for an average of 5 years demonstrated an even more robust potential to reduce recurrent stroke and other major cardiovascular events by treating patients to an LDL target of below 70 mg/dL. Treating LDL to a mean of 66 mg/dL versus 96 mg/dL was associated with a 26% relative risk reduction for the composite endpoint of ischemic stroke, MI, new symptoms requiring urgent coronary or carotid revascularization, and vascular death in an adjusted analysis.

“The results are similar to the main paper but even more spectacular, with no increase in hemorrhagic stroke whatsoever, and positive results on any stroke,” study investigator Pierre Amarenco, MD, professor and chair of the department of neurology and Stroke Centre, Bichat University Hospital, Paris, said.

Dr. Amarenco presented the findings as a late-breaking abstract at the International Stroke Conference sponsored by the American Heart Association. The trial was published simultaneously in the journal Stroke.

In the full TST trial population, risk was reduced by 22% with more-aggressive LDL-lowering treatment, compared with the more lax 90-110 mg/dL target.

The TST cohort included both French and Korean participants. Dr. Amarenco and colleagues focused on the French population in the current study because the group was larger (2,148 vs. 742 Korean participants) and had a longer follow-up, an average of 5.3 years compared to 2.0 years among Korean patients. The initial study had shown “very significant results in the French patients and no apparent effect in Korean patients,” he said. The longer duration of treatment in the French cohort could have contributed to the greater risk reduction, said Dr. Amarenco.

A 2017 European Atherosclerosis Society Consensus Panel statement noted that exposure time to lipid-lowering drugs correlates with outcomes. The European Stroke Organization and the American Heart Association/American Stroke Association guidelines each recommend intensive statin treatment to lower serum lipids following an ischemic stroke of atherosclerotic origin or after a transient ischemic attack (TIA). However, the current researchers noted that the recommendations do not specify specific target numbers.

“Therefore, there is uncertainty about the target levels of LDL cholesterol,” he said.
 

Aiming at different targets

To learn more, Dr. Amarenco and colleagues randomly assigned 1,073 of the French patients to a target LDL treatment group of 70 mg/dL and another 1,075 to a target range of 90-110 mg/dL. They enrolled participants at 61 sites in France. Mean age was 67 years. All participants had experienced an ischemic stroke within 3 months or a TIA within 15 days of baseline. They presented either with a modified Rankin Scale poststroke score of 0-3 or a TIA that included at least arm and leg motor deficit or speech disturbance that lasted more than 10 minutes.

Investigators could use any type and any dose of statin to reach the respective targets. Statins could be prescribed as monotherapy or in combination with ezetimibe (Zetia) or other agents. The baseline mean LDL cholesterol level was 137 mg/dL in the lower target group and 138 mg/dL in the higher target group, respectively (3.5 mmol/L in both groups). Dr. Amarenco and colleagues measured LDL cholesterol levels at 3 weeks postrandomization and then every 6 months.

A smaller proportion of the lower LDL cholesterol target group experienced the adverse composite outcome, 9.6%, compared with 12.9% of the higher LDL cholesterol target group. This translated to a hazard ratio of 0.73 (95% confidence interval, 0.57-0.94; P = .015). The absolute risk reduction was 3.3% with a number needed to treat of 30.

An analysis adjusted for covariates showed a hazard ratio of 0.74 (95% CI, 0.57-0.95; P = .019).

Cerebral infarction and acute cerebral artery revascularization were reduced by 27% (HR, 0.73; 95% CI, 0.54-0.99; P = .046). Cerebral infarction or intracranial hemorrhage (all strokes) were reduced by 28% (HR, 0.72; 95% CI, 0.54-0.98; P = .023). In this case, there was an absolute risk reduction of 2.9% and a number needed to treat of 34.

In contrast, MI or urgent coronary revascularization following new symptoms were not significantly reduced (HR, 0.66; 95% CI, 0.67-1.20; P = .18). The investigators also reported nonsignificant results regarding vascular death (HR, 0.76; 95% CI, 0.44-1.32; P = .32] and all deaths (HR, 1.0; 95% CI, 0.74-1.35; P = .99).

Dr. Amarenco and colleagues also tracked adverse events. They found intracranial hemorrhage occurred in 13 (1.2%) patients assigned an LDL cholesterol below 70 mg/dL and in 11 (1%) patients assigned an LDL cholesterol of 100 ± 10 mg/dL. In this analysis, the hazard ratio was 1.17 (95% CI, 0.53-2.62; P = .70), and the absolute difference was 0.2%.

The investigators also reported that 10.3% of the lower LDL target group vs 13.6% of the higher LDL target group experienced either the primary outcome or intracranial hemorrhage. This translated to a 25% relative risk reduction (HR, 0.75; 95% CI, 0.58-0.96; P = .021), an absolute risk reduction of 3.3% and a number needed to treat of 30.
 

Avoiding one in four events

Assessing the French participants in the TST trial showed that targeting LDL below 70 mg/dL for more than 5 years avoided more than one in four subsequent major cardiovascular events among adults who experienced a recent ischemic stroke or TIA.

Furthermore, more intense LDL lowering also avoided more than one in four recurrent cerebral infarctions or urgent carotid revascularizations following a TIA, as well as one in four recurrent cerebral infarctions or hemorrhages (all strokes), compared with the higher LDL target.

