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‘Huge step forward’ in advanced ovarian cancer
The results come from the DUO-O trial, in which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) and immunotherapy with the anti–PD-L1 antibody durvalumab (Imfinzi) were added on to standard of care with paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin) in patients with newly diagnosed,non–BRCA-mutated advanced ovarian cancer.
A preplanned interim analysis revealed that the addition of durvalumab and olaparib was associated with a 37% improvement of PFS, compared with the standard of care of chemotherapy plus bevacizumab alone.
This improvement increased to 51% in patients who had tumors positive for homologous recombination deficiency (HRD), which indicates the inability to effectively repair double-stranded DNA breaks, a defect that is present in approximately 70% of ovarian cancers.
Coprincipal investigator Carol Aghajanian, MD, chief of the gynecologic medical oncology service at Memorial Sloan Kettering Cancer Center, New York, described the benefit seen with the novel combination therapy as both “statistically significant and clinically meaningful.”
She was speaking at a press briefing held ahead of the annual meeting of the American Society of Clinical Oncology, where the results were presented.
Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at University of Florida Health, Gainesville, said the results represents a “huge step forward.”
She added the rate of progress it represents may not be “quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies that are important, like this one, really means so much to that individual patient in that exam room.”
Dr. Markham underlined that around 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage. “They know what they are facing,” she said. “The vast majority” of them will have a recurrence “at some point.”
“So while progression-free survival may not necessarily mean their overall survival, there will be hope it does. And I’m very excited to see where this study heads in that direction.” Dr. Markham added that PFS is “very important to our patients,” and the study does represent progress. “We are chipping away at improving outcomes for advanced ovarian cancer.”
Moreover, “women are often disappointed when their tumor doesn’t have a BRCA mutation because they know that that may limit some of their treatment options,” and so the current study suggests that there are “options for all-comers” and “there is still hope.”
Access to treatment and testing
When asked whether there could be any access issues for patients clinically eligible for the novel combination, Dr. Aghajanian said that all of the drugs have been approved by the Food and Drug Administration for indications that cover this usage.
They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to co-pay assistance programs and the like.”
She said that patients can then “be counseled on their expected benefit,” based on their BRCA and HRD testing.
Dr. Markham, on the other hand, said she is “a little less optimistic” about access, explaining that she practices in the southern United States, and “our populations [and] insurance coverages are a bit different.”
She noted that, at her institution, a “fair number of patients are underinsured,” and they “ran into a lot of issues with people not being able to afford their copays,” which can be “prohibitive.”
“A large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity, that that individual patient may experience and the need for copay assistance programs or other support mechanisms,” Markham said.
Dr. Aghajanian added that “financial toxicity and the access issue comes even prior to the treatment, in getting those BRCA1/2 tests and the HRD testing done, so patients have the information they need to make informed decisions.”
“We do have disparities with genetic testing and genomic testing that need to be solved,” she said.
Study details
Previous studies, including SOLO1 and PAOLA-1, have shown that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.
“However, there still remains unmet need, especially in some patient subgroups without a BRCA mutation,” Dr. Aghajanian said.
While the addition of immunotherapy to standard of care has yet to show a clinical benefit in this setting in phase 3 trials, the phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in nongermline, BRCA-mutated, platinum-sensitive relapsed cancer.
The phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as a maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without a tumor BRCA1/2 mutation.
Patients were required to have had no prior systemic therapy for ovarian cancer, and be naive to both PARP inhibition and immunotherapy. They also had to have completed up-front primary debulking surgery, or be scheduled to undergo the procedure.
After an initial cycle of paclitaxel/carboplatin chemotherapy, the patients were randomly assigned to one of three regimens:
- Standard of care treatment, comprising chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib-placebo (arm 2)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib (arm 3)
In the maintenance phase, bevacizumab was to be given for a total of 15 months, while durvalumab and olaparib, or their equivalent placebos, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or another discontinuation criteria was met.
Dr. Aghajanian presented results from a preplanned interim analysis, with a date cutoff of Dec. 5, 2022.
Among HRD-positive patients, those in arm 3 had a significantly longer PFS than those in arm 1, at a median of 37.3 months versus 23 months, or a hazard ratio of 0.49 (P < .0001).
In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS over arm 1, at 24.2 months versus 19.3 months, or an HR of 0.63 (P < .0001), indicating that the trial met both of its primary endpoints.
While there was a numerical difference in median PFS between arm 2 and arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means that relative contribution of adding durvalumab alone is not clear, Dr. Aghajanian commented, and said that this comparison “will be reassessed at the time of the final PFS analysis.”
