Liam Davenport

MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.

The research was presented May 23 at the 91st European Atherosclerosis Society Congress.

Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.

It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.

The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.

The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
 

Early diagnosis ‘imperative’

The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.

“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”

Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.

He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.

However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”

Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”

Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
 

Life-limiting condition

HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.

Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.

To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.

“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”

Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.

For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.

Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).

This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.

Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.

Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.

He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).

Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.

He said that, despite these figures, the adverse events were “mostly mild or moderate.”

The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”

Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”

The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.

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

MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.

The research was presented May 23 at the 91st European Atherosclerosis Society Congress.

Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.

It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.

The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.

The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
 

Early diagnosis ‘imperative’

The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.

“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”

Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.

He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.

However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”

Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”

Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
 

Life-limiting condition

HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.

Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.

To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.

“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”

Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.

For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.

Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).

This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.

Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.

Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.

He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).

Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.

He said that, despite these figures, the adverse events were “mostly mild or moderate.”

The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”

Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”

The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.

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

MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.

The research was presented May 23 at the 91st European Atherosclerosis Society Congress.

Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.

It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.

The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.

The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
 

Early diagnosis ‘imperative’

The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.

“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”

Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.

He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.

However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”

Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”

Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
 

Life-limiting condition

HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.

Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.

To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.

“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”

Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.

For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.

Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).

This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.

Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.

Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.

He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).

Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.

He said that, despite these figures, the adverse events were “mostly mild or moderate.”

The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”

Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”

The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

Patients with resectable, early-stage pancreatic cancer can safely undergo minimally invasive distal pancreatectomy (MIDP) as an alternative to traditional open surgery, suggest results from the international DIPLOMA study.

In the trial, around 260 patients were randomly assigned to undergo either open surgery or minimally invasive laparoscopic or robot-assisted surgery. Rates of complete tumor removal were comparable between the groups.

In addition, the disease-free and overall survival rates at 3 years were nearly identical.

“For pancreatic cancer, we have proven for the first time that minimally invasive distal pancreatectomy is as good as open surgery,” commented principal investigator Mohammad Abu Hilal, MD, PhD, surgical director at the Instituto Ospedaliero Fondazione Poliambulanza in Brescia, Italy.

“Our research provides reassurance for surgeons and can help patients by giving them the information they need to have a conversation with their doctor about how they want to be treated,” he added.

Dr. Hilal was speaking at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented (abstract 4163) on June 5.

The study was not able to show that there was a benefit in terms of shorter hospital stays or greater functional recovery with the minimally invasive approach, Dr. Hilal noted, but he suggested that this could be because of differences in postoperative procedures between the participating centers.

He said in an interview that minimally invasive surgery is becoming “very common all over the world,” particularly in the United States, and that randomized controlled trials are “always the last step” in convincing people to use the technique.

He also emphasized that the “best results are obtained in high-volume centers where surgeons do more than at least 50 pancreatic resections a year,” because the minimally invasive approach is “quite complex and difficult,” more so than open surgery.

“This confirmatory study proves that minimally invasive surgical techniques are a safe and effective option for resectable pancreatic cancer,” commented ASCO expert Jennifer F. Tseng, MD, chair of surgery at Boston University and surgeon-in-chief at the Boston Medical Center. It may also “provide benefits like faster recovery time and less infection risk, without increasing cancer risk.”

The results from this trial “will help both surgeons and patients feel comfortable that minimally invasive surgery, in expert hands, is not inferior to open surgery,” she commented in a statement.
 

Minimally invasive surgery

Only around 12% of patients with pancreatic cancer are diagnosed when the disease is at an early enough stage for surgical resection to be a possibility, Dr. Hilal noted. Minimally invasive pancreatectomy, particularly the distal procedure, was introduced around 25 years ago, but it was initially used only for benign tumors or borderline malignancies.

It took another 10 years before it was considered in cases of confirmed malignancies, “and the main reason for this delay was concerns about the oncological efficiency” of MIDP in terms of its ability to achieve radical resection and an adequate lymph node yield. At the same time, some concerns about minimally invasive surgery for cancer were raised because of results from randomized trials in other cancer types, such as hysterectomy for cervical cancer. Some studies showed worse survival after minimally invasive surgery than after open surgery.

In recent years, use of minimally invasive techniques for pancreatic cancer has become an increasingly “hot topic in many surgical forums,” Dr. Hilal said.

So his team set out to investigate the approach in a phase 3 noninferiority trial. The investigators focused on patients who had an indication for elective distal pancreatectomy plus splenectomy because of proven or highly suspected pancreatic ductal adenocarcinoma in the pancreatic body or tail.

Patients from 35 centers in 12 countries were recruited between May 2018 and May 2021 and were randomly assigned to undergo either MIDP or open distal pancreatectomy.

Patients, nurses, and pathologists were blinded to the surgical procedure by covering of the abdominal wall.

None of the patients underwent adjuvant or neoadjuvant chemotherapy.

Following the procedure, the patients were followed up at 2 weeks and at 1, 3, 6, and 12 months, and a CT scan was performed at 12 months. A range of assessments was performed at each visit, including quality of life measures.

From 1,146 patients initially screened, 261 patients were included.

A few patients withdrew; 131 patients underwent MIDP, and 127 underwent open surgery and were included in the intention-to-treat analysis. Of those, 129 and 125, respectively, were included in the follow-up analysis.

The results confirmed the noninferiority of MIDP, compared with open surgery, with a rate of R0 radical resection (defined as ≥ 1 mm distance between the tumor and the surgical margin) of 73% vs. 69% (P = .039).

In addition, the lymph node yield was comparable between the two approaches, at an average of 22 nodes for MIDP vs. 23 for open surgery (P = .89), and the time to functional recovery was identical, at 5 days for both (P = .22).

The rate of intraperitoneal recurrence was found to be 41% with MIDP, compared with 38% for patients who underwent open surgery.

Dr. Hilal also showed that the rate of serious adverse events, such as bleeding or organ damage, was similar between the two procedures, at 18% with minimally invasive surgery vs. 22% for the open procedure.

Turning to the survival curves, he noted that it is “very clear” that the two procedures achieved near-identical results, at a hazard ratio of 0.99 (P = .94) for overall survival and 0.97 (P = .88) for disease-free survival when comparing MIDP with open surgery.

The researchers will continue to follow up the patients for 3-5 years and will analyze the lymph nodes retrieved to determine whether removal of the spleen is necessary.

The study was funded by Medtronic and Ethicon. Dr. Hilal has relationships with Ethicon and Medtronic. Dr. Tseng has relationships with Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, Curadel Surgical Innovations, Daiichi Sankyo/Lilly, GlaxoSmithKline, Intarcia Therapeutics, Merck, MyoKardia, PanTher Therapeutics, Pfizer, Quest Diagnostics, Sanofi, Vertex, and Zeus.

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

Patients with resectable, early-stage pancreatic cancer can safely undergo minimally invasive distal pancreatectomy (MIDP) as an alternative to traditional open surgery, suggest results from the international DIPLOMA study.

In the trial, around 260 patients were randomly assigned to undergo either open surgery or minimally invasive laparoscopic or robot-assisted surgery. Rates of complete tumor removal were comparable between the groups.

In addition, the disease-free and overall survival rates at 3 years were nearly identical.

“For pancreatic cancer, we have proven for the first time that minimally invasive distal pancreatectomy is as good as open surgery,” commented principal investigator Mohammad Abu Hilal, MD, PhD, surgical director at the Instituto Ospedaliero Fondazione Poliambulanza in Brescia, Italy.

“Our research provides reassurance for surgeons and can help patients by giving them the information they need to have a conversation with their doctor about how they want to be treated,” he added.

Dr. Hilal was speaking at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented (abstract 4163) on June 5.

The study was not able to show that there was a benefit in terms of shorter hospital stays or greater functional recovery with the minimally invasive approach, Dr. Hilal noted, but he suggested that this could be because of differences in postoperative procedures between the participating centers.

He said in an interview that minimally invasive surgery is becoming “very common all over the world,” particularly in the United States, and that randomized controlled trials are “always the last step” in convincing people to use the technique.

He also emphasized that the “best results are obtained in high-volume centers where surgeons do more than at least 50 pancreatic resections a year,” because the minimally invasive approach is “quite complex and difficult,” more so than open surgery.

“This confirmatory study proves that minimally invasive surgical techniques are a safe and effective option for resectable pancreatic cancer,” commented ASCO expert Jennifer F. Tseng, MD, chair of surgery at Boston University and surgeon-in-chief at the Boston Medical Center. It may also “provide benefits like faster recovery time and less infection risk, without increasing cancer risk.”

The results from this trial “will help both surgeons and patients feel comfortable that minimally invasive surgery, in expert hands, is not inferior to open surgery,” she commented in a statement.
 

Minimally invasive surgery

Only around 12% of patients with pancreatic cancer are diagnosed when the disease is at an early enough stage for surgical resection to be a possibility, Dr. Hilal noted. Minimally invasive pancreatectomy, particularly the distal procedure, was introduced around 25 years ago, but it was initially used only for benign tumors or borderline malignancies.

It took another 10 years before it was considered in cases of confirmed malignancies, “and the main reason for this delay was concerns about the oncological efficiency” of MIDP in terms of its ability to achieve radical resection and an adequate lymph node yield. At the same time, some concerns about minimally invasive surgery for cancer were raised because of results from randomized trials in other cancer types, such as hysterectomy for cervical cancer. Some studies showed worse survival after minimally invasive surgery than after open surgery.

In recent years, use of minimally invasive techniques for pancreatic cancer has become an increasingly “hot topic in many surgical forums,” Dr. Hilal said.

So his team set out to investigate the approach in a phase 3 noninferiority trial. The investigators focused on patients who had an indication for elective distal pancreatectomy plus splenectomy because of proven or highly suspected pancreatic ductal adenocarcinoma in the pancreatic body or tail.

Patients from 35 centers in 12 countries were recruited between May 2018 and May 2021 and were randomly assigned to undergo either MIDP or open distal pancreatectomy.

Patients, nurses, and pathologists were blinded to the surgical procedure by covering of the abdominal wall.

None of the patients underwent adjuvant or neoadjuvant chemotherapy.

Following the procedure, the patients were followed up at 2 weeks and at 1, 3, 6, and 12 months, and a CT scan was performed at 12 months. A range of assessments was performed at each visit, including quality of life measures.

From 1,146 patients initially screened, 261 patients were included.

A few patients withdrew; 131 patients underwent MIDP, and 127 underwent open surgery and were included in the intention-to-treat analysis. Of those, 129 and 125, respectively, were included in the follow-up analysis.

The results confirmed the noninferiority of MIDP, compared with open surgery, with a rate of R0 radical resection (defined as ≥ 1 mm distance between the tumor and the surgical margin) of 73% vs. 69% (P = .039).

In addition, the lymph node yield was comparable between the two approaches, at an average of 22 nodes for MIDP vs. 23 for open surgery (P = .89), and the time to functional recovery was identical, at 5 days for both (P = .22).

The rate of intraperitoneal recurrence was found to be 41% with MIDP, compared with 38% for patients who underwent open surgery.

Dr. Hilal also showed that the rate of serious adverse events, such as bleeding or organ damage, was similar between the two procedures, at 18% with minimally invasive surgery vs. 22% for the open procedure.

Turning to the survival curves, he noted that it is “very clear” that the two procedures achieved near-identical results, at a hazard ratio of 0.99 (P = .94) for overall survival and 0.97 (P = .88) for disease-free survival when comparing MIDP with open surgery.

The researchers will continue to follow up the patients for 3-5 years and will analyze the lymph nodes retrieved to determine whether removal of the spleen is necessary.

The study was funded by Medtronic and Ethicon. Dr. Hilal has relationships with Ethicon and Medtronic. Dr. Tseng has relationships with Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, Curadel Surgical Innovations, Daiichi Sankyo/Lilly, GlaxoSmithKline, Intarcia Therapeutics, Merck, MyoKardia, PanTher Therapeutics, Pfizer, Quest Diagnostics, Sanofi, Vertex, and Zeus.

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

Patients with resectable, early-stage pancreatic cancer can safely undergo minimally invasive distal pancreatectomy (MIDP) as an alternative to traditional open surgery, suggest results from the international DIPLOMA study.

In the trial, around 260 patients were randomly assigned to undergo either open surgery or minimally invasive laparoscopic or robot-assisted surgery. Rates of complete tumor removal were comparable between the groups.

In addition, the disease-free and overall survival rates at 3 years were nearly identical.

“For pancreatic cancer, we have proven for the first time that minimally invasive distal pancreatectomy is as good as open surgery,” commented principal investigator Mohammad Abu Hilal, MD, PhD, surgical director at the Instituto Ospedaliero Fondazione Poliambulanza in Brescia, Italy.