“This was obtained without increasing the risk of intracranial hemorrhage with a number needed to treat of 30,” the researchers noted. “In the context of all randomized clinical trials with statin and other lipid-lowering drugs, there is no reason to think that Asian patients do not benefit from statin treatment and from a lower target LDL cholesterol,” the researchers added.

Therefore, they plan to continue assessing the 742 Korean participants until they reach a median of 5 years of follow-up.

Clinically validating results

“My feeling is that these data are highly supportive of a practice that many of us have been using for years without this level of evidence,” Mitchell S.V. Elkind, MD, said when asked to comment on the study.

Prior secondary analyses of studies, including research into patients with intracranial atherosclerosis, demonstrated benefit from treating to this lower LDL cholesterol target. “These studies were suggestive enough that many of us were treating patients aggressively with statins,” added Dr. Elkind, professor of neurology and epidemiology and chief of the division of neurology clinical outcomes research and population sciences at Columbia University in New York.

“But this really confirms that [fact] with clinical trial evidence,” said Dr. Elkind, “and I think will be very useful to us as clinicians.”

The results could be used to counsel patients about the potential benefits of statin therapy or to motivate primary care providers to treat patients more aggressively, said Dr. Elkind, who will begin his term as president of the American Heart Association/American Stroke Association in July.

This study was supported by a grant from the French Ministry of Health and from SOS-Attaque Cérébrale Association, with unrestricted grants from Pfizer, AstraZeneca, and Merck for French sites and from Pfizer for South Korean sites.

Dr. Amarenco receives research grant support and consulting fees from Pfizer, Merck, and AstraZeneca. Elkind had has disclosed no relevant financial relationships.

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

SOURCE: Amarenko P et al. ISC 2020. Late-breaking abstract 9.

LOS ANGELES – In a subanalysis of the TST (Treat Stroke to Target) trial, restricting analysis to only French participants followed for an average of 5 years demonstrated an even more robust potential to reduce recurrent stroke and other major cardiovascular events by treating patients to an LDL target of below 70 mg/dL. Treating LDL to a mean of 66 mg/dL versus 96 mg/dL was associated with a 26% relative risk reduction for the composite endpoint of ischemic stroke, MI, new symptoms requiring urgent coronary or carotid revascularization, and vascular death in an adjusted analysis.

“The results are similar to the main paper but even more spectacular, with no increase in hemorrhagic stroke whatsoever, and positive results on any stroke,” study investigator Pierre Amarenco, MD, professor and chair of the department of neurology and Stroke Centre, Bichat University Hospital, Paris, said.

Dr. Amarenco presented the findings as a late-breaking abstract at the International Stroke Conference sponsored by the American Heart Association. The trial was published simultaneously in the journal Stroke.

In the full TST trial population, risk was reduced by 22% with more-aggressive LDL-lowering treatment, compared with the more lax 90-110 mg/dL target.

The TST cohort included both French and Korean participants. Dr. Amarenco and colleagues focused on the French population in the current study because the group was larger (2,148 vs. 742 Korean participants) and had a longer follow-up, an average of 5.3 years compared to 2.0 years among Korean patients. The initial study had shown “very significant results in the French patients and no apparent effect in Korean patients,” he said. The longer duration of treatment in the French cohort could have contributed to the greater risk reduction, said Dr. Amarenco.

A 2017 European Atherosclerosis Society Consensus Panel statement noted that exposure time to lipid-lowering drugs correlates with outcomes. The European Stroke Organization and the American Heart Association/American Stroke Association guidelines each recommend intensive statin treatment to lower serum lipids following an ischemic stroke of atherosclerotic origin or after a transient ischemic attack (TIA). However, the current researchers noted that the recommendations do not specify specific target numbers.

“Therefore, there is uncertainty about the target levels of LDL cholesterol,” he said.
 

Aiming at different targets

To learn more, Dr. Amarenco and colleagues randomly assigned 1,073 of the French patients to a target LDL treatment group of 70 mg/dL and another 1,075 to a target range of 90-110 mg/dL. They enrolled participants at 61 sites in France. Mean age was 67 years. All participants had experienced an ischemic stroke within 3 months or a TIA within 15 days of baseline. They presented either with a modified Rankin Scale poststroke score of 0-3 or a TIA that included at least arm and leg motor deficit or speech disturbance that lasted more than 10 minutes.

Investigators could use any type and any dose of statin to reach the respective targets. Statins could be prescribed as monotherapy or in combination with ezetimibe (Zetia) or other agents. The baseline mean LDL cholesterol level was 137 mg/dL in the lower target group and 138 mg/dL in the higher target group, respectively (3.5 mmol/L in both groups). Dr. Amarenco and colleagues measured LDL cholesterol levels at 3 weeks postrandomization and then every 6 months.

A smaller proportion of the lower LDL cholesterol target group experienced the adverse composite outcome, 9.6%, compared with 12.9% of the higher LDL cholesterol target group. This translated to a hazard ratio of 0.73 (95% confidence interval, 0.57-0.94; P = .015). The absolute risk reduction was 3.3% with a number needed to treat of 30.

An analysis adjusted for covariates showed a hazard ratio of 0.74 (95% CI, 0.57-0.95; P = .019).

Cerebral infarction and acute cerebral artery revascularization were reduced by 27% (HR, 0.73; 95% CI, 0.54-0.99; P = .046). Cerebral infarction or intracranial hemorrhage (all strokes) were reduced by 28% (HR, 0.72; 95% CI, 0.54-0.98; P = .023). In this case, there was an absolute risk reduction of 2.9% and a number needed to treat of 34.