She added that a “PFS effect was observed across all subgroups for the arm 3 versus arm 1 comparison,” including in the HRD-negative subgroup, at a median of 20.9 months versus 17.4 months, or an HR of 0.68.
The safety and tolerability of the regimens were generally consistent with what is known for the individual agents, she commented.
Serious adverse events were reported in 34%, 43%, and 39% of patients in arms 1, 2, and 3, respectively.
The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of those in arm 2, and 31% of those in arm 3) followed by anemia (in 8%, 8%, and 24%, respectively).
Dose modifications were required in 72% of arm 1 patients, 80% of those in arm 2, and 85% of arm 3 patients. Treatment discontinuation was recorded in 20%, 26%, and 35%, respectively.
Tackling underserved patient populations
Discussing the results, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the department of surgery and cancer, Imperial College London, said that, while the regimen may seem new, the treatments involved are “veterans,” and that they are nevertheless tackling previously underserved patient populations.
Dr. Fotopoulou, who was not involved in the study, noted that the results were highly anticipated, and the study has delivered a “breakthrough in ovarian cancer.” She nevertheless questioned the choice of the control arm, and pointed out that the hazard ratio in favor of the combination therapy is “relatively modest” considering that it involves three drugs.
Dr. Fotopoulou highlighted, however, that one of the most important results was in the HRD-negative patients, which she characterized as the equivalent of the clinicians going to “the dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she underlined that the results are from an interim analysis.
The key question that remains, Dr. Fotopoulou asked, is “why? What is making the difference?” She noted that, unfortunately, the trial design does not allow the identification of the relative contribution of olaparib and durvalumab.
The study was sponsored by AstraZeneca, and conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups, GOG Foundation, and Myriad Genetic Laboratories. Dr. Aghajanian declared relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche. Dr. Markham declared relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, Lilly, Tesaro, Novartis, VBL Therapeutics, AstraZeneca, and Merck.
A version of this article first appeared on Medscape.com.
The results come from the DUO-O trial, in which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) and immunotherapy with the anti–PD-L1 antibody durvalumab (Imfinzi) were added on to standard of care with paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin) in patients with newly diagnosed,non–BRCA-mutated advanced ovarian cancer.
A preplanned interim analysis revealed that the addition of durvalumab and olaparib was associated with a 37% improvement of PFS, compared with the standard of care of chemotherapy plus bevacizumab alone.
This improvement increased to 51% in patients who had tumors positive for homologous recombination deficiency (HRD), which indicates the inability to effectively repair double-stranded DNA breaks, a defect that is present in approximately 70% of ovarian cancers.
Coprincipal investigator Carol Aghajanian, MD, chief of the gynecologic medical oncology service at Memorial Sloan Kettering Cancer Center, New York, described the benefit seen with the novel combination therapy as both “statistically significant and clinically meaningful.”
She was speaking at a press briefing held ahead of the annual meeting of the American Society of Clinical Oncology, where the results were presented.
Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at University of Florida Health, Gainesville, said the results represents a “huge step forward.”
She added the rate of progress it represents may not be “quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies that are important, like this one, really means so much to that individual patient in that exam room.”
Dr. Markham underlined that around 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage. “They know what they are facing,” she said. “The vast majority” of them will have a recurrence “at some point.”
“So while progression-free survival may not necessarily mean their overall survival, there will be hope it does. And I’m very excited to see where this study heads in that direction.” Dr. Markham added that PFS is “very important to our patients,” and the study does represent progress. “We are chipping away at improving outcomes for advanced ovarian cancer.”
Moreover, “women are often disappointed when their tumor doesn’t have a BRCA mutation because they know that that may limit some of their treatment options,” and so the current study suggests that there are “options for all-comers” and “there is still hope.”
Access to treatment and testing
When asked whether there could be any access issues for patients clinically eligible for the novel combination, Dr. Aghajanian said that all of the drugs have been approved by the Food and Drug Administration for indications that cover this usage.
They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to co-pay assistance programs and the like.”
She said that patients can then “be counseled on their expected benefit,” based on their BRCA and HRD testing.
Dr. Markham, on the other hand, said she is “a little less optimistic” about access, explaining that she practices in the southern United States, and “our populations [and] insurance coverages are a bit different.”
She noted that, at her institution, a “fair number of patients are underinsured,” and they “ran into a lot of issues with people not being able to afford their copays,” which can be “prohibitive.”
“A large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity, that that individual patient may experience and the need for copay assistance programs or other support mechanisms,” Markham said.
Dr. Aghajanian added that “financial toxicity and the access issue comes even prior to the treatment, in getting those BRCA1/2 tests and the HRD testing done, so patients have the information they need to make informed decisions.”