“Our research provides reassurance for surgeons and can help patients by giving them the information they need to have a conversation with their doctor about how they want to be treated,” he added.

Dr. Hilal was speaking at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented (abstract 4163) on June 5.

The study was not able to show that there was a benefit in terms of shorter hospital stays or greater functional recovery with the minimally invasive approach, Dr. Hilal noted, but he suggested that this could be because of differences in postoperative procedures between the participating centers.

He said in an interview that minimally invasive surgery is becoming “very common all over the world,” particularly in the United States, and that randomized controlled trials are “always the last step” in convincing people to use the technique.

He also emphasized that the “best results are obtained in high-volume centers where surgeons do more than at least 50 pancreatic resections a year,” because the minimally invasive approach is “quite complex and difficult,” more so than open surgery.

“This confirmatory study proves that minimally invasive surgical techniques are a safe and effective option for resectable pancreatic cancer,” commented ASCO expert Jennifer F. Tseng, MD, chair of surgery at Boston University and surgeon-in-chief at the Boston Medical Center. It may also “provide benefits like faster recovery time and less infection risk, without increasing cancer risk.”

The results from this trial “will help both surgeons and patients feel comfortable that minimally invasive surgery, in expert hands, is not inferior to open surgery,” she commented in a statement.
 

Minimally invasive surgery

Only around 12% of patients with pancreatic cancer are diagnosed when the disease is at an early enough stage for surgical resection to be a possibility, Dr. Hilal noted. Minimally invasive pancreatectomy, particularly the distal procedure, was introduced around 25 years ago, but it was initially used only for benign tumors or borderline malignancies.

It took another 10 years before it was considered in cases of confirmed malignancies, “and the main reason for this delay was concerns about the oncological efficiency” of MIDP in terms of its ability to achieve radical resection and an adequate lymph node yield. At the same time, some concerns about minimally invasive surgery for cancer were raised because of results from randomized trials in other cancer types, such as hysterectomy for cervical cancer. Some studies showed worse survival after minimally invasive surgery than after open surgery.

In recent years, use of minimally invasive techniques for pancreatic cancer has become an increasingly “hot topic in many surgical forums,” Dr. Hilal said.

So his team set out to investigate the approach in a phase 3 noninferiority trial. The investigators focused on patients who had an indication for elective distal pancreatectomy plus splenectomy because of proven or highly suspected pancreatic ductal adenocarcinoma in the pancreatic body or tail.

Patients from 35 centers in 12 countries were recruited between May 2018 and May 2021 and were randomly assigned to undergo either MIDP or open distal pancreatectomy.

Patients, nurses, and pathologists were blinded to the surgical procedure by covering of the abdominal wall.

None of the patients underwent adjuvant or neoadjuvant chemotherapy.

Following the procedure, the patients were followed up at 2 weeks and at 1, 3, 6, and 12 months, and a CT scan was performed at 12 months. A range of assessments was performed at each visit, including quality of life measures.

From 1,146 patients initially screened, 261 patients were included.

A few patients withdrew; 131 patients underwent MIDP, and 127 underwent open surgery and were included in the intention-to-treat analysis. Of those, 129 and 125, respectively, were included in the follow-up analysis.

The results confirmed the noninferiority of MIDP, compared with open surgery, with a rate of R0 radical resection (defined as ≥ 1 mm distance between the tumor and the surgical margin) of 73% vs. 69% (P = .039).

In addition, the lymph node yield was comparable between the two approaches, at an average of 22 nodes for MIDP vs. 23 for open surgery (P = .89), and the time to functional recovery was identical, at 5 days for both (P = .22).

The rate of intraperitoneal recurrence was found to be 41% with MIDP, compared with 38% for patients who underwent open surgery.

Dr. Hilal also showed that the rate of serious adverse events, such as bleeding or organ damage, was similar between the two procedures, at 18% with minimally invasive surgery vs. 22% for the open procedure.

Turning to the survival curves, he noted that it is “very clear” that the two procedures achieved near-identical results, at a hazard ratio of 0.99 (P = .94) for overall survival and 0.97 (P = .88) for disease-free survival when comparing MIDP with open surgery.

The researchers will continue to follow up the patients for 3-5 years and will analyze the lymph nodes retrieved to determine whether removal of the spleen is necessary.

The study was funded by Medtronic and Ethicon. Dr. Hilal has relationships with Ethicon and Medtronic. Dr. Tseng has relationships with Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, Curadel Surgical Innovations, Daiichi Sankyo/Lilly, GlaxoSmithKline, Intarcia Therapeutics, Merck, MyoKardia, PanTher Therapeutics, Pfizer, Quest Diagnostics, Sanofi, Vertex, and Zeus.

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

MANNHEIM, GERMANY – Contrary to expectations, individuals with familial hypercholesterolemia (FH) have rates of overweight and obesity that mirror the general population – rates that appear to have a substantial impact on these patients’ already increased risk of coronary artery disease, a registry analysis suggests.

Data on almost 36,000 individuals with FH were collated from an international registry, revealing that 55% of adults and 25% of children and adolescents with the homozygous form of FH had overweight or obesity. The figures for heterozygous FH were 52% and 27%, respectively.

Crucially, overweight or obesity was associated with substantially increased rates of coronary artery disease, particularly in persons with heterozygous FH, among whom adults with obesity faced a twofold increased risk, rising to more than sixfold in children and adolescents.

Moreover, “obesity is associated with a worse lipid profile, even from childhood, regardless of whether a patient is on medication,” said study presenter Amany Elshorbagy, DPhil, Cardiovascular Epidemiologist, department of primary care and public health, Imperial College London.

She added that, with the increased risk of coronary artery disease associated with heterozygous FH, the results showed that “together with lipid-lowering medication, weight management is needed.”

The research was presented at the annual meeting of the European Atherosclerosis Society.
 

Tended to be thin

Alberico L. Catapano, MD, PhD, director of cardiovascular research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, and past president of the EAS, said in an interview that, historically, few FH patients were overweight or obese; rather, they tended to be thin.

However, there is now “a trend for people with FH to show more diabetes and obesity,” with the “bottom line” being that, as they are already at increased risk of coronary artery disease, it pushes their risk up even further.

In other words, if a risk factor such as obesity is added “on top of the strongest risk factor, that is LDL cholesterol, it is not one plus one makes two, it is one plus one makes three,” he said.

As such, Dr. Catapano believes that the study is “very interesting,” because it further underlines the importance of weight management for individuals with increased LDL cholesterol, “especially when you have genetic forms, like FH.”

Dr. Catapano’s comments were echoed by session co-chair Ulrike Schatz, MD, leader of the lipidology specialty department at the University Hospital Carl Gustav Carus, Technical University of Dresden (Germany).

Indeed, she told Dr. Elshorbagy before her presentation that she finds “a lot of my FH patients have a tendency towards anorexia.”

In an interview, Dr. Elshorbagy said that that reaction was typical of “most of the clinicians” she had spoken to. Upon seeing her data, especially for homozygous FH patients, they say, “They are on the lean side.”

Consequently, the research team went into the study “with the expectation that they might have a lower prevalence of obesity and overweight than the general population,” but “that’s not what we’re seeing.”

Dr. Elshorbagy noted that it would be helpful to have longitudinal data to determine whether, 50 years ago, patients with HF “were leaner, along with the rest of the population.”

The registry data are cross-sectional, and the team is now reaching out to the respective national lead investigators to submit follow-up data on their patients, with the aim of looking at changes in body weight and the impact on outcomes over time.

Another key question for the researchers is in regard to fat distribution, as body mass index “is not the best predictor of heart disease,” Dr. Elshorbagy said, but is rather central obesity.

Although they have also asked investigators to share waist circumference data, she conceded that it is a measurement that “is a lot harder to standardize across centers and countries; it’s not like putting patients on a scale.”

Overall, Dr. Elshorbagy believes that her findings indicate that clinicians should take a broader, more holistic approach toward their patients – in other words, an approach in which lipid lowering medication is “key but is just one of several things we need to do to make sure the coronary event rate goes down.”
 

More with than without

Dr. Elshorbagy began her presentation by highlighting that the prevalence of overweight and obesity ranges from 50% to 70% and that it is “the only health condition where you’ve got more people worldwide with the condition than without.”

Crucially, overweight increases the risk of coronary artery disease by approximately 20%. Among patients with obesity, the risk rises to 50%.

Given that FH patients “already have a very high risk of cardiovascular disease from their high cholesterol levels,” the team set out to determine rates of obesity and overweight in this population and their impact on coronary artery disease risk.

They used cross-sectional data from the EAS FH Studies Collaboration Global Registry, which involves 29,262 adults aged greater than or equal to 18 years and 6,275 children and adolescents aged 5 to 17 years with heterozygous FH, and 325 adults and 57 children with homozygous FH.

Dividing the adults into standard BMI categories, they found that 16% of heterozygous and 23% of homozygous FH patients had obesity, while 52% and 55%, respectively, had overweight or obesity.

For children, the team used World Health Organization z score cutoffs, which indicated that 9% of patients with heterozygous FH and 7% of patients with homozygous FH had obesity. Rates of overweight or obesity were 27% and 25%, respectively.

Among patients with heterozygous FH, rates of overweight or obesity among adults were 50% in high-income countries and 63% in other countries; among children, the rates were and 27% and 29%, respectively.

Stratified by region, the team found that the lowest rate of overweight or obesity among adult patients with heterozygous FH was in Eastern Asia, at 27%, while the highest was in Northern Africa/Western Asia (the Middle East), at 82%.

In North America, 56% of adult patients had overweight or obesity. The prevalence of coronary artery disease rose with increasing BMI.

Among adult patients with heterozygous FH, 11.3% of those with normal weight had coronary artery disease; the percentage rose to 22.9% among those with overweight, and 30.9% among those with obesity. Among children, the corresponding figures were 0.1%, 0.2%, and 0.7%.

Putting adults and children with homozygous FH together, the researchers found that 29.0% of patients with normal weight had coronary artery disease, compared with 31.3% of those with overweight and 49.3% of those with obesity.

Moreover, the results showed that levels of LDL and remnant cholesterol were significantly associated with BMI in adults and children with heterozygous FH, even after adjusting for age, sex, and lipid-lowering medication (P < .001 for all).

Multivariate analysis that took into account age, sex, lipid-lowering medication, and LDL cholesterol revealed that having obesity, compared with not having obesity, was associated with a substantial increase in the risk of coronary artery disease among patients with heterozygous FH.

Among adults with the condition, the odds ratio was 2.16 (95% confidence interval, 1.97-2.36), while among children and adolescents, it was 6.87 (95% CI, 1.55-30.46).

The results remained similar after further adjustment for the presence of diabetes and when considering peripheral artery disease and stroke.

No funding for the study was declared. Dr. Elshorbagy has relationships with Amgen, Daiichi Sankyo, and Regeneron.

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

MANNHEIM, GERMANY – Contrary to expectations, individuals with familial hypercholesterolemia (FH) have rates of overweight and obesity that mirror the general population – rates that appear to have a substantial impact on these patients’ already increased risk of coronary artery disease, a registry analysis suggests.

Data on almost 36,000 individuals with FH were collated from an international registry, revealing that 55% of adults and 25% of children and adolescents with the homozygous form of FH had overweight or obesity. The figures for heterozygous FH were 52% and 27%, respectively.

Crucially, overweight or obesity was associated with substantially increased rates of coronary artery disease, particularly in persons with heterozygous FH, among whom adults with obesity faced a twofold increased risk, rising to more than sixfold in children and adolescents.

Moreover, “obesity is associated with a worse lipid profile, even from childhood, regardless of whether a patient is on medication,” said study presenter Amany Elshorbagy, DPhil, Cardiovascular Epidemiologist, department of primary care and public health, Imperial College London.

She added that, with the increased risk of coronary artery disease associated with heterozygous FH, the results showed that “together with lipid-lowering medication, weight management is needed.”

The research was presented at the annual meeting of the European Atherosclerosis Society.
 

Tended to be thin

Alberico L. Catapano, MD, PhD, director of cardiovascular research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, and past president of the EAS, said in an interview that, historically, few FH patients were overweight or obese; rather, they tended to be thin.

However, there is now “a trend for people with FH to show more diabetes and obesity,” with the “bottom line” being that, as they are already at increased risk of coronary artery disease, it pushes their risk up even further.

In other words, if a risk factor such as obesity is added “on top of the strongest risk factor, that is LDL cholesterol, it is not one plus one makes two, it is one plus one makes three,” he said.

As such, Dr. Catapano believes that the study is “very interesting,” because it further underlines the importance of weight management for individuals with increased LDL cholesterol, “especially when you have genetic forms, like FH.”

Dr. Catapano’s comments were echoed by session co-chair Ulrike Schatz, MD, leader of the lipidology specialty department at the University Hospital Carl Gustav Carus, Technical University of Dresden (Germany).