In contrast, MI or urgent coronary revascularization following new symptoms were not significantly reduced (HR, 0.66; 95% CI, 0.67-1.20; P = .18). The investigators also reported nonsignificant results regarding vascular death (HR, 0.76; 95% CI, 0.44-1.32; P = .32] and all deaths (HR, 1.0; 95% CI, 0.74-1.35; P = .99).

Dr. Amarenco and colleagues also tracked adverse events. They found intracranial hemorrhage occurred in 13 (1.2%) patients assigned an LDL cholesterol below 70 mg/dL and in 11 (1%) patients assigned an LDL cholesterol of 100 ± 10 mg/dL. In this analysis, the hazard ratio was 1.17 (95% CI, 0.53-2.62; P = .70), and the absolute difference was 0.2%.

The investigators also reported that 10.3% of the lower LDL target group vs 13.6% of the higher LDL target group experienced either the primary outcome or intracranial hemorrhage. This translated to a 25% relative risk reduction (HR, 0.75; 95% CI, 0.58-0.96; P = .021), an absolute risk reduction of 3.3% and a number needed to treat of 30.
 

Avoiding one in four events

Assessing the French participants in the TST trial showed that targeting LDL below 70 mg/dL for more than 5 years avoided more than one in four subsequent major cardiovascular events among adults who experienced a recent ischemic stroke or TIA.

Furthermore, more intense LDL lowering also avoided more than one in four recurrent cerebral infarctions or urgent carotid revascularizations following a TIA, as well as one in four recurrent cerebral infarctions or hemorrhages (all strokes), compared with the higher LDL target.

“This was obtained without increasing the risk of intracranial hemorrhage with a number needed to treat of 30,” the researchers noted. “In the context of all randomized clinical trials with statin and other lipid-lowering drugs, there is no reason to think that Asian patients do not benefit from statin treatment and from a lower target LDL cholesterol,” the researchers added.

Therefore, they plan to continue assessing the 742 Korean participants until they reach a median of 5 years of follow-up.

Clinically validating results

“My feeling is that these data are highly supportive of a practice that many of us have been using for years without this level of evidence,” Mitchell S.V. Elkind, MD, said when asked to comment on the study.

Prior secondary analyses of studies, including research into patients with intracranial atherosclerosis, demonstrated benefit from treating to this lower LDL cholesterol target. “These studies were suggestive enough that many of us were treating patients aggressively with statins,” added Dr. Elkind, professor of neurology and epidemiology and chief of the division of neurology clinical outcomes research and population sciences at Columbia University in New York.

“But this really confirms that [fact] with clinical trial evidence,” said Dr. Elkind, “and I think will be very useful to us as clinicians.”

The results could be used to counsel patients about the potential benefits of statin therapy or to motivate primary care providers to treat patients more aggressively, said Dr. Elkind, who will begin his term as president of the American Heart Association/American Stroke Association in July.

This study was supported by a grant from the French Ministry of Health and from SOS-Attaque Cérébrale Association, with unrestricted grants from Pfizer, AstraZeneca, and Merck for French sites and from Pfizer for South Korean sites.

Dr. Amarenco receives research grant support and consulting fees from Pfizer, Merck, and AstraZeneca. Elkind had has disclosed no relevant financial relationships.

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

SOURCE: Amarenko P et al. ISC 2020. Late-breaking abstract 9.

NATIONAL HARBOR, MD. – Researchers have created an artificial intelligence algorithm that can evaluate a 10-second ECG recording of a person in normal sinus rhythm and tell with a sensitivity and specificity of almost 80% whether or not that person ever had atrial fibrillation episodes some time in the past or will have a first arrhythmia episode in the near future.

Mitchel L. Zoler/MDedge News

Although this algorithm – derived from and then validated with a dataset of nearly 650,000 ECG recordings from more than 180,000 patients – still needs prospective validation, it offers the prospect for a potential revolution in screening for atrial fibrillation (AFib), Paul A. Friedman, MD, cautioned at the annual International AF Symposium. If initial clinical findings are confirmed, it would show that a 10-second, 12-lead ECG recording can provide the same screening scope as what otherwise takes weeks of ambulatory ECG recording with a Holter monitor or an implanted device, explained Dr. Friedman, professor of medicine and chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.

This finding “could have important implications for atrial fibrillation screening and for the management of patients with unexplained stroke,” Dr. Friedman and his associates noted in the published report of their study (Lancet. 2019 Sep 7;394[10201]:861-7). “We’re still working to define the window of ECG” recording time that provides the optimal assessment for a history of asymptomatic AFib, but the “possibilities this opens are huge,” Dr. Friedman said in his talk at the symposium. This work sprang from the premise that “subtle signatures” in a brief, apparently normal sinus rhythm ECG tracing can harbor reliable clues about AFib history or an imminent episode.