“We do have disparities with genetic testing and genomic testing that need to be solved,” she said.
Study details
Previous studies, including SOLO1 and PAOLA-1, have shown that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.
“However, there still remains unmet need, especially in some patient subgroups without a BRCA mutation,” Dr. Aghajanian said.
While the addition of immunotherapy to standard of care has yet to show a clinical benefit in this setting in phase 3 trials, the phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in nongermline, BRCA-mutated, platinum-sensitive relapsed cancer.
The phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as a maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without a tumor BRCA1/2 mutation.
Patients were required to have had no prior systemic therapy for ovarian cancer, and be naive to both PARP inhibition and immunotherapy. They also had to have completed up-front primary debulking surgery, or be scheduled to undergo the procedure.
After an initial cycle of paclitaxel/carboplatin chemotherapy, the patients were randomly assigned to one of three regimens:
- Standard of care treatment, comprising chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib-placebo (arm 2)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib (arm 3)
In the maintenance phase, bevacizumab was to be given for a total of 15 months, while durvalumab and olaparib, or their equivalent placebos, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or another discontinuation criteria was met.
Dr. Aghajanian presented results from a preplanned interim analysis, with a date cutoff of Dec. 5, 2022.
Among HRD-positive patients, those in arm 3 had a significantly longer PFS than those in arm 1, at a median of 37.3 months versus 23 months, or a hazard ratio of 0.49 (P < .0001).
In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS over arm 1, at 24.2 months versus 19.3 months, or an HR of 0.63 (P < .0001), indicating that the trial met both of its primary endpoints.
While there was a numerical difference in median PFS between arm 2 and arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means that relative contribution of adding durvalumab alone is not clear, Dr. Aghajanian commented, and said that this comparison “will be reassessed at the time of the final PFS analysis.”
She added that a “PFS effect was observed across all subgroups for the arm 3 versus arm 1 comparison,” including in the HRD-negative subgroup, at a median of 20.9 months versus 17.4 months, or an HR of 0.68.
The safety and tolerability of the regimens were generally consistent with what is known for the individual agents, she commented.
Serious adverse events were reported in 34%, 43%, and 39% of patients in arms 1, 2, and 3, respectively.
The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of those in arm 2, and 31% of those in arm 3) followed by anemia (in 8%, 8%, and 24%, respectively).
Dose modifications were required in 72% of arm 1 patients, 80% of those in arm 2, and 85% of arm 3 patients. Treatment discontinuation was recorded in 20%, 26%, and 35%, respectively.
Tackling underserved patient populations
Discussing the results, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the department of surgery and cancer, Imperial College London, said that, while the regimen may seem new, the treatments involved are “veterans,” and that they are nevertheless tackling previously underserved patient populations.
Dr. Fotopoulou, who was not involved in the study, noted that the results were highly anticipated, and the study has delivered a “breakthrough in ovarian cancer.” She nevertheless questioned the choice of the control arm, and pointed out that the hazard ratio in favor of the combination therapy is “relatively modest” considering that it involves three drugs.
Dr. Fotopoulou highlighted, however, that one of the most important results was in the HRD-negative patients, which she characterized as the equivalent of the clinicians going to “the dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she underlined that the results are from an interim analysis.
The key question that remains, Dr. Fotopoulou asked, is “why? What is making the difference?” She noted that, unfortunately, the trial design does not allow the identification of the relative contribution of olaparib and durvalumab.
The study was sponsored by AstraZeneca, and conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups, GOG Foundation, and Myriad Genetic Laboratories. Dr. Aghajanian declared relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche. Dr. Markham declared relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, Lilly, Tesaro, Novartis, VBL Therapeutics, AstraZeneca, and Merck.
A version of this article first appeared on Medscape.com.
The results come from the DUO-O trial, in which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) and immunotherapy with the anti–PD-L1 antibody durvalumab (Imfinzi) were added on to standard of care with paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin) in patients with newly diagnosed,non–BRCA-mutated advanced ovarian cancer.
A preplanned interim analysis revealed that the addition of durvalumab and olaparib was associated with a 37% improvement of PFS, compared with the standard of care of chemotherapy plus bevacizumab alone.
This improvement increased to 51% in patients who had tumors positive for homologous recombination deficiency (HRD), which indicates the inability to effectively repair double-stranded DNA breaks, a defect that is present in approximately 70% of ovarian cancers.
Coprincipal investigator Carol Aghajanian, MD, chief of the gynecologic medical oncology service at Memorial Sloan Kettering Cancer Center, New York, described the benefit seen with the novel combination therapy as both “statistically significant and clinically meaningful.”