Indeed, she told Dr. Elshorbagy before her presentation that she finds “a lot of my FH patients have a tendency towards anorexia.”

In an interview, Dr. Elshorbagy said that that reaction was typical of “most of the clinicians” she had spoken to. Upon seeing her data, especially for homozygous FH patients, they say, “They are on the lean side.”

Consequently, the research team went into the study “with the expectation that they might have a lower prevalence of obesity and overweight than the general population,” but “that’s not what we’re seeing.”

Dr. Elshorbagy noted that it would be helpful to have longitudinal data to determine whether, 50 years ago, patients with HF “were leaner, along with the rest of the population.”

The registry data are cross-sectional, and the team is now reaching out to the respective national lead investigators to submit follow-up data on their patients, with the aim of looking at changes in body weight and the impact on outcomes over time.

Another key question for the researchers is in regard to fat distribution, as body mass index “is not the best predictor of heart disease,” Dr. Elshorbagy said, but is rather central obesity.

Although they have also asked investigators to share waist circumference data, she conceded that it is a measurement that “is a lot harder to standardize across centers and countries; it’s not like putting patients on a scale.”

Overall, Dr. Elshorbagy believes that her findings indicate that clinicians should take a broader, more holistic approach toward their patients – in other words, an approach in which lipid lowering medication is “key but is just one of several things we need to do to make sure the coronary event rate goes down.”
 

More with than without

Dr. Elshorbagy began her presentation by highlighting that the prevalence of overweight and obesity ranges from 50% to 70% and that it is “the only health condition where you’ve got more people worldwide with the condition than without.”

Crucially, overweight increases the risk of coronary artery disease by approximately 20%. Among patients with obesity, the risk rises to 50%.

Given that FH patients “already have a very high risk of cardiovascular disease from their high cholesterol levels,” the team set out to determine rates of obesity and overweight in this population and their impact on coronary artery disease risk.

They used cross-sectional data from the EAS FH Studies Collaboration Global Registry, which involves 29,262 adults aged greater than or equal to 18 years and 6,275 children and adolescents aged 5 to 17 years with heterozygous FH, and 325 adults and 57 children with homozygous FH.

Dividing the adults into standard BMI categories, they found that 16% of heterozygous and 23% of homozygous FH patients had obesity, while 52% and 55%, respectively, had overweight or obesity.

For children, the team used World Health Organization z score cutoffs, which indicated that 9% of patients with heterozygous FH and 7% of patients with homozygous FH had obesity. Rates of overweight or obesity were 27% and 25%, respectively.

Among patients with heterozygous FH, rates of overweight or obesity among adults were 50% in high-income countries and 63% in other countries; among children, the rates were and 27% and 29%, respectively.

Stratified by region, the team found that the lowest rate of overweight or obesity among adult patients with heterozygous FH was in Eastern Asia, at 27%, while the highest was in Northern Africa/Western Asia (the Middle East), at 82%.

In North America, 56% of adult patients had overweight or obesity. The prevalence of coronary artery disease rose with increasing BMI.

Among adult patients with heterozygous FH, 11.3% of those with normal weight had coronary artery disease; the percentage rose to 22.9% among those with overweight, and 30.9% among those with obesity. Among children, the corresponding figures were 0.1%, 0.2%, and 0.7%.

Putting adults and children with homozygous FH together, the researchers found that 29.0% of patients with normal weight had coronary artery disease, compared with 31.3% of those with overweight and 49.3% of those with obesity.

Moreover, the results showed that levels of LDL and remnant cholesterol were significantly associated with BMI in adults and children with heterozygous FH, even after adjusting for age, sex, and lipid-lowering medication (P < .001 for all).

Multivariate analysis that took into account age, sex, lipid-lowering medication, and LDL cholesterol revealed that having obesity, compared with not having obesity, was associated with a substantial increase in the risk of coronary artery disease among patients with heterozygous FH.

Among adults with the condition, the odds ratio was 2.16 (95% confidence interval, 1.97-2.36), while among children and adolescents, it was 6.87 (95% CI, 1.55-30.46).

The results remained similar after further adjustment for the presence of diabetes and when considering peripheral artery disease and stroke.

No funding for the study was declared. Dr. Elshorbagy has relationships with Amgen, Daiichi Sankyo, and Regeneron.

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

MANNHEIM, GERMANY – Contrary to expectations, individuals with familial hypercholesterolemia (FH) have rates of overweight and obesity that mirror the general population – rates that appear to have a substantial impact on these patients’ already increased risk of coronary artery disease, a registry analysis suggests.

Data on almost 36,000 individuals with FH were collated from an international registry, revealing that 55% of adults and 25% of children and adolescents with the homozygous form of FH had overweight or obesity. The figures for heterozygous FH were 52% and 27%, respectively.

Crucially, overweight or obesity was associated with substantially increased rates of coronary artery disease, particularly in persons with heterozygous FH, among whom adults with obesity faced a twofold increased risk, rising to more than sixfold in children and adolescents.

Moreover, “obesity is associated with a worse lipid profile, even from childhood, regardless of whether a patient is on medication,” said study presenter Amany Elshorbagy, DPhil, Cardiovascular Epidemiologist, department of primary care and public health, Imperial College London.

She added that, with the increased risk of coronary artery disease associated with heterozygous FH, the results showed that “together with lipid-lowering medication, weight management is needed.”

The research was presented at the annual meeting of the European Atherosclerosis Society.
 

Tended to be thin

Alberico L. Catapano, MD, PhD, director of cardiovascular research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, and past president of the EAS, said in an interview that, historically, few FH patients were overweight or obese; rather, they tended to be thin.

However, there is now “a trend for people with FH to show more diabetes and obesity,” with the “bottom line” being that, as they are already at increased risk of coronary artery disease, it pushes their risk up even further.

In other words, if a risk factor such as obesity is added “on top of the strongest risk factor, that is LDL cholesterol, it is not one plus one makes two, it is one plus one makes three,” he said.

As such, Dr. Catapano believes that the study is “very interesting,” because it further underlines the importance of weight management for individuals with increased LDL cholesterol, “especially when you have genetic forms, like FH.”

Dr. Catapano’s comments were echoed by session co-chair Ulrike Schatz, MD, leader of the lipidology specialty department at the University Hospital Carl Gustav Carus, Technical University of Dresden (Germany).

Indeed, she told Dr. Elshorbagy before her presentation that she finds “a lot of my FH patients have a tendency towards anorexia.”

In an interview, Dr. Elshorbagy said that that reaction was typical of “most of the clinicians” she had spoken to. Upon seeing her data, especially for homozygous FH patients, they say, “They are on the lean side.”

Consequently, the research team went into the study “with the expectation that they might have a lower prevalence of obesity and overweight than the general population,” but “that’s not what we’re seeing.”

Dr. Elshorbagy noted that it would be helpful to have longitudinal data to determine whether, 50 years ago, patients with HF “were leaner, along with the rest of the population.”

The registry data are cross-sectional, and the team is now reaching out to the respective national lead investigators to submit follow-up data on their patients, with the aim of looking at changes in body weight and the impact on outcomes over time.

Another key question for the researchers is in regard to fat distribution, as body mass index “is not the best predictor of heart disease,” Dr. Elshorbagy said, but is rather central obesity.

Although they have also asked investigators to share waist circumference data, she conceded that it is a measurement that “is a lot harder to standardize across centers and countries; it’s not like putting patients on a scale.”

Overall, Dr. Elshorbagy believes that her findings indicate that clinicians should take a broader, more holistic approach toward their patients – in other words, an approach in which lipid lowering medication is “key but is just one of several things we need to do to make sure the coronary event rate goes down.”
 

More with than without

Dr. Elshorbagy began her presentation by highlighting that the prevalence of overweight and obesity ranges from 50% to 70% and that it is “the only health condition where you’ve got more people worldwide with the condition than without.”

Crucially, overweight increases the risk of coronary artery disease by approximately 20%. Among patients with obesity, the risk rises to 50%.

Given that FH patients “already have a very high risk of cardiovascular disease from their high cholesterol levels,” the team set out to determine rates of obesity and overweight in this population and their impact on coronary artery disease risk.

They used cross-sectional data from the EAS FH Studies Collaboration Global Registry, which involves 29,262 adults aged greater than or equal to 18 years and 6,275 children and adolescents aged 5 to 17 years with heterozygous FH, and 325 adults and 57 children with homozygous FH.

Dividing the adults into standard BMI categories, they found that 16% of heterozygous and 23% of homozygous FH patients had obesity, while 52% and 55%, respectively, had overweight or obesity.

For children, the team used World Health Organization z score cutoffs, which indicated that 9% of patients with heterozygous FH and 7% of patients with homozygous FH had obesity. Rates of overweight or obesity were 27% and 25%, respectively.

Among patients with heterozygous FH, rates of overweight or obesity among adults were 50% in high-income countries and 63% in other countries; among children, the rates were and 27% and 29%, respectively.

Stratified by region, the team found that the lowest rate of overweight or obesity among adult patients with heterozygous FH was in Eastern Asia, at 27%, while the highest was in Northern Africa/Western Asia (the Middle East), at 82%.

In North America, 56% of adult patients had overweight or obesity. The prevalence of coronary artery disease rose with increasing BMI.

Among adult patients with heterozygous FH, 11.3% of those with normal weight had coronary artery disease; the percentage rose to 22.9% among those with overweight, and 30.9% among those with obesity. Among children, the corresponding figures were 0.1%, 0.2%, and 0.7%.

Putting adults and children with homozygous FH together, the researchers found that 29.0% of patients with normal weight had coronary artery disease, compared with 31.3% of those with overweight and 49.3% of those with obesity.

Moreover, the results showed that levels of LDL and remnant cholesterol were significantly associated with BMI in adults and children with heterozygous FH, even after adjusting for age, sex, and lipid-lowering medication (P < .001 for all).

Multivariate analysis that took into account age, sex, lipid-lowering medication, and LDL cholesterol revealed that having obesity, compared with not having obesity, was associated with a substantial increase in the risk of coronary artery disease among patients with heterozygous FH.

Among adults with the condition, the odds ratio was 2.16 (95% confidence interval, 1.97-2.36), while among children and adolescents, it was 6.87 (95% CI, 1.55-30.46).

The results remained similar after further adjustment for the presence of diabetes and when considering peripheral artery disease and stroke.

No funding for the study was declared. Dr. Elshorbagy has relationships with Amgen, Daiichi Sankyo, and Regeneron.

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

MUNICH, GERMANY – Anticoagulation using apixaban (Eliquis) offers no benefit over aspirin in patients with embolic stroke of undetermined source (ESUS) who have atrial cardiopathy but no overt atrial fibrillation, suggest findings from the ARCADIA trial.

The trial, which was halted early, randomized more than 1,000 ESUS patients with atrial cardiomyopathy to apixaban or placebo. Results showed that apixaban did not improve rates of recurrent stroke of any kind nor safety outcomes such as major hemorrhage and all-cause mortality.

The results were presented at the annual meeting of the European Stroke Organisation Conference.

“We found no benefit of apixaban over aspirin in patients with ESUS who had evidence of atrial cardiopathy, at least based on the criteria in our trial,” said study presenter Hooman Kamel, MD, MS, vice chair for research and chief of neurocritical care in the department of neurology, Weill Cornell Medicine, New York.

“It could be that this concept of thrombogenic atrial cardiopathy really isn’t present unless there is also atrial fibrillation,” he continued, suggesting alternatively that results may be caused by the “incorrect choice of atrial cardiopathy biomarkers or thresholds.”

“We chose these because they were clinically scalable and usable in a multicenter design,” Dr. Kamel explained, adding that there are a number of different proposed biomarkers that could be used in a future study.

The team will now perform secondary analyses over the coming months to “try to help sort out some of these potential explanations.”

Dr. Kamel concluded, however, that, “as of now, no strategy of anticoagulation has been found to be better than antiplatelet therapy for secondary stroke prevention after ESUS.”
 

Similar results

Approached for comment, session cochair Robin Lemmens, MD, PhD, a neurologist in the department of neurosciences, UZ Leuven (Belgium), noted that this is the third ESUS trial, after the NAVIGATE and RE-SPECT trials, and they have all showed “similar results.”

He said, however, that there “could be various reasons for that, and it’s good that they mentioned looking into the subgroups,” as has been done for those other studies.

“Most of these trials were initiated under the concept that most of these patients would have had underlying atrial fibrillation, and then of course there would have been a benefit for anticoagulation.”

“It turns out that that’s not the case,” Dr. Lemmens said, “probably because there’s a lot of heterogeneity in these patients,” with different reasons for developing stroke, “not just only potentially underlying atrial fibrillation.”