The 2019 report by Dr. Friedman and associates documented that in the validation phase of their study, the trained artificial intelligence (AI) program identified patients with a history of AFib or an impending arrhythmia event from a single, 10-second ECG that to the naked eye seemed to show normal sinus rhythm with a sensitivity of 79.0%, a specificity of 79.5%, and an accuracy of 79.4%. It also showed an area under a receiver operating characteristic curve of 0.87, meaning that screening for AFib by this method compared favorably with the area-under-the-curve (AUC) results tallied by several widely accepted screening tools, including Pap smears for cervical cancer (AUC of 0.70), mammograms for breast cancer (AUC of 0.85), and CHA2DS2-VASc scoring for estimating stroke risk in AFib patients (AUC of 0.57-0.72), Dr. Friedman said.

The researchers developed the AI algorithm with more than 450,000 10-second ECG tracings collected from roughly 126,000 patients who underwent at least one ECG recording as part of their routine care at the Mayo Clinic during 1993-2017. The goal was for the program to find and validate recurring characteristics in the ECG that consistently linked with a history of or an impending AFib episode and that did not appear in ECG recordings from people without any AFib history. The program this effort produced then underwent further adjustment with the use of more than 64,340 ECGs from an additional 18,116 patients, and then the final product underwent validation testing with a further 130,802 ECGs collected from an additional 36,280 people, the study phase that resulted in the reported sensitivity and specificity estimates.

It’s currently unclear to Dr. Friedman and associates what specific features the program uses to classify patients. It’s an important question, but if the results are reproducible and reliable, this uncertainty shouldn’t slow clinical adoption, he said in an interview.

While “this particular algorithm needs prospective vetting,” a similar algorithm developed by Dr. Friedman and the same research team that uses a 10-second ECG to identify patients with a left ventricular ejection fraction of 35% or less is further advanced in development, and a device that uses this algorithm will soon receive Food and Drug Administration review under a fast track designation that the agency approved in late 2019.

The researchers developed this algorithm for estimating left ventricular function using a strategy similar to their development of a tool for diagnosing AFib (Nat Med. 2019 Jan 7;25[1]:70-4), and results from 100 patients prospectively studied with this approach to ECG analysis and reported at the American Heart Association scientific sessions in November 2019 showed that the algorithm identified substantial left ventricular dysfunction with an AUC of 0.906 (Circulation. 2019 Nov 19;140[suppl 1]:A13447). The same team of investigators has developed an AI algorithm that can calculate a person’s physiologic age based on the ECG recording (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: 10.1161/CIRCEP.119.007284).

The study received no commercial funding, and Dr. Friedman and coauthors had no relevant disclosures. The Mayo Clinic has licensed a related artificial intelligence algorithm to EKO, and Dr. Friedman may benefit financially from this arrangement.

mzoler@mdedge.com

NATIONAL HARBOR, MD. – Researchers have created an artificial intelligence algorithm that can evaluate a 10-second ECG recording of a person in normal sinus rhythm and tell with a sensitivity and specificity of almost 80% whether or not that person ever had atrial fibrillation episodes some time in the past or will have a first arrhythmia episode in the near future.

Mitchel L. Zoler/MDedge News

Although this algorithm – derived from and then validated with a dataset of nearly 650,000 ECG recordings from more than 180,000 patients – still needs prospective validation, it offers the prospect for a potential revolution in screening for atrial fibrillation (AFib), Paul A. Friedman, MD, cautioned at the annual International AF Symposium. If initial clinical findings are confirmed, it would show that a 10-second, 12-lead ECG recording can provide the same screening scope as what otherwise takes weeks of ambulatory ECG recording with a Holter monitor or an implanted device, explained Dr. Friedman, professor of medicine and chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.

This finding “could have important implications for atrial fibrillation screening and for the management of patients with unexplained stroke,” Dr. Friedman and his associates noted in the published report of their study (Lancet. 2019 Sep 7;394[10201]:861-7). “We’re still working to define the window of ECG” recording time that provides the optimal assessment for a history of asymptomatic AFib, but the “possibilities this opens are huge,” Dr. Friedman said in his talk at the symposium. This work sprang from the premise that “subtle signatures” in a brief, apparently normal sinus rhythm ECG tracing can harbor reliable clues about AFib history or an imminent episode.

The 2019 report by Dr. Friedman and associates documented that in the validation phase of their study, the trained artificial intelligence (AI) program identified patients with a history of AFib or an impending arrhythmia event from a single, 10-second ECG that to the naked eye seemed to show normal sinus rhythm with a sensitivity of 79.0%, a specificity of 79.5%, and an accuracy of 79.4%. It also showed an area under a receiver operating characteristic curve of 0.87, meaning that screening for AFib by this method compared favorably with the area-under-the-curve (AUC) results tallied by several widely accepted screening tools, including Pap smears for cervical cancer (AUC of 0.70), mammograms for breast cancer (AUC of 0.85), and CHA2DS2-VASc scoring for estimating stroke risk in AFib patients (AUC of 0.57-0.72), Dr. Friedman said.

The researchers developed the AI algorithm with more than 450,000 10-second ECG tracings collected from roughly 126,000 patients who underwent at least one ECG recording as part of their routine care at the Mayo Clinic during 1993-2017. The goal was for the program to find and validate recurring characteristics in the ECG that consistently linked with a history of or an impending AFib episode and that did not appear in ECG recordings from people without any AFib history. The program this effort produced then underwent further adjustment with the use of more than 64,340 ECGs from an additional 18,116 patients, and then the final product underwent validation testing with a further 130,802 ECGs collected from an additional 36,280 people, the study phase that resulted in the reported sensitivity and specificity estimates.