She was speaking at a press briefing held ahead of the annual meeting of the American Society of Clinical Oncology, where the results were presented.
Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at University of Florida Health, Gainesville, said the results represents a “huge step forward.”
She added the rate of progress it represents may not be “quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies that are important, like this one, really means so much to that individual patient in that exam room.”
Dr. Markham underlined that around 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage. “They know what they are facing,” she said. “The vast majority” of them will have a recurrence “at some point.”
“So while progression-free survival may not necessarily mean their overall survival, there will be hope it does. And I’m very excited to see where this study heads in that direction.” Dr. Markham added that PFS is “very important to our patients,” and the study does represent progress. “We are chipping away at improving outcomes for advanced ovarian cancer.”
Moreover, “women are often disappointed when their tumor doesn’t have a BRCA mutation because they know that that may limit some of their treatment options,” and so the current study suggests that there are “options for all-comers” and “there is still hope.”
Access to treatment and testing
When asked whether there could be any access issues for patients clinically eligible for the novel combination, Dr. Aghajanian said that all of the drugs have been approved by the Food and Drug Administration for indications that cover this usage.
They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to co-pay assistance programs and the like.”
She said that patients can then “be counseled on their expected benefit,” based on their BRCA and HRD testing.
Dr. Markham, on the other hand, said she is “a little less optimistic” about access, explaining that she practices in the southern United States, and “our populations [and] insurance coverages are a bit different.”
She noted that, at her institution, a “fair number of patients are underinsured,” and they “ran into a lot of issues with people not being able to afford their copays,” which can be “prohibitive.”
“A large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity, that that individual patient may experience and the need for copay assistance programs or other support mechanisms,” Markham said.
Dr. Aghajanian added that “financial toxicity and the access issue comes even prior to the treatment, in getting those BRCA1/2 tests and the HRD testing done, so patients have the information they need to make informed decisions.”
“We do have disparities with genetic testing and genomic testing that need to be solved,” she said.
Study details
Previous studies, including SOLO1 and PAOLA-1, have shown that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.
“However, there still remains unmet need, especially in some patient subgroups without a BRCA mutation,” Dr. Aghajanian said.
While the addition of immunotherapy to standard of care has yet to show a clinical benefit in this setting in phase 3 trials, the phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in nongermline, BRCA-mutated, platinum-sensitive relapsed cancer.
The phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as a maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without a tumor BRCA1/2 mutation.
Patients were required to have had no prior systemic therapy for ovarian cancer, and be naive to both PARP inhibition and immunotherapy. They also had to have completed up-front primary debulking surgery, or be scheduled to undergo the procedure.
After an initial cycle of paclitaxel/carboplatin chemotherapy, the patients were randomly assigned to one of three regimens:
- Standard of care treatment, comprising chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib-placebo (arm 2)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib (arm 3)
In the maintenance phase, bevacizumab was to be given for a total of 15 months, while durvalumab and olaparib, or their equivalent placebos, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or another discontinuation criteria was met.
Dr. Aghajanian presented results from a preplanned interim analysis, with a date cutoff of Dec. 5, 2022.
Among HRD-positive patients, those in arm 3 had a significantly longer PFS than those in arm 1, at a median of 37.3 months versus 23 months, or a hazard ratio of 0.49 (P < .0001).
In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS over arm 1, at 24.2 months versus 19.3 months, or an HR of 0.63 (P < .0001), indicating that the trial met both of its primary endpoints.
While there was a numerical difference in median PFS between arm 2 and arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means that relative contribution of adding durvalumab alone is not clear, Dr. Aghajanian commented, and said that this comparison “will be reassessed at the time of the final PFS analysis.”
She added that a “PFS effect was observed across all subgroups for the arm 3 versus arm 1 comparison,” including in the HRD-negative subgroup, at a median of 20.9 months versus 17.4 months, or an HR of 0.68.
The safety and tolerability of the regimens were generally consistent with what is known for the individual agents, she commented.
Serious adverse events were reported in 34%, 43%, and 39% of patients in arms 1, 2, and 3, respectively.
The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of those in arm 2, and 31% of those in arm 3) followed by anemia (in 8%, 8%, and 24%, respectively).
Dose modifications were required in 72% of arm 1 patients, 80% of those in arm 2, and 85% of arm 3 patients. Treatment discontinuation was recorded in 20%, 26%, and 35%, respectively.
Tackling underserved patient populations
Discussing the results, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the department of surgery and cancer, Imperial College London, said that, while the regimen may seem new, the treatments involved are “veterans,” and that they are nevertheless tackling previously underserved patient populations.