Session cochair Arthur Liesz, MD, PhD, Institute for Stroke and Dementia Research, University Hospital, LMU Munich, added that it is important to consider the definition of atrial cardiopathy in this context.

If this was limited only to structural cardiopathy, then this “was a rather small subpopulation in this study,” he said in an interview.

Dr. Liesz said that it could instead have been conducted with “more stringent cutoffs,” and could have considered blood biomarkers, “which then would have delivered more overlap with structural cardiopathy,” and allowed those patients to be analyzed separately.
 

Heterogeneous etiologies?

Dr. Kamel began by noting that the failure of NAVIGATE and RESPECT to show a benefit from anticoagulation in the prevention of recurrent stroke in patients with ESUS led to the hypothesis that this is “perhaps due to heterogeneous underlying etiologies.”

Moreover, these etiologies “may require different types of antithrombotic therapy to best prevent recurrence, and one such underlying etiology may be atrial cardiopathy.”

He explained that several observational studies have found, in the absence of atrial fibrillation, associations between stroke and different markers of atrial cardiopathy and, “given the proven benefit of anticoagulation in preventing strokes in patients with atrial fibrillation, it seems plausible” that they may also benefit.

To investigate further, the team conducted ARCADIA, an investigator-initiated, multicenter, randomized trial involving patients aged 45 years and older from 185 sites in the United States and Canada with a clinical diagnosis of stroke that met the consensus criteria for ESUS.

They also were required to have undergone brain imaging to rule out hemorrhagic stroke, and to have a modified Rankin Scale score of 4 or less, indicating up to a moderately severe degree of disability.

They also had atrial cardiopathy, as determined by P-wave terminal force in V1 greater than 5,000mcV*ms on electrocardiography, serum N-terminal prohormone of brain natriuretic peptide levels greater than 250 pg/mL, or a left atrium diameter of at least 3 cm/m².

The patients were randomly assigned to apixaban 5 mg or 2.5 mg twice daily plus aspirin placebo, or apixaban placebo plus aspirin 81 mg daily. Those diagnosed with atrial fibrillation after randomization crossed over to open-label anticoagulant therapy at physician discretion.

Dr. Kamel reported that, in 2022, after enrollment of 1015 patients with a mean follow-up of 1.8 years, the trial was halted at the planned interim efficacy/futility analysis, adding that there were “no safety concerns.”

The apixaban and aspirin groups were well balanced in terms of their baseline characteristics. The mean age was 68 years, and 54% were female. Three-quarters of the participants were White; 21.1% were Black.

Prior stroke was reported in 19% of patients. Hypertension was common, in about 77%, and type 2 diabetes was seen in 31%. There were relatively few cases of ischemic heart disease, heart failure, and peripheral arterial disease.

The primary efficacy outcome of recurrent stroke of any type occurred in 4.4% of both patients treated with apixaban and those given aspirin, at a hazard ratio of 1.00 (95% confidence interval, 0.64-1.55). Similar findings were seen when looking individually at ischemic and hemorrhagic stroke, and stroke of undetermined type.

There was also no significant difference in the secondary outcomes of recurrent ischemic stroke or systemic embolism, at 4.1% versus 4.4% (HR, 0.92; 95% CI, 0.59-1.44), and recurrent stroke of any type or death from any cause, at 7.3% versus 6.8% (HR, 1.08; 95% CI, 0.76-1.52).

In terms of safety, rates of major hemorrhage were low and almost identical between the groups, at 0.7% with apixaban and 0.8% for aspirin (HR, 1.02; 95% CI, 0.29-3.51), and were similar for all-cause mortality, at 1.8% versus 1.2% (HR, 1.53; 95% CI, 0.63-3.74).

Proportionately more patients treated with aspirin experienced symptomatic intracranial hemorrhage, at 1.1% versus 0%.

The trial results generated a flurry of interest on Twitter.

Thomas Ford, MD, a vascular neurology fellow from Boston Medical Center, described the results as “disappointing,” although he was “curious to see if there was any signal of benefit in subgroup analyses.”

Shadi Yaghi, codirector of the Comprehensive Stroke Center at Brown University, Providence, R.I., added that the trial “begs the question [as to] whether all device-detected atrial fibrillation warrants anticoagulation.”

Replying, Mitchell Elkind, MD, MPhil, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said that he agrees with this interpretation.

“Maybe the issue is not with the concept of atrial cardiopathy but with the need to [anticoagulate] all patients with low [atrial fibrillation] burden or incidental [atrial fibrillation] after stroke.”

The study was funded by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. The study drug was provided in kind by BMS-Pfizer, and ancillary funding for the NTproBNP assays was provided by Roche. No relevant financial relationships were reported.

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

MUNICH, GERMANY – Anticoagulation using apixaban (Eliquis) offers no benefit over aspirin in patients with embolic stroke of undetermined source (ESUS) who have atrial cardiopathy but no overt atrial fibrillation, suggest findings from the ARCADIA trial.

The trial, which was halted early, randomized more than 1,000 ESUS patients with atrial cardiomyopathy to apixaban or placebo. Results showed that apixaban did not improve rates of recurrent stroke of any kind nor safety outcomes such as major hemorrhage and all-cause mortality.

The results were presented at the annual meeting of the European Stroke Organisation Conference.

“We found no benefit of apixaban over aspirin in patients with ESUS who had evidence of atrial cardiopathy, at least based on the criteria in our trial,” said study presenter Hooman Kamel, MD, MS, vice chair for research and chief of neurocritical care in the department of neurology, Weill Cornell Medicine, New York.

“It could be that this concept of thrombogenic atrial cardiopathy really isn’t present unless there is also atrial fibrillation,” he continued, suggesting alternatively that results may be caused by the “incorrect choice of atrial cardiopathy biomarkers or thresholds.”

“We chose these because they were clinically scalable and usable in a multicenter design,” Dr. Kamel explained, adding that there are a number of different proposed biomarkers that could be used in a future study.

The team will now perform secondary analyses over the coming months to “try to help sort out some of these potential explanations.”

Dr. Kamel concluded, however, that, “as of now, no strategy of anticoagulation has been found to be better than antiplatelet therapy for secondary stroke prevention after ESUS.”
 

Similar results

Approached for comment, session cochair Robin Lemmens, MD, PhD, a neurologist in the department of neurosciences, UZ Leuven (Belgium), noted that this is the third ESUS trial, after the NAVIGATE and RE-SPECT trials, and they have all showed “similar results.”

He said, however, that there “could be various reasons for that, and it’s good that they mentioned looking into the subgroups,” as has been done for those other studies.

“Most of these trials were initiated under the concept that most of these patients would have had underlying atrial fibrillation, and then of course there would have been a benefit for anticoagulation.”

“It turns out that that’s not the case,” Dr. Lemmens said, “probably because there’s a lot of heterogeneity in these patients,” with different reasons for developing stroke, “not just only potentially underlying atrial fibrillation.”

Session cochair Arthur Liesz, MD, PhD, Institute for Stroke and Dementia Research, University Hospital, LMU Munich, added that it is important to consider the definition of atrial cardiopathy in this context.

If this was limited only to structural cardiopathy, then this “was a rather small subpopulation in this study,” he said in an interview.

Dr. Liesz said that it could instead have been conducted with “more stringent cutoffs,” and could have considered blood biomarkers, “which then would have delivered more overlap with structural cardiopathy,” and allowed those patients to be analyzed separately.
 

Heterogeneous etiologies?

Dr. Kamel began by noting that the failure of NAVIGATE and RESPECT to show a benefit from anticoagulation in the prevention of recurrent stroke in patients with ESUS led to the hypothesis that this is “perhaps due to heterogeneous underlying etiologies.”

Moreover, these etiologies “may require different types of antithrombotic therapy to best prevent recurrence, and one such underlying etiology may be atrial cardiopathy.”

He explained that several observational studies have found, in the absence of atrial fibrillation, associations between stroke and different markers of atrial cardiopathy and, “given the proven benefit of anticoagulation in preventing strokes in patients with atrial fibrillation, it seems plausible” that they may also benefit.

To investigate further, the team conducted ARCADIA, an investigator-initiated, multicenter, randomized trial involving patients aged 45 years and older from 185 sites in the United States and Canada with a clinical diagnosis of stroke that met the consensus criteria for ESUS.

They also were required to have undergone brain imaging to rule out hemorrhagic stroke, and to have a modified Rankin Scale score of 4 or less, indicating up to a moderately severe degree of disability.

They also had atrial cardiopathy, as determined by P-wave terminal force in V1 greater than 5,000mcV*ms on electrocardiography, serum N-terminal prohormone of brain natriuretic peptide levels greater than 250 pg/mL, or a left atrium diameter of at least 3 cm/m².

The patients were randomly assigned to apixaban 5 mg or 2.5 mg twice daily plus aspirin placebo, or apixaban placebo plus aspirin 81 mg daily. Those diagnosed with atrial fibrillation after randomization crossed over to open-label anticoagulant therapy at physician discretion.

Dr. Kamel reported that, in 2022, after enrollment of 1015 patients with a mean follow-up of 1.8 years, the trial was halted at the planned interim efficacy/futility analysis, adding that there were “no safety concerns.”

The apixaban and aspirin groups were well balanced in terms of their baseline characteristics. The mean age was 68 years, and 54% were female. Three-quarters of the participants were White; 21.1% were Black.

Prior stroke was reported in 19% of patients. Hypertension was common, in about 77%, and type 2 diabetes was seen in 31%. There were relatively few cases of ischemic heart disease, heart failure, and peripheral arterial disease.

The primary efficacy outcome of recurrent stroke of any type occurred in 4.4% of both patients treated with apixaban and those given aspirin, at a hazard ratio of 1.00 (95% confidence interval, 0.64-1.55). Similar findings were seen when looking individually at ischemic and hemorrhagic stroke, and stroke of undetermined type.

There was also no significant difference in the secondary outcomes of recurrent ischemic stroke or systemic embolism, at 4.1% versus 4.4% (HR, 0.92; 95% CI, 0.59-1.44), and recurrent stroke of any type or death from any cause, at 7.3% versus 6.8% (HR, 1.08; 95% CI, 0.76-1.52).

In terms of safety, rates of major hemorrhage were low and almost identical between the groups, at 0.7% with apixaban and 0.8% for aspirin (HR, 1.02; 95% CI, 0.29-3.51), and were similar for all-cause mortality, at 1.8% versus 1.2% (HR, 1.53; 95% CI, 0.63-3.74).

Proportionately more patients treated with aspirin experienced symptomatic intracranial hemorrhage, at 1.1% versus 0%.

The trial results generated a flurry of interest on Twitter.

Thomas Ford, MD, a vascular neurology fellow from Boston Medical Center, described the results as “disappointing,” although he was “curious to see if there was any signal of benefit in subgroup analyses.”

Shadi Yaghi, codirector of the Comprehensive Stroke Center at Brown University, Providence, R.I., added that the trial “begs the question [as to] whether all device-detected atrial fibrillation warrants anticoagulation.”

Replying, Mitchell Elkind, MD, MPhil, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said that he agrees with this interpretation.

“Maybe the issue is not with the concept of atrial cardiopathy but with the need to [anticoagulate] all patients with low [atrial fibrillation] burden or incidental [atrial fibrillation] after stroke.”

The study was funded by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. The study drug was provided in kind by BMS-Pfizer, and ancillary funding for the NTproBNP assays was provided by Roche. No relevant financial relationships were reported.

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

MUNICH, GERMANY – Anticoagulation using apixaban (Eliquis) offers no benefit over aspirin in patients with embolic stroke of undetermined source (ESUS) who have atrial cardiopathy but no overt atrial fibrillation, suggest findings from the ARCADIA trial.

The trial, which was halted early, randomized more than 1,000 ESUS patients with atrial cardiomyopathy to apixaban or placebo. Results showed that apixaban did not improve rates of recurrent stroke of any kind nor safety outcomes such as major hemorrhage and all-cause mortality.

The results were presented at the annual meeting of the European Stroke Organisation Conference.

“We found no benefit of apixaban over aspirin in patients with ESUS who had evidence of atrial cardiopathy, at least based on the criteria in our trial,” said study presenter Hooman Kamel, MD, MS, vice chair for research and chief of neurocritical care in the department of neurology, Weill Cornell Medicine, New York.

“It could be that this concept of thrombogenic atrial cardiopathy really isn’t present unless there is also atrial fibrillation,” he continued, suggesting alternatively that results may be caused by the “incorrect choice of atrial cardiopathy biomarkers or thresholds.”

“We chose these because they were clinically scalable and usable in a multicenter design,” Dr. Kamel explained, adding that there are a number of different proposed biomarkers that could be used in a future study.

The team will now perform secondary analyses over the coming months to “try to help sort out some of these potential explanations.”