It’s currently unclear to Dr. Friedman and associates what specific features the program uses to classify patients. It’s an important question, but if the results are reproducible and reliable, this uncertainty shouldn’t slow clinical adoption, he said in an interview.

While “this particular algorithm needs prospective vetting,” a similar algorithm developed by Dr. Friedman and the same research team that uses a 10-second ECG to identify patients with a left ventricular ejection fraction of 35% or less is further advanced in development, and a device that uses this algorithm will soon receive Food and Drug Administration review under a fast track designation that the agency approved in late 2019.

The researchers developed this algorithm for estimating left ventricular function using a strategy similar to their development of a tool for diagnosing AFib (Nat Med. 2019 Jan 7;25[1]:70-4), and results from 100 patients prospectively studied with this approach to ECG analysis and reported at the American Heart Association scientific sessions in November 2019 showed that the algorithm identified substantial left ventricular dysfunction with an AUC of 0.906 (Circulation. 2019 Nov 19;140[suppl 1]:A13447). The same team of investigators has developed an AI algorithm that can calculate a person’s physiologic age based on the ECG recording (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: 10.1161/CIRCEP.119.007284).

The study received no commercial funding, and Dr. Friedman and coauthors had no relevant disclosures. The Mayo Clinic has licensed a related artificial intelligence algorithm to EKO, and Dr. Friedman may benefit financially from this arrangement.

mzoler@mdedge.com

NATIONAL HARBOR, MD. – Researchers have created an artificial intelligence algorithm that can evaluate a 10-second ECG recording of a person in normal sinus rhythm and tell with a sensitivity and specificity of almost 80% whether or not that person ever had atrial fibrillation episodes some time in the past or will have a first arrhythmia episode in the near future.

Mitchel L. Zoler/MDedge News

Although this algorithm – derived from and then validated with a dataset of nearly 650,000 ECG recordings from more than 180,000 patients – still needs prospective validation, it offers the prospect for a potential revolution in screening for atrial fibrillation (AFib), Paul A. Friedman, MD, cautioned at the annual International AF Symposium. If initial clinical findings are confirmed, it would show that a 10-second, 12-lead ECG recording can provide the same screening scope as what otherwise takes weeks of ambulatory ECG recording with a Holter monitor or an implanted device, explained Dr. Friedman, professor of medicine and chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.

This finding “could have important implications for atrial fibrillation screening and for the management of patients with unexplained stroke,” Dr. Friedman and his associates noted in the published report of their study (Lancet. 2019 Sep 7;394[10201]:861-7). “We’re still working to define the window of ECG” recording time that provides the optimal assessment for a history of asymptomatic AFib, but the “possibilities this opens are huge,” Dr. Friedman said in his talk at the symposium. This work sprang from the premise that “subtle signatures” in a brief, apparently normal sinus rhythm ECG tracing can harbor reliable clues about AFib history or an imminent episode.

The 2019 report by Dr. Friedman and associates documented that in the validation phase of their study, the trained artificial intelligence (AI) program identified patients with a history of AFib or an impending arrhythmia event from a single, 10-second ECG that to the naked eye seemed to show normal sinus rhythm with a sensitivity of 79.0%, a specificity of 79.5%, and an accuracy of 79.4%. It also showed an area under a receiver operating characteristic curve of 0.87, meaning that screening for AFib by this method compared favorably with the area-under-the-curve (AUC) results tallied by several widely accepted screening tools, including Pap smears for cervical cancer (AUC of 0.70), mammograms for breast cancer (AUC of 0.85), and CHA2DS2-VASc scoring for estimating stroke risk in AFib patients (AUC of 0.57-0.72), Dr. Friedman said.

The researchers developed the AI algorithm with more than 450,000 10-second ECG tracings collected from roughly 126,000 patients who underwent at least one ECG recording as part of their routine care at the Mayo Clinic during 1993-2017. The goal was for the program to find and validate recurring characteristics in the ECG that consistently linked with a history of or an impending AFib episode and that did not appear in ECG recordings from people without any AFib history. The program this effort produced then underwent further adjustment with the use of more than 64,340 ECGs from an additional 18,116 patients, and then the final product underwent validation testing with a further 130,802 ECGs collected from an additional 36,280 people, the study phase that resulted in the reported sensitivity and specificity estimates.

It’s currently unclear to Dr. Friedman and associates what specific features the program uses to classify patients. It’s an important question, but if the results are reproducible and reliable, this uncertainty shouldn’t slow clinical adoption, he said in an interview.

While “this particular algorithm needs prospective vetting,” a similar algorithm developed by Dr. Friedman and the same research team that uses a 10-second ECG to identify patients with a left ventricular ejection fraction of 35% or less is further advanced in development, and a device that uses this algorithm will soon receive Food and Drug Administration review under a fast track designation that the agency approved in late 2019.

The researchers developed this algorithm for estimating left ventricular function using a strategy similar to their development of a tool for diagnosing AFib (Nat Med. 2019 Jan 7;25[1]:70-4), and results from 100 patients prospectively studied with this approach to ECG analysis and reported at the American Heart Association scientific sessions in November 2019 showed that the algorithm identified substantial left ventricular dysfunction with an AUC of 0.906 (Circulation. 2019 Nov 19;140[suppl 1]:A13447). The same team of investigators has developed an AI algorithm that can calculate a person’s physiologic age based on the ECG recording (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: 10.1161/CIRCEP.119.007284).