Dr. Fotopoulou, who was not involved in the study, noted that the results were highly anticipated, and the study has delivered a “breakthrough in ovarian cancer.” She nevertheless questioned the choice of the control arm, and pointed out that the hazard ratio in favor of the combination therapy is “relatively modest” considering that it involves three drugs.
Dr. Fotopoulou highlighted, however, that one of the most important results was in the HRD-negative patients, which she characterized as the equivalent of the clinicians going to “the dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she underlined that the results are from an interim analysis.
The key question that remains, Dr. Fotopoulou asked, is “why? What is making the difference?” She noted that, unfortunately, the trial design does not allow the identification of the relative contribution of olaparib and durvalumab.
The study was sponsored by AstraZeneca, and conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups, GOG Foundation, and Myriad Genetic Laboratories. Dr. Aghajanian declared relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche. Dr. Markham declared relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, Lilly, Tesaro, Novartis, VBL Therapeutics, AstraZeneca, and Merck.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
Omitting radiation in rectal cancer: ‘Less is more’
“This study establishes preoperative therapy with FOLFOX and only selective use of chemoradiation for patients with locally advanced rectal cancer,” commented principal investigator Deborah Schrag, MD, MPH, gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center, New York.
“Having this option is important for several reasons,” she said. “First, in many parts of the world, radiation therapy is not readily accessible. An all-chemotherapy approach may make curative intent treatment accessible for patients in these resource-constrained settings. Additionally, given the rising rates of colorectal cancer in young patients, this provides an option for patients who wish to preserve fertility or avoid early menopause.”
Reacting to the findings, Pamela Kunz, MD, leader of the gastrointestinal cancers program at Yale Cancer Center, New Haven, Conn., commented: “What’s important here is that radiation can be safely omitted in many patients with clinically advanced rectal cancer – this is really ‘less is more.’ ”
“We can spare select patients from receiving radiation without compromising efficacy,” she said. “This leads to improved quality of life, and reduced side effects, including things like early menopause and infertility.”
Dr. Kunz spoke at a press briefing where the results were highlighted prior to being presented at a plenary session at the annual meeting of the American Society of Clinical Oncology.
She said the trial was “practice changing, and it aligns incredibly well with the theme at this year’s annual meeting around de-escalation of therapy and partnering with patients.”
Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, added that the theme may be de-escalation, but in this case it is “really more accurately optimization, because you were able to de-escalate in 91%, but you found the 9% who really needed that escalation, if you will.”
The efficacy results were published simultaneously in the New England Journal of Medicine, while the patient-reported outcomes were published in the Journal of Clinical Oncology.
Chemoradiation is standard approach
Presenting the findings, Dr. Schrag began by noting that approximately half of all new rectal cancer diagnoses have locally advanced disease, which in the United States represents 48,000 cases per year.
She explained that the “standard approach” to treatment is 5½ weeks of daily chemoradiation, comprising radiation to the pelvis alongside sensitizing chemotherapy with a fluoropyrimidine, followed by surgery, and then approximately 16 weeks of adjuvant chemotherapy.
“This way, we have achieved very good outcomes,” Dr. Schrag noted, with the inclusion of radiation in the 1980s a “critically important advance” in slowing rates of recurrence, which is a “cause of enormous suffering.”
However, the treatment is “long and hard,” and the pelvic radiation causes “real toxicities,” she said. These can include impaired bowel, bladder, and sexual function, and an increase in late effects, such as increased risk of pelvic fractures and secondary cancers, as well as infertility and early menopause, and impaired bone marrow function.
This depressed bone marrow function can “become a problem for people going into chemotherapy into the future,” while infertility and early menopause are “a big deal because we’re seeing increasing diagnosis of rectal cancer in people before the age of 50 years.”
Dr. Schrag said that, since chemoradiotherapy became the standard of care, there has been “so much progress,” with better chemotherapy, better surgical techniques, and more screening, so we’re finding more tumors when they are smaller and easier to treat.”
The impetus for the PROSPECT trial, Dr. Schrag said, was therefore: “Could we use radiotherapy more selectively, and only give it to people who don’t respond to chemotherapy rather than giving [it] to everybody?”
The trial enrolled 1,128 patients with rectal cancer with clinically staged T2 node–positive, T3 node–negative, or T3 node–positive disease and who were candidates for sphincter-sparing surgery.
They were randomly assigned to receive either a modified chemotherapy regimen (n = 585) or standard chemoradiation (n = 543). The mean age of the patients was 57 years; 34.5% were female. The majority (85%) were White.
All patients then underwent surgery, with low anterior resection with total mesorectal excision.
The standard chemoradiotherapy consisted of pelvic radiotherapy at 50.4 Gy over 28 fractions alongside sensitizing chemotherapy with either fluorouracil or capecitabine.