Dr. Kamel concluded, however, that, “as of now, no strategy of anticoagulation has been found to be better than antiplatelet therapy for secondary stroke prevention after ESUS.”
 

Similar results

Approached for comment, session cochair Robin Lemmens, MD, PhD, a neurologist in the department of neurosciences, UZ Leuven (Belgium), noted that this is the third ESUS trial, after the NAVIGATE and RE-SPECT trials, and they have all showed “similar results.”

He said, however, that there “could be various reasons for that, and it’s good that they mentioned looking into the subgroups,” as has been done for those other studies.

“Most of these trials were initiated under the concept that most of these patients would have had underlying atrial fibrillation, and then of course there would have been a benefit for anticoagulation.”

“It turns out that that’s not the case,” Dr. Lemmens said, “probably because there’s a lot of heterogeneity in these patients,” with different reasons for developing stroke, “not just only potentially underlying atrial fibrillation.”

Session cochair Arthur Liesz, MD, PhD, Institute for Stroke and Dementia Research, University Hospital, LMU Munich, added that it is important to consider the definition of atrial cardiopathy in this context.

If this was limited only to structural cardiopathy, then this “was a rather small subpopulation in this study,” he said in an interview.

Dr. Liesz said that it could instead have been conducted with “more stringent cutoffs,” and could have considered blood biomarkers, “which then would have delivered more overlap with structural cardiopathy,” and allowed those patients to be analyzed separately.
 

Heterogeneous etiologies?

Dr. Kamel began by noting that the failure of NAVIGATE and RESPECT to show a benefit from anticoagulation in the prevention of recurrent stroke in patients with ESUS led to the hypothesis that this is “perhaps due to heterogeneous underlying etiologies.”

Moreover, these etiologies “may require different types of antithrombotic therapy to best prevent recurrence, and one such underlying etiology may be atrial cardiopathy.”

He explained that several observational studies have found, in the absence of atrial fibrillation, associations between stroke and different markers of atrial cardiopathy and, “given the proven benefit of anticoagulation in preventing strokes in patients with atrial fibrillation, it seems plausible” that they may also benefit.

To investigate further, the team conducted ARCADIA, an investigator-initiated, multicenter, randomized trial involving patients aged 45 years and older from 185 sites in the United States and Canada with a clinical diagnosis of stroke that met the consensus criteria for ESUS.

They also were required to have undergone brain imaging to rule out hemorrhagic stroke, and to have a modified Rankin Scale score of 4 or less, indicating up to a moderately severe degree of disability.

They also had atrial cardiopathy, as determined by P-wave terminal force in V1 greater than 5,000mcV*ms on electrocardiography, serum N-terminal prohormone of brain natriuretic peptide levels greater than 250 pg/mL, or a left atrium diameter of at least 3 cm/m².

The patients were randomly assigned to apixaban 5 mg or 2.5 mg twice daily plus aspirin placebo, or apixaban placebo plus aspirin 81 mg daily. Those diagnosed with atrial fibrillation after randomization crossed over to open-label anticoagulant therapy at physician discretion.

Dr. Kamel reported that, in 2022, after enrollment of 1015 patients with a mean follow-up of 1.8 years, the trial was halted at the planned interim efficacy/futility analysis, adding that there were “no safety concerns.”

The apixaban and aspirin groups were well balanced in terms of their baseline characteristics. The mean age was 68 years, and 54% were female. Three-quarters of the participants were White; 21.1% were Black.

Prior stroke was reported in 19% of patients. Hypertension was common, in about 77%, and type 2 diabetes was seen in 31%. There were relatively few cases of ischemic heart disease, heart failure, and peripheral arterial disease.

The primary efficacy outcome of recurrent stroke of any type occurred in 4.4% of both patients treated with apixaban and those given aspirin, at a hazard ratio of 1.00 (95% confidence interval, 0.64-1.55). Similar findings were seen when looking individually at ischemic and hemorrhagic stroke, and stroke of undetermined type.

There was also no significant difference in the secondary outcomes of recurrent ischemic stroke or systemic embolism, at 4.1% versus 4.4% (HR, 0.92; 95% CI, 0.59-1.44), and recurrent stroke of any type or death from any cause, at 7.3% versus 6.8% (HR, 1.08; 95% CI, 0.76-1.52).

In terms of safety, rates of major hemorrhage were low and almost identical between the groups, at 0.7% with apixaban and 0.8% for aspirin (HR, 1.02; 95% CI, 0.29-3.51), and were similar for all-cause mortality, at 1.8% versus 1.2% (HR, 1.53; 95% CI, 0.63-3.74).

Proportionately more patients treated with aspirin experienced symptomatic intracranial hemorrhage, at 1.1% versus 0%.

The trial results generated a flurry of interest on Twitter.

Thomas Ford, MD, a vascular neurology fellow from Boston Medical Center, described the results as “disappointing,” although he was “curious to see if there was any signal of benefit in subgroup analyses.”

Shadi Yaghi, codirector of the Comprehensive Stroke Center at Brown University, Providence, R.I., added that the trial “begs the question [as to] whether all device-detected atrial fibrillation warrants anticoagulation.”

Replying, Mitchell Elkind, MD, MPhil, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said that he agrees with this interpretation.

“Maybe the issue is not with the concept of atrial cardiopathy but with the need to [anticoagulate] all patients with low [atrial fibrillation] burden or incidental [atrial fibrillation] after stroke.”

The study was funded by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. The study drug was provided in kind by BMS-Pfizer, and ancillary funding for the NTproBNP assays was provided by Roche. No relevant financial relationships were reported.

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

MUNICH – Adding carotid revascularization to optimized medical therapy (OMT) does not appear to offer a clinical benefit in patients with significant carotid stenosis and a low to intermediate 5-year risk of stroke, suggests a planned interim analysis of ECST-2.

Almost 430 patients with symptomatic and asymptomatic atherosclerotic carotid stenosis greater than or equal to 50% and a Carotid Artery Risk (CAR) score less than 20% were randomly assigned to OMT alone or OMT plus revascularization with carotid endarterectomy (CEA) or carotid artery stenting.

The study, which was presented at the annual European Stroke Organisation Conference, was stopped early because of slow recruitment.

Nevertheless, the current results showed that there was no significant difference at 2 years between the treatment groups in the rate of a composite endpoint, as well as the occurrence of any stroke, myocardial infarction, and periprocedural death.

In other words, “there was no evidence of benefit at 2 years from additional carotid revascularization” in patients with carotid stenosis who had a low to intermediate predicted stroke risk, said study presenter Paul Nederkoorn, MD, PhD, department of neurology, Amsterdam UMC, University of Amsterdam.

He added, however, that the complete 2 years will include additional analyses, including an analysis of silent infarcts on MRI, which may affect the results, and that longer clinical follow-up is required.

Future work will include the design and validation of a novel stroke risk prediction tool that will include MRI plaque imaging and will allow individualized patient selection for revascularization, as well as a cost-effectiveness analysis, he noted.
 

Conclusions ‘difficult’

Session co-chair Peter Kelly, MD, professor of neurology at Mater University Hospital/University College Dublin, and president-elect of the European Stroke Association, described the findings as “interesting” and that it was “great to see them.”

“I’m sure we’ll be discussing these results for a while,” he added.

But co-chair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the Stroke Unit, department of neurology, Oslo University Hospital, said that it’s “difficult to draw firm conclusions from the trial.”

The patients were highly selected, recruitment was “perhaps a bit too slow,” and the study was probably conducted over too many sites, she said in an interview.

Dr. Sandset also noted that the options available for OMT have changed over the course of the study, as well as the overall approach to management.

“We are more aware of how we should treat” these patients, and “we’re probably a bit more aggressive,” which will have shifted the outcomes in the comparator arm as the study progressed.

“That is the challenge of doing these trials that take many years to run – our practice changes.”
 

‘Old evidence’

In his presentation, Dr. Nederkoorn pointed out that, while the current guidelines for CEA are “robust,” they are based on “old evidence” from trials conducted 20-30 years ago.

During that time, he said, medical treatment has improved significantly, and the risk for stroke has approximately halved. Yet the decision to perform CEA is still largely based on the degree of stenosis and the patient’s symptom status.

Dr. Nederkoorn suggested, however, that factors such as plaque ulceration and patient characteristics and comorbidities might influence the risk-benefit ratio for revascularization.

The current trial was therefore established to test the hypothesis that patients with carotid stenosis greater than or equal to 50% and a low to intermediate risk of stroke will not benefit from additional carotid revascularization on top of optimized medical therapy.

The team conducted a prospective, multicenter, open clinical trial in which patients with both symptomatic and asymptomatic atherosclerotic carotid stenosis were randomly assigned to revascularization plus OMT or OMT alone.

Dr. Nederkoorn explained that a low to intermediate 5-year risk for stroke was established using the CAR score less than 20%.

This is based on a range of parameters, including the sex and age of the patient, degree of stenosis, the type of and time since the event, and the presence of comorbidities, among other factors.

He said that the data was originally derived from the NASCET trial, which was published in 1998, and the first ECST trial, published in the same year.

Since then, the risk of ipsilateral stroke has “strongly declined,” Dr. Nederkoorn said, and so the CAR score was recalibrated to reflect the likely benefit of current OMT.

For the trial, OMT included antihypertensive and cholesterol-lowering medications, and dietary changes, alongside antiplatelet agents and anticoagulation, if indicated, to achieve predefined, guideline-led lipid and blood pressure targets.

Revascularization included CEA and coronary artery stenting in selected patients and was recommended to be performed within 2 weeks of randomization in symptomatic patients and within 4 weeks in asymptomatic patients.

When the trial started in 2012, the intention was to recruit 2,000 patients, with a planned interim analysis after enrollment of 320 patients.

However, recruitment was suspended in 2019, with 429 patients having been enrolled, as it was clear that achieving a cohort of 2,000 patients was “not practical without a change in the trial design” to include MRI plaque imaging and without further funding.

Dr. Nederkoorn showed that the baseline characteristics of the OMT and revascularization plus OMT groups were comparable. The average age of the patients in the groups was 71-72 years, and 31% were female.

Symptomatic disease was present in about 40% of patients, and about 76% had hypertension. Type 2 diabetes was reported in roughly one-quarter of the patients.

There was no difference in the time from randomization to the revascularization procedure between patients with asymptomatic and symptomatic disease.

Moving to the primary outcome, which was a composite of periprocedural death within 90 days of randomization and clinically manifest stroke or myocardial infarction at 2 years, Dr. Nederkoorn showed that there was no significant difference between the treatment groups.

Despite a suggestion that patients undergoing revascularization experienced “more harm” in the initial follow-up period, particularly in patients with a CAR score greater than 10%, the event curves met at around 18 months.

Overall, the hazard ratio between revascularization plus OMT versus OMT alone was 0.96 (95% confidence interval, 0.53-1.76, P = .90).

Breaking down the composite endpoint, there was a numerically lower rate of any stroke with OMT alone, compared with revascularization plus OMT over the study period, but again the difference was not significant at 2 years, at a hazard ratio of 0.68 (95% CI, 0.32-1.42, P = .30).

There was only one case of periprocedural death, in the revascularization arm. Although myocardial infarction was numerically twice as likely with OMT alone, compared with the combined intervention arm, the difference was not significant, at a hazard ratio of 2.00 (95% CI, 0.68-5.84, P = .21).

The study was funded by the National Institute for Health and Care Research, the Swiss National Science Foundation, The Netherlands Organisation of Scientific Research, and the Leeds Neurology Foundation. No relevant financial relationships were declared.

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

MUNICH – Adding carotid revascularization to optimized medical therapy (OMT) does not appear to offer a clinical benefit in patients with significant carotid stenosis and a low to intermediate 5-year risk of stroke, suggests a planned interim analysis of ECST-2.

Almost 430 patients with symptomatic and asymptomatic atherosclerotic carotid stenosis greater than or equal to 50% and a Carotid Artery Risk (CAR) score less than 20% were randomly assigned to OMT alone or OMT plus revascularization with carotid endarterectomy (CEA) or carotid artery stenting.

The study, which was presented at the annual European Stroke Organisation Conference, was stopped early because of slow recruitment.

Nevertheless, the current results showed that there was no significant difference at 2 years between the treatment groups in the rate of a composite endpoint, as well as the occurrence of any stroke, myocardial infarction, and periprocedural death.

In other words, “there was no evidence of benefit at 2 years from additional carotid revascularization” in patients with carotid stenosis who had a low to intermediate predicted stroke risk, said study presenter Paul Nederkoorn, MD, PhD, department of neurology, Amsterdam UMC, University of Amsterdam.

He added, however, that the complete 2 years will include additional analyses, including an analysis of silent infarcts on MRI, which may affect the results, and that longer clinical follow-up is required.