The study received no commercial funding, and Dr. Friedman and coauthors had no relevant disclosures. The Mayo Clinic has licensed a related artificial intelligence algorithm to EKO, and Dr. Friedman may benefit financially from this arrangement.

mzoler@mdedge.com

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.

Ted Bosworth/MDedge News

“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.

Ted Bosworth/MDedge News

“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.

Ted Bosworth/MDedge News

“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.

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.

The US Food and Drug Administration (FDA) has additionally approved dulaglutide (Trulicity) for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes with and without established cardiovascular disease (CVD) or multiple CV risk factors, the company has announced.

Dulaglutide is a once-weekly injectable glucagonlike peptide-1 (GLP-1) receptor agonist first approved in the United States in 2014 for the treatment of type 2 diabetes.

It is now the first and only type 2 diabetes medicine approved to reduce the risk of CV events for both primary and secondary prevention populations. The European Medicines Agency approved a similar indication for dulaglutide last fall.

The new US indication is based on results of the CV outcomes trial for dulaglutide, known as REWIND, which was the longest-running CV outcomes trial in the GLP-1 agonist class.

Chair of the REWIND study, Hertzel Gerstein, MD, professor of medicine at McMaster University and Hamilton Health Sciences, Ontario, Canada, said in a Lilly statement that the trial included a “broad population of people living with type 2 diabetes, reflective of those in the general population. We therefore assessed the effect of Trulicity in people with established CVD as well as those with multiple CV risk factors.”

“Globally, over 415 million people have type 2 diabetes, which is itself a CV risk factor. However, only about one third have established CVD, which is why this new indication, and the supporting evidence, is important for the millions of people in the United States living with diabetes,” he added.

Other GLP-1 agonists have been granted approvals for additional reduction of CV events in patients with type 2 diabetes, but only for secondary prevention.

Most recently the FDA expanded the indication for once-weekly semaglutide to include reducing the risk for MACE, including CV death, nonfatal myocardial infarction, or nonfatal stroke, in adults with type 2 diabetes who have established CVD.
 

Additional approval based on REWIND trial

The REWIND trial included primarily people with type 2 diabetes without established CVD. The full study results were presented at the 2019 American Diabetes Association Scientific Sessions.

REWIND showed a significant reduction in risk of MACE – a composite endpoint of nonfatal myocardial infarction, nonfatal stroke, or CV death – which occurred in 12.0% of patients in the dulaglutide group, compared with 13.4% of patients in the placebo group, for a risk reduction of 0.88 (95% confidence interval, 0.79-0.99; P = .026), which was consistent across subgroups.

All three components of the MACE primary endpoint showed a reduction with dulaglutide, compared with placebo, including CV death (hazard ratio, 0.91; 95% CI, 0.78-1.06) and nonfatal MI (HR, 0.96; 95% CI, 0.79-1.16), with the strongest and only significant effect seen in nonfatal stroke (HR, 0.76; 95% CI, 0.61-0.95).

No difference was seen between groups in hospital admissions for heart failure.

Dulaglutide was also found to modestly reduce weight by around 1.5 kg (P = .0001) and systolic blood pressure by 1.7 mm Hg (P = .0001).

The safety profile of dulaglutide in REWIND was consistent with other members of the GLP-1 agonist class, with gastrointestinal events being the most common adverse event leading to discontinuation.

Sherry Martin, MD, Lilly’s vice president, medical affairs, noted in the company statement: “For the first time, health care providers can prescribe a diabetes medicine proven to significantly reduce the risk of experiencing a CV event for people with type 2 diabetes with and without established CVD.”

“Trulicity can help people achieve their A_1C goals and protect them from experiencing a CV event with a once-weekly, easy-to-use treatment option,” added Martin.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has additionally approved dulaglutide (Trulicity) for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes with and without established cardiovascular disease (CVD) or multiple CV risk factors, the company has announced.

Dulaglutide is a once-weekly injectable glucagonlike peptide-1 (GLP-1) receptor agonist first approved in the United States in 2014 for the treatment of type 2 diabetes.

It is now the first and only type 2 diabetes medicine approved to reduce the risk of CV events for both primary and secondary prevention populations. The European Medicines Agency approved a similar indication for dulaglutide last fall.

The new US indication is based on results of the CV outcomes trial for dulaglutide, known as REWIND, which was the longest-running CV outcomes trial in the GLP-1 agonist class.

Chair of the REWIND study, Hertzel Gerstein, MD, professor of medicine at McMaster University and Hamilton Health Sciences, Ontario, Canada, said in a Lilly statement that the trial included a “broad population of people living with type 2 diabetes, reflective of those in the general population. We therefore assessed the effect of Trulicity in people with established CVD as well as those with multiple CV risk factors.”

“Globally, over 415 million people have type 2 diabetes, which is itself a CV risk factor. However, only about one third have established CVD, which is why this new indication, and the supporting evidence, is important for the millions of people in the United States living with diabetes,” he added.

Other GLP-1 agonists have been granted approvals for additional reduction of CV events in patients with type 2 diabetes, but only for secondary prevention.

Most recently the FDA expanded the indication for once-weekly semaglutide to include reducing the risk for MACE, including CV death, nonfatal myocardial infarction, or nonfatal stroke, in adults with type 2 diabetes who have established CVD.
 