The modified chemotherapy regimen consisted of mFOLFOX6, which included modified oxaliplatin with l-leucovorin, and bolus/continuous infusion of 5-fluorouracil.
Patients in the mFOLFOX6 group whose primary tumor decreased in size by at least 20% after the six cycles proceeded straight to surgery, while were rest given the chemoradiotherapy before surgery (9% ended up receiving chemoradiotherapy).
Postoperative adjuvant chemotherapy with six cycles in the mFOLFOX6 group, or eight cycles in the chemoradiotherapy group, was suggested but not mandated.
Dr. Schrag said in an interview that the team chose to use mFOLFOX6 because of their long experience in using it.
FOLFOX first became available in 2002, and randomized controlled trials showed that it was more effective than 5-fluorouracil alone in colon cancer trials.
She explained that locally advanced rectal cancer patients were “never included” in those trials because they were already receiving chemoradiotherapy, but that its use in metastatic rectal cancer, coupled with the data in colon cancer, led them to try it in the current setting.
“It’s also quite tolerable, it’s given every 2 weeks, and it’s familiar to oncologists everywhere,” Dr. Schrag added.
She noted that it’s “not risk free,” with an increased risk of neuropathy, “which is not a great side effect, but we’re able to modulate that.”
Trial results
After a median follow-up of 58 months, mFOLFOX6 was found to be noninferior to chemoradiotherapy for disease-free survival, at a hazard ratio for disease recurrence or death of 0.92 (P = .005 for noninferiority).
The 5-year disease-free survival was 80.8% in the mFOLFOX6 group and 78.6% among patients assigned to chemoradiotherapy, while 5-year overall survival was 89.5% versus 90.2%, at a nonsignificant HR for death of 1.04.
Rates of local recurrence at 5 years were low, at 1.8% with mFOLFOX6 and 1.6% with chemoradiotherapy.
Grade 3 or higher adverse effects were twice as common in the mFOLFOX6 group than among patients who received chemoradiotherapy, at 41% versus 22.8%, although the researchers noted that the treatment period was also twice as long in the chemotherapy arm.
The most common grade 3 or higher adverse effects with mFOLFOX6 were neutropenia (20.3%), pain (3.1%), and hypertension (2.9%), while those with chemoradiotherapy were lymphopenia (8.3%), diarrhea (6.4%), and hypertension (1.7%).
In terms of patient reported outcomes, patients receiving mFOLFOX6 reported lower rates of diarrhea and better overall bowel function during the neoadjuvant phase than those given chemoradiotherapy (P < .05 for all).
However, those assigned to chemoradiotherapy experienced lower rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting during treatment (P < .05 for all).
At 12-month postoperative follow-up, however, those differences had disappeared, and patients originally assigned to mFOLFOX6 had lower rates of fatigue and neuropathy, and better sexual function, than those given chemoradiotherapy (P < .05 for all).
“During the treatment itself, multiple symptoms were worse with chemotherapy, but a year after treatment ended, those symptoms resolved and the pattern flipped so that patients who received radiation exhibited lingering symptoms,” said coinvestigator Ethan Basch, MD, MSc, chief of medical oncology, and director of the cancer outcomes research program at University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill.
“Patients ideally will understand the potential impact of treatments on how they feel and function when making choices, so as oncologists we need to talk with our patients about their options and the consequences of those options,” he said in a statement.
The study was funded by the National Cancer Institute of the National Institutes of Health. Dr. Schrag reported relationships with Merck, JAMA, the American Association for Cancer Research, and Grail. Dr. Basch reported relationships with AstraZeneca, Navigating Cancer, Resilience Care, SIVAN Innovation, ASCO, Centers for Medicare & Medicaid Services, JAMA, the National Cancer Institute, and the Patient-Centered Outcomes Research Institute. Dr. Kunz reported relationships with Novartis, Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich. Dr. Gralow reported relationships with Genentech/Roche.
A version of this article first appeared on Medscape.com.
“This study establishes preoperative therapy with FOLFOX and only selective use of chemoradiation for patients with locally advanced rectal cancer,” commented principal investigator Deborah Schrag, MD, MPH, gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center, New York.
“Having this option is important for several reasons,” she said. “First, in many parts of the world, radiation therapy is not readily accessible. An all-chemotherapy approach may make curative intent treatment accessible for patients in these resource-constrained settings. Additionally, given the rising rates of colorectal cancer in young patients, this provides an option for patients who wish to preserve fertility or avoid early menopause.”