Future work will include the design and validation of a novel stroke risk prediction tool that will include MRI plaque imaging and will allow individualized patient selection for revascularization, as well as a cost-effectiveness analysis, he noted.
 

Conclusions ‘difficult’

Session co-chair Peter Kelly, MD, professor of neurology at Mater University Hospital/University College Dublin, and president-elect of the European Stroke Association, described the findings as “interesting” and that it was “great to see them.”

“I’m sure we’ll be discussing these results for a while,” he added.

But co-chair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the Stroke Unit, department of neurology, Oslo University Hospital, said that it’s “difficult to draw firm conclusions from the trial.”

The patients were highly selected, recruitment was “perhaps a bit too slow,” and the study was probably conducted over too many sites, she said in an interview.

Dr. Sandset also noted that the options available for OMT have changed over the course of the study, as well as the overall approach to management.

“We are more aware of how we should treat” these patients, and “we’re probably a bit more aggressive,” which will have shifted the outcomes in the comparator arm as the study progressed.

“That is the challenge of doing these trials that take many years to run – our practice changes.”
 

‘Old evidence’

In his presentation, Dr. Nederkoorn pointed out that, while the current guidelines for CEA are “robust,” they are based on “old evidence” from trials conducted 20-30 years ago.

During that time, he said, medical treatment has improved significantly, and the risk for stroke has approximately halved. Yet the decision to perform CEA is still largely based on the degree of stenosis and the patient’s symptom status.

Dr. Nederkoorn suggested, however, that factors such as plaque ulceration and patient characteristics and comorbidities might influence the risk-benefit ratio for revascularization.

The current trial was therefore established to test the hypothesis that patients with carotid stenosis greater than or equal to 50% and a low to intermediate risk of stroke will not benefit from additional carotid revascularization on top of optimized medical therapy.

The team conducted a prospective, multicenter, open clinical trial in which patients with both symptomatic and asymptomatic atherosclerotic carotid stenosis were randomly assigned to revascularization plus OMT or OMT alone.

Dr. Nederkoorn explained that a low to intermediate 5-year risk for stroke was established using the CAR score less than 20%.

This is based on a range of parameters, including the sex and age of the patient, degree of stenosis, the type of and time since the event, and the presence of comorbidities, among other factors.

He said that the data was originally derived from the NASCET trial, which was published in 1998, and the first ECST trial, published in the same year.

Since then, the risk of ipsilateral stroke has “strongly declined,” Dr. Nederkoorn said, and so the CAR score was recalibrated to reflect the likely benefit of current OMT.

For the trial, OMT included antihypertensive and cholesterol-lowering medications, and dietary changes, alongside antiplatelet agents and anticoagulation, if indicated, to achieve predefined, guideline-led lipid and blood pressure targets.

Revascularization included CEA and coronary artery stenting in selected patients and was recommended to be performed within 2 weeks of randomization in symptomatic patients and within 4 weeks in asymptomatic patients.

When the trial started in 2012, the intention was to recruit 2,000 patients, with a planned interim analysis after enrollment of 320 patients.

However, recruitment was suspended in 2019, with 429 patients having been enrolled, as it was clear that achieving a cohort of 2,000 patients was “not practical without a change in the trial design” to include MRI plaque imaging and without further funding.

Dr. Nederkoorn showed that the baseline characteristics of the OMT and revascularization plus OMT groups were comparable. The average age of the patients in the groups was 71-72 years, and 31% were female.

Symptomatic disease was present in about 40% of patients, and about 76% had hypertension. Type 2 diabetes was reported in roughly one-quarter of the patients.

There was no difference in the time from randomization to the revascularization procedure between patients with asymptomatic and symptomatic disease.

Moving to the primary outcome, which was a composite of periprocedural death within 90 days of randomization and clinically manifest stroke or myocardial infarction at 2 years, Dr. Nederkoorn showed that there was no significant difference between the treatment groups.

Despite a suggestion that patients undergoing revascularization experienced “more harm” in the initial follow-up period, particularly in patients with a CAR score greater than 10%, the event curves met at around 18 months.

Overall, the hazard ratio between revascularization plus OMT versus OMT alone was 0.96 (95% confidence interval, 0.53-1.76, P = .90).

Breaking down the composite endpoint, there was a numerically lower rate of any stroke with OMT alone, compared with revascularization plus OMT over the study period, but again the difference was not significant at 2 years, at a hazard ratio of 0.68 (95% CI, 0.32-1.42, P = .30).

There was only one case of periprocedural death, in the revascularization arm. Although myocardial infarction was numerically twice as likely with OMT alone, compared with the combined intervention arm, the difference was not significant, at a hazard ratio of 2.00 (95% CI, 0.68-5.84, P = .21).

The study was funded by the National Institute for Health and Care Research, the Swiss National Science Foundation, The Netherlands Organisation of Scientific Research, and the Leeds Neurology Foundation. No relevant financial relationships were declared.

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

MUNICH – Adding carotid revascularization to optimized medical therapy (OMT) does not appear to offer a clinical benefit in patients with significant carotid stenosis and a low to intermediate 5-year risk of stroke, suggests a planned interim analysis of ECST-2.

Almost 430 patients with symptomatic and asymptomatic atherosclerotic carotid stenosis greater than or equal to 50% and a Carotid Artery Risk (CAR) score less than 20% were randomly assigned to OMT alone or OMT plus revascularization with carotid endarterectomy (CEA) or carotid artery stenting.

The study, which was presented at the annual European Stroke Organisation Conference, was stopped early because of slow recruitment.

Nevertheless, the current results showed that there was no significant difference at 2 years between the treatment groups in the rate of a composite endpoint, as well as the occurrence of any stroke, myocardial infarction, and periprocedural death.

In other words, “there was no evidence of benefit at 2 years from additional carotid revascularization” in patients with carotid stenosis who had a low to intermediate predicted stroke risk, said study presenter Paul Nederkoorn, MD, PhD, department of neurology, Amsterdam UMC, University of Amsterdam.

He added, however, that the complete 2 years will include additional analyses, including an analysis of silent infarcts on MRI, which may affect the results, and that longer clinical follow-up is required.

Future work will include the design and validation of a novel stroke risk prediction tool that will include MRI plaque imaging and will allow individualized patient selection for revascularization, as well as a cost-effectiveness analysis, he noted.
 

Conclusions ‘difficult’

Session co-chair Peter Kelly, MD, professor of neurology at Mater University Hospital/University College Dublin, and president-elect of the European Stroke Association, described the findings as “interesting” and that it was “great to see them.”

“I’m sure we’ll be discussing these results for a while,” he added.

But co-chair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the Stroke Unit, department of neurology, Oslo University Hospital, said that it’s “difficult to draw firm conclusions from the trial.”

The patients were highly selected, recruitment was “perhaps a bit too slow,” and the study was probably conducted over too many sites, she said in an interview.

Dr. Sandset also noted that the options available for OMT have changed over the course of the study, as well as the overall approach to management.

“We are more aware of how we should treat” these patients, and “we’re probably a bit more aggressive,” which will have shifted the outcomes in the comparator arm as the study progressed.

“That is the challenge of doing these trials that take many years to run – our practice changes.”
 

‘Old evidence’

In his presentation, Dr. Nederkoorn pointed out that, while the current guidelines for CEA are “robust,” they are based on “old evidence” from trials conducted 20-30 years ago.

During that time, he said, medical treatment has improved significantly, and the risk for stroke has approximately halved. Yet the decision to perform CEA is still largely based on the degree of stenosis and the patient’s symptom status.

Dr. Nederkoorn suggested, however, that factors such as plaque ulceration and patient characteristics and comorbidities might influence the risk-benefit ratio for revascularization.

The current trial was therefore established to test the hypothesis that patients with carotid stenosis greater than or equal to 50% and a low to intermediate risk of stroke will not benefit from additional carotid revascularization on top of optimized medical therapy.

The team conducted a prospective, multicenter, open clinical trial in which patients with both symptomatic and asymptomatic atherosclerotic carotid stenosis were randomly assigned to revascularization plus OMT or OMT alone.

Dr. Nederkoorn explained that a low to intermediate 5-year risk for stroke was established using the CAR score less than 20%.

This is based on a range of parameters, including the sex and age of the patient, degree of stenosis, the type of and time since the event, and the presence of comorbidities, among other factors.

He said that the data was originally derived from the NASCET trial, which was published in 1998, and the first ECST trial, published in the same year.

Since then, the risk of ipsilateral stroke has “strongly declined,” Dr. Nederkoorn said, and so the CAR score was recalibrated to reflect the likely benefit of current OMT.

For the trial, OMT included antihypertensive and cholesterol-lowering medications, and dietary changes, alongside antiplatelet agents and anticoagulation, if indicated, to achieve predefined, guideline-led lipid and blood pressure targets.

Revascularization included CEA and coronary artery stenting in selected patients and was recommended to be performed within 2 weeks of randomization in symptomatic patients and within 4 weeks in asymptomatic patients.

When the trial started in 2012, the intention was to recruit 2,000 patients, with a planned interim analysis after enrollment of 320 patients.

However, recruitment was suspended in 2019, with 429 patients having been enrolled, as it was clear that achieving a cohort of 2,000 patients was “not practical without a change in the trial design” to include MRI plaque imaging and without further funding.

Dr. Nederkoorn showed that the baseline characteristics of the OMT and revascularization plus OMT groups were comparable. The average age of the patients in the groups was 71-72 years, and 31% were female.

Symptomatic disease was present in about 40% of patients, and about 76% had hypertension. Type 2 diabetes was reported in roughly one-quarter of the patients.

There was no difference in the time from randomization to the revascularization procedure between patients with asymptomatic and symptomatic disease.

Moving to the primary outcome, which was a composite of periprocedural death within 90 days of randomization and clinically manifest stroke or myocardial infarction at 2 years, Dr. Nederkoorn showed that there was no significant difference between the treatment groups.

Despite a suggestion that patients undergoing revascularization experienced “more harm” in the initial follow-up period, particularly in patients with a CAR score greater than 10%, the event curves met at around 18 months.

Overall, the hazard ratio between revascularization plus OMT versus OMT alone was 0.96 (95% confidence interval, 0.53-1.76, P = .90).

Breaking down the composite endpoint, there was a numerically lower rate of any stroke with OMT alone, compared with revascularization plus OMT over the study period, but again the difference was not significant at 2 years, at a hazard ratio of 0.68 (95% CI, 0.32-1.42, P = .30).

There was only one case of periprocedural death, in the revascularization arm. Although myocardial infarction was numerically twice as likely with OMT alone, compared with the combined intervention arm, the difference was not significant, at a hazard ratio of 2.00 (95% CI, 0.68-5.84, P = .21).

The study was funded by the National Institute for Health and Care Research, the Swiss National Science Foundation, The Netherlands Organisation of Scientific Research, and the Leeds Neurology Foundation. No relevant financial relationships were declared.

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

MANNHEIM, GERMANY – Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.

The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.

Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.

Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.

Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
 

Call to action

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”

He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”

Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.

“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.

“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”

He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”

“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
 

Rare genetic condition

Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”

This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.

Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.

To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.

It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.

Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.

The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.

Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.

In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.

Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”

Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.

There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.

The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.

There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.

During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.

“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.

Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”

She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.

Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.

No funding or relevant financial relationships were declared.

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

MANNHEIM, GERMANY – Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.

The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.

Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.

Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.

Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
 

Call to action

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”

He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”

Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.

“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.

“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”

He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”

“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
 

Rare genetic condition

Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”

This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.

Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.

To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.

It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.

Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.

The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.

Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.

In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.

Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”

Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.

There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.

The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.

There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.

During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.

“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.

Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”

She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.

Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.

No funding or relevant financial relationships were declared.

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

MANNHEIM, GERMANY – Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.

The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.

Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.

Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.

Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
 

Call to action

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”

He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”

Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.

“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.

“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”

He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”

“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
 

Rare genetic condition

Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”

This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.

Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.

To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.

It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.

Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.

The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.

Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.

In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.

Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”

Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.

There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.

The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.

There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.

During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.

“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.

Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”

She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.

Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.

No funding or relevant financial relationships were declared.

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

Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
 

Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.

As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.

The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.

The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m² and in those who weighed more than 80 kg (176 lb).

“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.

Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”

However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).

He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”

In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”

And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.

She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”

The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.

“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.

The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.

Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.

Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.

The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.

Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.

The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.

Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.

In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm² and the average ulcer duration was 49.8 weeks.

The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.

Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).

The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.

In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).

Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).

Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.

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

Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
 

Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.

As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.

The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.

The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m² and in those who weighed more than 80 kg (176 lb).

“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.

Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”

However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).

He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”

In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”

And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.

She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”

The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.

“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.

The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.

Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.

Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.

The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.

Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.

The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.

Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.

In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm² and the average ulcer duration was 49.8 weeks.