Additional approval based on REWIND trial

The REWIND trial included primarily people with type 2 diabetes without established CVD. The full study results were presented at the 2019 American Diabetes Association Scientific Sessions.

REWIND showed a significant reduction in risk of MACE – a composite endpoint of nonfatal myocardial infarction, nonfatal stroke, or CV death – which occurred in 12.0% of patients in the dulaglutide group, compared with 13.4% of patients in the placebo group, for a risk reduction of 0.88 (95% confidence interval, 0.79-0.99; P = .026), which was consistent across subgroups.

All three components of the MACE primary endpoint showed a reduction with dulaglutide, compared with placebo, including CV death (hazard ratio, 0.91; 95% CI, 0.78-1.06) and nonfatal MI (HR, 0.96; 95% CI, 0.79-1.16), with the strongest and only significant effect seen in nonfatal stroke (HR, 0.76; 95% CI, 0.61-0.95).

No difference was seen between groups in hospital admissions for heart failure.

Dulaglutide was also found to modestly reduce weight by around 1.5 kg (P = .0001) and systolic blood pressure by 1.7 mm Hg (P = .0001).

The safety profile of dulaglutide in REWIND was consistent with other members of the GLP-1 agonist class, with gastrointestinal events being the most common adverse event leading to discontinuation.

Sherry Martin, MD, Lilly’s vice president, medical affairs, noted in the company statement: “For the first time, health care providers can prescribe a diabetes medicine proven to significantly reduce the risk of experiencing a CV event for people with type 2 diabetes with and without established CVD.”

“Trulicity can help people achieve their A_1C goals and protect them from experiencing a CV event with a once-weekly, easy-to-use treatment option,” added Martin.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has additionally approved dulaglutide (Trulicity) for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes with and without established cardiovascular disease (CVD) or multiple CV risk factors, the company has announced.

Dulaglutide is a once-weekly injectable glucagonlike peptide-1 (GLP-1) receptor agonist first approved in the United States in 2014 for the treatment of type 2 diabetes.

It is now the first and only type 2 diabetes medicine approved to reduce the risk of CV events for both primary and secondary prevention populations. The European Medicines Agency approved a similar indication for dulaglutide last fall.

The new US indication is based on results of the CV outcomes trial for dulaglutide, known as REWIND, which was the longest-running CV outcomes trial in the GLP-1 agonist class.

Chair of the REWIND study, Hertzel Gerstein, MD, professor of medicine at McMaster University and Hamilton Health Sciences, Ontario, Canada, said in a Lilly statement that the trial included a “broad population of people living with type 2 diabetes, reflective of those in the general population. We therefore assessed the effect of Trulicity in people with established CVD as well as those with multiple CV risk factors.”

“Globally, over 415 million people have type 2 diabetes, which is itself a CV risk factor. However, only about one third have established CVD, which is why this new indication, and the supporting evidence, is important for the millions of people in the United States living with diabetes,” he added.

Other GLP-1 agonists have been granted approvals for additional reduction of CV events in patients with type 2 diabetes, but only for secondary prevention.

Most recently the FDA expanded the indication for once-weekly semaglutide to include reducing the risk for MACE, including CV death, nonfatal myocardial infarction, or nonfatal stroke, in adults with type 2 diabetes who have established CVD.
 

Additional approval based on REWIND trial

The REWIND trial included primarily people with type 2 diabetes without established CVD. The full study results were presented at the 2019 American Diabetes Association Scientific Sessions.

REWIND showed a significant reduction in risk of MACE – a composite endpoint of nonfatal myocardial infarction, nonfatal stroke, or CV death – which occurred in 12.0% of patients in the dulaglutide group, compared with 13.4% of patients in the placebo group, for a risk reduction of 0.88 (95% confidence interval, 0.79-0.99; P = .026), which was consistent across subgroups.

All three components of the MACE primary endpoint showed a reduction with dulaglutide, compared with placebo, including CV death (hazard ratio, 0.91; 95% CI, 0.78-1.06) and nonfatal MI (HR, 0.96; 95% CI, 0.79-1.16), with the strongest and only significant effect seen in nonfatal stroke (HR, 0.76; 95% CI, 0.61-0.95).

No difference was seen between groups in hospital admissions for heart failure.

Dulaglutide was also found to modestly reduce weight by around 1.5 kg (P = .0001) and systolic blood pressure by 1.7 mm Hg (P = .0001).

The safety profile of dulaglutide in REWIND was consistent with other members of the GLP-1 agonist class, with gastrointestinal events being the most common adverse event leading to discontinuation.

Sherry Martin, MD, Lilly’s vice president, medical affairs, noted in the company statement: “For the first time, health care providers can prescribe a diabetes medicine proven to significantly reduce the risk of experiencing a CV event for people with type 2 diabetes with and without established CVD.”

“Trulicity can help people achieve their A_1C goals and protect them from experiencing a CV event with a once-weekly, easy-to-use treatment option,” added Martin.

This article first appeared on Medscape.com.

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

mzoler@mdedge.com

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

mzoler@mdedge.com

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

mzoler@mdedge.com

A unique collection of bacteria in the gut may have a strong association with pulmonary arterial hypertension and could be highly predictive of the disease in undiagnosed patients, according to a study published in the journal Hypertension.

This is the first study to show that people with PAH have a common specific gut microbiota profile, wrote lead study author Mohan Raizada, PhD, distinguished professor in the department of physiology and functional genomics at the University of Florida, Gainesville.