Reacting to the findings, Pamela Kunz, MD, leader of the gastrointestinal cancers program at Yale Cancer Center, New Haven, Conn., commented: “What’s important here is that radiation can be safely omitted in many patients with clinically advanced rectal cancer – this is really ‘less is more.’ ”
“We can spare select patients from receiving radiation without compromising efficacy,” she said. “This leads to improved quality of life, and reduced side effects, including things like early menopause and infertility.”
Dr. Kunz spoke at a press briefing where the results were highlighted prior to being presented at a plenary session at the annual meeting of the American Society of Clinical Oncology.
She said the trial was “practice changing, and it aligns incredibly well with the theme at this year’s annual meeting around de-escalation of therapy and partnering with patients.”
Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, added that the theme may be de-escalation, but in this case it is “really more accurately optimization, because you were able to de-escalate in 91%, but you found the 9% who really needed that escalation, if you will.”
The efficacy results were published simultaneously in the New England Journal of Medicine, while the patient-reported outcomes were published in the Journal of Clinical Oncology.
Chemoradiation is standard approach
Presenting the findings, Dr. Schrag began by noting that approximately half of all new rectal cancer diagnoses have locally advanced disease, which in the United States represents 48,000 cases per year.
She explained that the “standard approach” to treatment is 5½ weeks of daily chemoradiation, comprising radiation to the pelvis alongside sensitizing chemotherapy with a fluoropyrimidine, followed by surgery, and then approximately 16 weeks of adjuvant chemotherapy.
“This way, we have achieved very good outcomes,” Dr. Schrag noted, with the inclusion of radiation in the 1980s a “critically important advance” in slowing rates of recurrence, which is a “cause of enormous suffering.”
However, the treatment is “long and hard,” and the pelvic radiation causes “real toxicities,” she said. These can include impaired bowel, bladder, and sexual function, and an increase in late effects, such as increased risk of pelvic fractures and secondary cancers, as well as infertility and early menopause, and impaired bone marrow function.
This depressed bone marrow function can “become a problem for people going into chemotherapy into the future,” while infertility and early menopause are “a big deal because we’re seeing increasing diagnosis of rectal cancer in people before the age of 50 years.”
Dr. Schrag said that, since chemoradiotherapy became the standard of care, there has been “so much progress,” with better chemotherapy, better surgical techniques, and more screening, so we’re finding more tumors when they are smaller and easier to treat.”
The impetus for the PROSPECT trial, Dr. Schrag said, was therefore: “Could we use radiotherapy more selectively, and only give it to people who don’t respond to chemotherapy rather than giving [it] to everybody?”
The trial enrolled 1,128 patients with rectal cancer with clinically staged T2 node–positive, T3 node–negative, or T3 node–positive disease and who were candidates for sphincter-sparing surgery.
They were randomly assigned to receive either a modified chemotherapy regimen (n = 585) or standard chemoradiation (n = 543). The mean age of the patients was 57 years; 34.5% were female. The majority (85%) were White.
All patients then underwent surgery, with low anterior resection with total mesorectal excision.
The standard chemoradiotherapy consisted of pelvic radiotherapy at 50.4 Gy over 28 fractions alongside sensitizing chemotherapy with either fluorouracil or capecitabine.
The modified chemotherapy regimen consisted of mFOLFOX6, which included modified oxaliplatin with l-leucovorin, and bolus/continuous infusion of 5-fluorouracil.
Patients in the mFOLFOX6 group whose primary tumor decreased in size by at least 20% after the six cycles proceeded straight to surgery, while were rest given the chemoradiotherapy before surgery (9% ended up receiving chemoradiotherapy).
Postoperative adjuvant chemotherapy with six cycles in the mFOLFOX6 group, or eight cycles in the chemoradiotherapy group, was suggested but not mandated.
Dr. Schrag said in an interview that the team chose to use mFOLFOX6 because of their long experience in using it.
FOLFOX first became available in 2002, and randomized controlled trials showed that it was more effective than 5-fluorouracil alone in colon cancer trials.
She explained that locally advanced rectal cancer patients were “never included” in those trials because they were already receiving chemoradiotherapy, but that its use in metastatic rectal cancer, coupled with the data in colon cancer, led them to try it in the current setting.
“It’s also quite tolerable, it’s given every 2 weeks, and it’s familiar to oncologists everywhere,” Dr. Schrag added.
She noted that it’s “not risk free,” with an increased risk of neuropathy, “which is not a great side effect, but we’re able to modulate that.”
Trial results
After a median follow-up of 58 months, mFOLFOX6 was found to be noninferior to chemoradiotherapy for disease-free survival, at a hazard ratio for disease recurrence or death of 0.92 (P = .005 for noninferiority).