The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.

Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).

The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.

In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).

Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).

Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.

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

Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
 

Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.

As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.

The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.

The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m² and in those who weighed more than 80 kg (176 lb).

“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.

Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”

However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).

He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”

In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”

And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.

She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”

The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.

“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.

The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.

Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.

Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.

The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.

Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.

The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.

Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.

In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm² and the average ulcer duration was 49.8 weeks.

The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.

Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).

The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.

In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).

Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).

Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.

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

Certain relatives of women with early onset breast cancer appear to face an increased risk of other early-onset cancers, a Finnish population-based study suggests.

The researchers found, for instance, that children of breast cancer patients had a 27% higher risk of any discordant early-onset cancer, and patients’ siblings had a 7.6-fold higher risk of early pancreatic cancer. The analysis also indicated that children of patients’ siblings had a significantly increased risk of testicular and ovarian cancers.

“The findings suggest that the familial risk extends to discordant early-onset cancers, including ovarian, testicular, and pancreatic cancers, as well as beyond first-degree relatives,” the researchers, led by Janne M. Pitkäniemi, PhD, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, say. “Our findings are interesting but raise some questions about unknown [genetic] and environmental mechanisms that need to be further studied.”

Erin F. Cobain, MD, who was not involved in the research, said the findings are “not very surprising to me.”

Dr. Cobain said that at her institution, she has seen “many, many cases” of family members of early-onset breast cancer patients with discordant cancers “where we are unable to find a clear genetic cause.”

Not being able to find an identifiable cause for the clustering of early-onset cancers can be “very frustrating” for patients and their families, said Dr. Cobain, a medical oncologist at the University of Michigan Health, Ann Arbor.

The study was published online in the International Journal of Cancer.

Family members of patients with early-onset breast cancer are at elevated risk for early-onset breast cancer. However, it is “unclear whether the familial risk is limited to early-onset cancer of the same site,” the authors explained.

To investigate, the researchers studied data from the Finnish Cancer Registry and the Finnish Population System, which included 54,753 relatives from 5,562 families of females diagnosed with early-onset breast cancer, defined as probands. A proband was the first member of the family diagnosed with female breast cancer at age 40 years or younger in Finland between January 1970 and December 31, 2012. Cancers were considered familial if they occurred in a family with a previously diagnosed proband and were deemed early onset if diagnosed before age 41.

The researchers found that only 5.5% of probands’ families had a family member with a discordant early-onset cancer. The most common diagnoses were testicular cancer (0.6% of families) and cancer of the thyroid gland (also 0.6%), followed by melanoma (0.5%).

Overall, the risk of any nonbreast early-onset cancer among first-degree relatives of probands was comparable with the risk in the general population (standardized incidence ratio, 0.99; 95% confidence interval, 0.84-1.16).

However, the risk was elevated for certain family members and certain cancers.

Specifically, the children of probands had an increased risk for any discordant cancer (SIR, 1.27; 95% CI, 1.05-1.55).

The siblings of probands had an elevated risk for early-onset pancreatic cancer (SIR, 7.61) but not overall for any discordant cancer (SIR, 0.93; 95% CI, 0.68-1.25).

And siblings’ children faced an elevated risk for testicular (SIR, 1.74) and ovarian (SIR, 2.69) cancer, though not of any discordant cancer (SIR, 1.16; 95% CI, 0.97-1.37).

The researchers also found that the fathers (SIR, 0.43), mothers (SIR, 0.48), and spouses (SIR, 0.58) of probands appeared to have a decreased risk of any discordant early-onset cancer.

A potential limitation to the study was that the authors could not identify individuals with hereditary cancer syndromes or concerning gene mutations, such as BRCA carriers, because “registry data do not include comprehensive information on the gene mutation carriage status.” But the authors note that the number of BRCA carriers is likely low because of the low number of ovarian cancers observed in first-degree relatives of probands.

Dr. Cobain noted as well that the current study is potentially limited by its “very homogeneous” cohort.

But, overall, the findings indicate that familial risk is often “a much more complicated problem, mathematically and statistically,” than were there a single genetic culprit, Dr. Cobain said. One possibility is that some shared environmental exposure may be increasing the cancer risk among members of the same family.

“Genetic diversity is so vast and understanding how the interplay of multiple genes can influence an individual’s cancer risk is so much more complicated than a single BRCA1 mutation that clearly influences your breast cancer risk,” she added. However, “we’re starting to get there.”

The study was funded by the Cancer Foundation Finland and Academy of Finland. The authors and Dr. Cobain had no relevant financial relationships to declare.

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

Certain relatives of women with early onset breast cancer appear to face an increased risk of other early-onset cancers, a Finnish population-based study suggests.

The researchers found, for instance, that children of breast cancer patients had a 27% higher risk of any discordant early-onset cancer, and patients’ siblings had a 7.6-fold higher risk of early pancreatic cancer. The analysis also indicated that children of patients’ siblings had a significantly increased risk of testicular and ovarian cancers.

“The findings suggest that the familial risk extends to discordant early-onset cancers, including ovarian, testicular, and pancreatic cancers, as well as beyond first-degree relatives,” the researchers, led by Janne M. Pitkäniemi, PhD, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, say. “Our findings are interesting but raise some questions about unknown [genetic] and environmental mechanisms that need to be further studied.”

Erin F. Cobain, MD, who was not involved in the research, said the findings are “not very surprising to me.”

Dr. Cobain said that at her institution, she has seen “many, many cases” of family members of early-onset breast cancer patients with discordant cancers “where we are unable to find a clear genetic cause.”

Not being able to find an identifiable cause for the clustering of early-onset cancers can be “very frustrating” for patients and their families, said Dr. Cobain, a medical oncologist at the University of Michigan Health, Ann Arbor.

The study was published online in the International Journal of Cancer.

Family members of patients with early-onset breast cancer are at elevated risk for early-onset breast cancer. However, it is “unclear whether the familial risk is limited to early-onset cancer of the same site,” the authors explained.

To investigate, the researchers studied data from the Finnish Cancer Registry and the Finnish Population System, which included 54,753 relatives from 5,562 families of females diagnosed with early-onset breast cancer, defined as probands. A proband was the first member of the family diagnosed with female breast cancer at age 40 years or younger in Finland between January 1970 and December 31, 2012. Cancers were considered familial if they occurred in a family with a previously diagnosed proband and were deemed early onset if diagnosed before age 41.

The researchers found that only 5.5% of probands’ families had a family member with a discordant early-onset cancer. The most common diagnoses were testicular cancer (0.6% of families) and cancer of the thyroid gland (also 0.6%), followed by melanoma (0.5%).

Overall, the risk of any nonbreast early-onset cancer among first-degree relatives of probands was comparable with the risk in the general population (standardized incidence ratio, 0.99; 95% confidence interval, 0.84-1.16).

However, the risk was elevated for certain family members and certain cancers.

Specifically, the children of probands had an increased risk for any discordant cancer (SIR, 1.27; 95% CI, 1.05-1.55).

The siblings of probands had an elevated risk for early-onset pancreatic cancer (SIR, 7.61) but not overall for any discordant cancer (SIR, 0.93; 95% CI, 0.68-1.25).

And siblings’ children faced an elevated risk for testicular (SIR, 1.74) and ovarian (SIR, 2.69) cancer, though not of any discordant cancer (SIR, 1.16; 95% CI, 0.97-1.37).

The researchers also found that the fathers (SIR, 0.43), mothers (SIR, 0.48), and spouses (SIR, 0.58) of probands appeared to have a decreased risk of any discordant early-onset cancer.

A potential limitation to the study was that the authors could not identify individuals with hereditary cancer syndromes or concerning gene mutations, such as BRCA carriers, because “registry data do not include comprehensive information on the gene mutation carriage status.” But the authors note that the number of BRCA carriers is likely low because of the low number of ovarian cancers observed in first-degree relatives of probands.

Dr. Cobain noted as well that the current study is potentially limited by its “very homogeneous” cohort.

But, overall, the findings indicate that familial risk is often “a much more complicated problem, mathematically and statistically,” than were there a single genetic culprit, Dr. Cobain said. One possibility is that some shared environmental exposure may be increasing the cancer risk among members of the same family.

“Genetic diversity is so vast and understanding how the interplay of multiple genes can influence an individual’s cancer risk is so much more complicated than a single BRCA1 mutation that clearly influences your breast cancer risk,” she added. However, “we’re starting to get there.”

The study was funded by the Cancer Foundation Finland and Academy of Finland. The authors and Dr. Cobain had no relevant financial relationships to declare.

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

Certain relatives of women with early onset breast cancer appear to face an increased risk of other early-onset cancers, a Finnish population-based study suggests.

The researchers found, for instance, that children of breast cancer patients had a 27% higher risk of any discordant early-onset cancer, and patients’ siblings had a 7.6-fold higher risk of early pancreatic cancer. The analysis also indicated that children of patients’ siblings had a significantly increased risk of testicular and ovarian cancers.

“The findings suggest that the familial risk extends to discordant early-onset cancers, including ovarian, testicular, and pancreatic cancers, as well as beyond first-degree relatives,” the researchers, led by Janne M. Pitkäniemi, PhD, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, say. “Our findings are interesting but raise some questions about unknown [genetic] and environmental mechanisms that need to be further studied.”

Erin F. Cobain, MD, who was not involved in the research, said the findings are “not very surprising to me.”

Dr. Cobain said that at her institution, she has seen “many, many cases” of family members of early-onset breast cancer patients with discordant cancers “where we are unable to find a clear genetic cause.”

Not being able to find an identifiable cause for the clustering of early-onset cancers can be “very frustrating” for patients and their families, said Dr. Cobain, a medical oncologist at the University of Michigan Health, Ann Arbor.

The study was published online in the International Journal of Cancer.

Family members of patients with early-onset breast cancer are at elevated risk for early-onset breast cancer. However, it is “unclear whether the familial risk is limited to early-onset cancer of the same site,” the authors explained.

To investigate, the researchers studied data from the Finnish Cancer Registry and the Finnish Population System, which included 54,753 relatives from 5,562 families of females diagnosed with early-onset breast cancer, defined as probands. A proband was the first member of the family diagnosed with female breast cancer at age 40 years or younger in Finland between January 1970 and December 31, 2012. Cancers were considered familial if they occurred in a family with a previously diagnosed proband and were deemed early onset if diagnosed before age 41.

The researchers found that only 5.5% of probands’ families had a family member with a discordant early-onset cancer. The most common diagnoses were testicular cancer (0.6% of families) and cancer of the thyroid gland (also 0.6%), followed by melanoma (0.5%).

Overall, the risk of any nonbreast early-onset cancer among first-degree relatives of probands was comparable with the risk in the general population (standardized incidence ratio, 0.99; 95% confidence interval, 0.84-1.16).

However, the risk was elevated for certain family members and certain cancers.

Specifically, the children of probands had an increased risk for any discordant cancer (SIR, 1.27; 95% CI, 1.05-1.55).

The siblings of probands had an elevated risk for early-onset pancreatic cancer (SIR, 7.61) but not overall for any discordant cancer (SIR, 0.93; 95% CI, 0.68-1.25).

And siblings’ children faced an elevated risk for testicular (SIR, 1.74) and ovarian (SIR, 2.69) cancer, though not of any discordant cancer (SIR, 1.16; 95% CI, 0.97-1.37).

The researchers also found that the fathers (SIR, 0.43), mothers (SIR, 0.48), and spouses (SIR, 0.58) of probands appeared to have a decreased risk of any discordant early-onset cancer.

A potential limitation to the study was that the authors could not identify individuals with hereditary cancer syndromes or concerning gene mutations, such as BRCA carriers, because “registry data do not include comprehensive information on the gene mutation carriage status.” But the authors note that the number of BRCA carriers is likely low because of the low number of ovarian cancers observed in first-degree relatives of probands.

Dr. Cobain noted as well that the current study is potentially limited by its “very homogeneous” cohort.

But, overall, the findings indicate that familial risk is often “a much more complicated problem, mathematically and statistically,” than were there a single genetic culprit, Dr. Cobain said. One possibility is that some shared environmental exposure may be increasing the cancer risk among members of the same family.

“Genetic diversity is so vast and understanding how the interplay of multiple genes can influence an individual’s cancer risk is so much more complicated than a single BRCA1 mutation that clearly influences your breast cancer risk,” she added. However, “we’re starting to get there.”

The study was funded by the Cancer Foundation Finland and Academy of Finland. The authors and Dr. Cobain had no relevant financial relationships to declare.

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

BOSTON – Having a preoperative MRI scan does not help surgeons to reduce the likelihood of positive surgical margins when they are performing lumpectomy for early stage breast cancer, a new study concludes.