The findings have the potential to change how cardiologists diagnose and treat PAH, he added. “While current PAH treatments focus on the lungs, looking at the lung/gut axis could open the door to new therapies centered in the digestive system,” Dr. Raizada said.

The researchers developed a model that found the specific microbiota profile was 83% accurate in predicting the presence or absence of PAH. If a larger study can validate the findings, the researchers wrote, this could lead to a new test for diagnosing PAH that’s less invasive than cardiac catheterization. It could also lead to new treatments that target the gut microbiome.

Study investigators collected stool samples from 18 PAH patients and 12 people without a history of cardiopulmonary disease. The microbiota DNA from the stool samples were isolated and sequenced. The analysis revealed that PAH patients had reduced richness and evenness of the gut bacteria, known as alpha diversity. They had increased levels of bacteria associated with atherosclerosis, and healthy patients had increased levels of bacteria that produced short-chain fatty acids.

Although recent studies have begun to show potential associations between the gut microbiome and cardiovascular diseases, this research is in its infancy, Mariell Jessup, MD, commented. “Even though the study by Dr. Raizada and colleagues predicted pulmonary arterial hypertension based on an individual’s microbiome with some accuracy, it is an observational study, so it does not prove cause and effect. Many other factors, especially diet, affect the gut microbiome,” added Dr. Jessup, Chief Science and Medical Officer for the American Heart Association.

SOURCE: Raizada MK et al. Hypertension. 2020. doi: 10.1161/HYPERTENSIONAHA.119.14294.

A unique collection of bacteria in the gut may have a strong association with pulmonary arterial hypertension and could be highly predictive of the disease in undiagnosed patients, according to a study published in the journal Hypertension.

This is the first study to show that people with PAH have a common specific gut microbiota profile, wrote lead study author Mohan Raizada, PhD, distinguished professor in the department of physiology and functional genomics at the University of Florida, Gainesville.

The findings have the potential to change how cardiologists diagnose and treat PAH, he added. “While current PAH treatments focus on the lungs, looking at the lung/gut axis could open the door to new therapies centered in the digestive system,” Dr. Raizada said.

The researchers developed a model that found the specific microbiota profile was 83% accurate in predicting the presence or absence of PAH. If a larger study can validate the findings, the researchers wrote, this could lead to a new test for diagnosing PAH that’s less invasive than cardiac catheterization. It could also lead to new treatments that target the gut microbiome.

Study investigators collected stool samples from 18 PAH patients and 12 people without a history of cardiopulmonary disease. The microbiota DNA from the stool samples were isolated and sequenced. The analysis revealed that PAH patients had reduced richness and evenness of the gut bacteria, known as alpha diversity. They had increased levels of bacteria associated with atherosclerosis, and healthy patients had increased levels of bacteria that produced short-chain fatty acids.

Although recent studies have begun to show potential associations between the gut microbiome and cardiovascular diseases, this research is in its infancy, Mariell Jessup, MD, commented. “Even though the study by Dr. Raizada and colleagues predicted pulmonary arterial hypertension based on an individual’s microbiome with some accuracy, it is an observational study, so it does not prove cause and effect. Many other factors, especially diet, affect the gut microbiome,” added Dr. Jessup, Chief Science and Medical Officer for the American Heart Association.

SOURCE: Raizada MK et al. Hypertension. 2020. doi: 10.1161/HYPERTENSIONAHA.119.14294.

A unique collection of bacteria in the gut may have a strong association with pulmonary arterial hypertension and could be highly predictive of the disease in undiagnosed patients, according to a study published in the journal Hypertension.

This is the first study to show that people with PAH have a common specific gut microbiota profile, wrote lead study author Mohan Raizada, PhD, distinguished professor in the department of physiology and functional genomics at the University of Florida, Gainesville.

The findings have the potential to change how cardiologists diagnose and treat PAH, he added. “While current PAH treatments focus on the lungs, looking at the lung/gut axis could open the door to new therapies centered in the digestive system,” Dr. Raizada said.

The researchers developed a model that found the specific microbiota profile was 83% accurate in predicting the presence or absence of PAH. If a larger study can validate the findings, the researchers wrote, this could lead to a new test for diagnosing PAH that’s less invasive than cardiac catheterization. It could also lead to new treatments that target the gut microbiome.

Study investigators collected stool samples from 18 PAH patients and 12 people without a history of cardiopulmonary disease. The microbiota DNA from the stool samples were isolated and sequenced. The analysis revealed that PAH patients had reduced richness and evenness of the gut bacteria, known as alpha diversity. They had increased levels of bacteria associated with atherosclerosis, and healthy patients had increased levels of bacteria that produced short-chain fatty acids.

Although recent studies have begun to show potential associations between the gut microbiome and cardiovascular diseases, this research is in its infancy, Mariell Jessup, MD, commented. “Even though the study by Dr. Raizada and colleagues predicted pulmonary arterial hypertension based on an individual’s microbiome with some accuracy, it is an observational study, so it does not prove cause and effect. Many other factors, especially diet, affect the gut microbiome,” added Dr. Jessup, Chief Science and Medical Officer for the American Heart Association.

SOURCE: Raizada MK et al. Hypertension. 2020. doi: 10.1161/HYPERTENSIONAHA.119.14294.

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.

“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.

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.

“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.

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.

“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.

This article first appeared on Medscape.com.