The current results suggest that MRI is “not useful to achieve this goal and not a productive use of health care resources,” said senior author Marissa Howard-McNatt, MD, director of the Breast Care Center, Wake Forest University, Winston-Salem, N.C.

“Researchers continue to look for better ways to assess margin status while the patient is still on the operating table,” she said, as a re-operation “can be traumatic.”

The study was presented at the annual meeting of the American Society of Breast Surgeons and was highlighted in a press briefing.

In the study, more than 630 patients with early stage breast cancer were randomly assigned to partial mastectomy with or without cavity shaving of the tumor margins, of whom 193 underwent MRI before their operation.

Although there was a difference in the rate of positive surgical margins before cavity shaving between patients who did and did not undergo MRI, the difference did not reach statistical significance.

“MRI exams are costly and potentially stressful for patients,” Dr. Howard-McNatt commented in a press statement. “The thought is that they will help physicians achieve negative margins during the initial surgery. However, our study shows this is simply not the case.”

Approached for comment, Mediget Teshome, MD, MPH, said, “In my practice, I primarily utilize MRI preoperatively to evaluate the extent of disease in cases where the information is not clear from mammogram and ultrasound.”

This may be when there is “discordance between the size of the malignancy or concern for chest wall or muscle involvement,” Dr. Teshome said in an interview.

MRI is also useful when there may be occult disease, such as in patients “with high suspicion for extensive intraductal component not evident on mammography and those who present with axillary metastasis and unknown breast primary,” as well as in high-risk patients with a genetic predisposition for breast cancer, she explained.

However, Dr. Teshome, an associate professor in the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center, Houston, stressed that, “as with any test, it is important that preoperative MRI is performed with the specific intent to inform clinical decision-making in a meaningful way.”

“While it can provide a benefit in selected cases given its high sensitivity, MRI is associated with false positives and can also contribute to increased patient anxiety and additional procedures,” she cautioned.
 

Study details

Lumpectomy has become “a mainstay of breast cancer management, with safe and reliable outcomes as compared to mastectomy,” said Dr. Howard-McNatt, but it is associated with a higher rate of positive margins, of up to 27%.

She underlined that “re-excision surgery can contribute to greater morbidity, patient anxiety, poor cosmetic outcomes, and health care system overload,” and the desire to reduce re-operations has led to “much attention” being paid to preoperative imaging.

Their study set out to investigate the value of preoperative MRI in this regard, and for this they analyzed data on 631 women who had participated in two prior randomized trials (SHAVE1 and SHAVE2).

These women were randomly assigned to standard partial mastectomy with or without resection of cavity shave margins, with preoperative MRI performed prior to randomization in both trials at the surgeon’s discretion.

The median tumor size was 1.3 cm. An extensive intraductal component was identified in 32.8% of patients, 26.1% had palpable tumors, and 7% had invasive lobular histology. Neoadjuvant chemotherapy was administered in 6.5% of patients.

In all, 193 individuals underwent MRI. These women were less likely to have a positive surgical margin before resection of cavity shave margins, at 31.1% vs. 38.8% in those who did not have MRI, although the difference was not statistically significant (P = .073).

Multivariate analysis taking into account patient age, race, receipt of neoadjuvant chemotherapy, the presence of an extensive intraductal component, as well as histologic subtype and tumor size, revealed that MRI was not associated with a higher rate of negative surgical margins (P = .110).

However, it was shown that both tumor size (P = .040) and age (P = .032) were predictive of margin status.

It was notable that MRI use was associated with younger patient age, at a median of 63 years vs. 66 years, and smaller tumor size, at a median of 2.0 cm vs. 2.1 cm.

This latter finding “may be attributable to an inaccurate initial assessment of the extent of the actual tumor size for a variety of reasons,” Dr. Howard-McNatt commented. “For example, tumors may be discontinuous or have satellite lesions which may touch the edge of a specimen.”

The study was funded in part by the David and Katie Burke Fund for Breast Cancer Research, the Connecticut Breast Health Initiative, the Troy Cancer Program, Cleveland Clinic Akron General Operations, the Cleveland Clinic Akron General Foundation, the Lineberger Comprehensive Cancer Center, the Watson Clinic Center for Research, and LifeCycle. The study authors report no relevant financial relationships.

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

BOSTON – Having a preoperative MRI scan does not help surgeons to reduce the likelihood of positive surgical margins when they are performing lumpectomy for early stage breast cancer, a new study concludes.

The current results suggest that MRI is “not useful to achieve this goal and not a productive use of health care resources,” said senior author Marissa Howard-McNatt, MD, director of the Breast Care Center, Wake Forest University, Winston-Salem, N.C.

“Researchers continue to look for better ways to assess margin status while the patient is still on the operating table,” she said, as a re-operation “can be traumatic.”

The study was presented at the annual meeting of the American Society of Breast Surgeons and was highlighted in a press briefing.

In the study, more than 630 patients with early stage breast cancer were randomly assigned to partial mastectomy with or without cavity shaving of the tumor margins, of whom 193 underwent MRI before their operation.

Although there was a difference in the rate of positive surgical margins before cavity shaving between patients who did and did not undergo MRI, the difference did not reach statistical significance.

“MRI exams are costly and potentially stressful for patients,” Dr. Howard-McNatt commented in a press statement. “The thought is that they will help physicians achieve negative margins during the initial surgery. However, our study shows this is simply not the case.”

Approached for comment, Mediget Teshome, MD, MPH, said, “In my practice, I primarily utilize MRI preoperatively to evaluate the extent of disease in cases where the information is not clear from mammogram and ultrasound.”

This may be when there is “discordance between the size of the malignancy or concern for chest wall or muscle involvement,” Dr. Teshome said in an interview.

MRI is also useful when there may be occult disease, such as in patients “with high suspicion for extensive intraductal component not evident on mammography and those who present with axillary metastasis and unknown breast primary,” as well as in high-risk patients with a genetic predisposition for breast cancer, she explained.

However, Dr. Teshome, an associate professor in the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center, Houston, stressed that, “as with any test, it is important that preoperative MRI is performed with the specific intent to inform clinical decision-making in a meaningful way.”

“While it can provide a benefit in selected cases given its high sensitivity, MRI is associated with false positives and can also contribute to increased patient anxiety and additional procedures,” she cautioned.
 

Study details

Lumpectomy has become “a mainstay of breast cancer management, with safe and reliable outcomes as compared to mastectomy,” said Dr. Howard-McNatt, but it is associated with a higher rate of positive margins, of up to 27%.

She underlined that “re-excision surgery can contribute to greater morbidity, patient anxiety, poor cosmetic outcomes, and health care system overload,” and the desire to reduce re-operations has led to “much attention” being paid to preoperative imaging.

Their study set out to investigate the value of preoperative MRI in this regard, and for this they analyzed data on 631 women who had participated in two prior randomized trials (SHAVE1 and SHAVE2).

These women were randomly assigned to standard partial mastectomy with or without resection of cavity shave margins, with preoperative MRI performed prior to randomization in both trials at the surgeon’s discretion.

The median tumor size was 1.3 cm. An extensive intraductal component was identified in 32.8% of patients, 26.1% had palpable tumors, and 7% had invasive lobular histology. Neoadjuvant chemotherapy was administered in 6.5% of patients.

In all, 193 individuals underwent MRI. These women were less likely to have a positive surgical margin before resection of cavity shave margins, at 31.1% vs. 38.8% in those who did not have MRI, although the difference was not statistically significant (P = .073).

Multivariate analysis taking into account patient age, race, receipt of neoadjuvant chemotherapy, the presence of an extensive intraductal component, as well as histologic subtype and tumor size, revealed that MRI was not associated with a higher rate of negative surgical margins (P = .110).

However, it was shown that both tumor size (P = .040) and age (P = .032) were predictive of margin status.

It was notable that MRI use was associated with younger patient age, at a median of 63 years vs. 66 years, and smaller tumor size, at a median of 2.0 cm vs. 2.1 cm.

This latter finding “may be attributable to an inaccurate initial assessment of the extent of the actual tumor size for a variety of reasons,” Dr. Howard-McNatt commented. “For example, tumors may be discontinuous or have satellite lesions which may touch the edge of a specimen.”

The study was funded in part by the David and Katie Burke Fund for Breast Cancer Research, the Connecticut Breast Health Initiative, the Troy Cancer Program, Cleveland Clinic Akron General Operations, the Cleveland Clinic Akron General Foundation, the Lineberger Comprehensive Cancer Center, the Watson Clinic Center for Research, and LifeCycle. The study authors report no relevant financial relationships.

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

BOSTON – Having a preoperative MRI scan does not help surgeons to reduce the likelihood of positive surgical margins when they are performing lumpectomy for early stage breast cancer, a new study concludes.

The current results suggest that MRI is “not useful to achieve this goal and not a productive use of health care resources,” said senior author Marissa Howard-McNatt, MD, director of the Breast Care Center, Wake Forest University, Winston-Salem, N.C.

“Researchers continue to look for better ways to assess margin status while the patient is still on the operating table,” she said, as a re-operation “can be traumatic.”

The study was presented at the annual meeting of the American Society of Breast Surgeons and was highlighted in a press briefing.

In the study, more than 630 patients with early stage breast cancer were randomly assigned to partial mastectomy with or without cavity shaving of the tumor margins, of whom 193 underwent MRI before their operation.

Although there was a difference in the rate of positive surgical margins before cavity shaving between patients who did and did not undergo MRI, the difference did not reach statistical significance.

“MRI exams are costly and potentially stressful for patients,” Dr. Howard-McNatt commented in a press statement. “The thought is that they will help physicians achieve negative margins during the initial surgery. However, our study shows this is simply not the case.”

Approached for comment, Mediget Teshome, MD, MPH, said, “In my practice, I primarily utilize MRI preoperatively to evaluate the extent of disease in cases where the information is not clear from mammogram and ultrasound.”

This may be when there is “discordance between the size of the malignancy or concern for chest wall or muscle involvement,” Dr. Teshome said in an interview.

MRI is also useful when there may be occult disease, such as in patients “with high suspicion for extensive intraductal component not evident on mammography and those who present with axillary metastasis and unknown breast primary,” as well as in high-risk patients with a genetic predisposition for breast cancer, she explained.

However, Dr. Teshome, an associate professor in the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center, Houston, stressed that, “as with any test, it is important that preoperative MRI is performed with the specific intent to inform clinical decision-making in a meaningful way.”

“While it can provide a benefit in selected cases given its high sensitivity, MRI is associated with false positives and can also contribute to increased patient anxiety and additional procedures,” she cautioned.
 

Study details

Lumpectomy has become “a mainstay of breast cancer management, with safe and reliable outcomes as compared to mastectomy,” said Dr. Howard-McNatt, but it is associated with a higher rate of positive margins, of up to 27%.

She underlined that “re-excision surgery can contribute to greater morbidity, patient anxiety, poor cosmetic outcomes, and health care system overload,” and the desire to reduce re-operations has led to “much attention” being paid to preoperative imaging.

Their study set out to investigate the value of preoperative MRI in this regard, and for this they analyzed data on 631 women who had participated in two prior randomized trials (SHAVE1 and SHAVE2).

These women were randomly assigned to standard partial mastectomy with or without resection of cavity shave margins, with preoperative MRI performed prior to randomization in both trials at the surgeon’s discretion.

The median tumor size was 1.3 cm. An extensive intraductal component was identified in 32.8% of patients, 26.1% had palpable tumors, and 7% had invasive lobular histology. Neoadjuvant chemotherapy was administered in 6.5% of patients.

In all, 193 individuals underwent MRI. These women were less likely to have a positive surgical margin before resection of cavity shave margins, at 31.1% vs. 38.8% in those who did not have MRI, although the difference was not statistically significant (P = .073).

Multivariate analysis taking into account patient age, race, receipt of neoadjuvant chemotherapy, the presence of an extensive intraductal component, as well as histologic subtype and tumor size, revealed that MRI was not associated with a higher rate of negative surgical margins (P = .110).

However, it was shown that both tumor size (P = .040) and age (P = .032) were predictive of margin status.

It was notable that MRI use was associated with younger patient age, at a median of 63 years vs. 66 years, and smaller tumor size, at a median of 2.0 cm vs. 2.1 cm.

This latter finding “may be attributable to an inaccurate initial assessment of the extent of the actual tumor size for a variety of reasons,” Dr. Howard-McNatt commented. “For example, tumors may be discontinuous or have satellite lesions which may touch the edge of a specimen.”

The study was funded in part by the David and Katie Burke Fund for Breast Cancer Research, the Connecticut Breast Health Initiative, the Troy Cancer Program, Cleveland Clinic Akron General Operations, the Cleveland Clinic Akron General Foundation, the Lineberger Comprehensive Cancer Center, the Watson Clinic Center for Research, and LifeCycle. The study authors report no relevant financial relationships.

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