The 5-year disease-free survival was 80.8% in the mFOLFOX6 group and 78.6% among patients assigned to chemoradiotherapy, while 5-year overall survival was 89.5% versus 90.2%, at a nonsignificant HR for death of 1.04.
Rates of local recurrence at 5 years were low, at 1.8% with mFOLFOX6 and 1.6% with chemoradiotherapy.
Grade 3 or higher adverse effects were twice as common in the mFOLFOX6 group than among patients who received chemoradiotherapy, at 41% versus 22.8%, although the researchers noted that the treatment period was also twice as long in the chemotherapy arm.
The most common grade 3 or higher adverse effects with mFOLFOX6 were neutropenia (20.3%), pain (3.1%), and hypertension (2.9%), while those with chemoradiotherapy were lymphopenia (8.3%), diarrhea (6.4%), and hypertension (1.7%).
In terms of patient reported outcomes, patients receiving mFOLFOX6 reported lower rates of diarrhea and better overall bowel function during the neoadjuvant phase than those given chemoradiotherapy (P < .05 for all).
However, those assigned to chemoradiotherapy experienced lower rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting during treatment (P < .05 for all).
At 12-month postoperative follow-up, however, those differences had disappeared, and patients originally assigned to mFOLFOX6 had lower rates of fatigue and neuropathy, and better sexual function, than those given chemoradiotherapy (P < .05 for all).
“During the treatment itself, multiple symptoms were worse with chemotherapy, but a year after treatment ended, those symptoms resolved and the pattern flipped so that patients who received radiation exhibited lingering symptoms,” said coinvestigator Ethan Basch, MD, MSc, chief of medical oncology, and director of the cancer outcomes research program at University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill.
“Patients ideally will understand the potential impact of treatments on how they feel and function when making choices, so as oncologists we need to talk with our patients about their options and the consequences of those options,” he said in a statement.
The study was funded by the National Cancer Institute of the National Institutes of Health. Dr. Schrag reported relationships with Merck, JAMA, the American Association for Cancer Research, and Grail. Dr. Basch reported relationships with AstraZeneca, Navigating Cancer, Resilience Care, SIVAN Innovation, ASCO, Centers for Medicare & Medicaid Services, JAMA, the National Cancer Institute, and the Patient-Centered Outcomes Research Institute. Dr. Kunz reported relationships with Novartis, Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich. Dr. Gralow reported relationships with Genentech/Roche.
A version of this article first appeared on Medscape.com.
“This study establishes preoperative therapy with FOLFOX and only selective use of chemoradiation for patients with locally advanced rectal cancer,” commented principal investigator Deborah Schrag, MD, MPH, gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center, New York.
“Having this option is important for several reasons,” she said. “First, in many parts of the world, radiation therapy is not readily accessible. An all-chemotherapy approach may make curative intent treatment accessible for patients in these resource-constrained settings. Additionally, given the rising rates of colorectal cancer in young patients, this provides an option for patients who wish to preserve fertility or avoid early menopause.”
Reacting to the findings, Pamela Kunz, MD, leader of the gastrointestinal cancers program at Yale Cancer Center, New Haven, Conn., commented: “What’s important here is that radiation can be safely omitted in many patients with clinically advanced rectal cancer – this is really ‘less is more.’ ”
“We can spare select patients from receiving radiation without compromising efficacy,” she said. “This leads to improved quality of life, and reduced side effects, including things like early menopause and infertility.”
Dr. Kunz spoke at a press briefing where the results were highlighted prior to being presented at a plenary session at the annual meeting of the American Society of Clinical Oncology.
She said the trial was “practice changing, and it aligns incredibly well with the theme at this year’s annual meeting around de-escalation of therapy and partnering with patients.”
Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, added that the theme may be de-escalation, but in this case it is “really more accurately optimization, because you were able to de-escalate in 91%, but you found the 9% who really needed that escalation, if you will.”
The efficacy results were published simultaneously in the New England Journal of Medicine, while the patient-reported outcomes were published in the Journal of Clinical Oncology.
Chemoradiation is standard approach
Presenting the findings, Dr. Schrag began by noting that approximately half of all new rectal cancer diagnoses have locally advanced disease, which in the United States represents 48,000 cases per year.
She explained that the “standard approach” to treatment is 5½ weeks of daily chemoradiation, comprising radiation to the pelvis alongside sensitizing chemotherapy with a fluoropyrimidine, followed by surgery, and then approximately 16 weeks of adjuvant chemotherapy.
“This way, we have achieved very good outcomes,” Dr. Schrag noted, with the inclusion of radiation in the 1980s a “critically important advance” in slowing rates of recurrence, which is a “cause of enormous suffering.”
However, the treatment is “long and hard,” and the pelvic radiation causes “real toxicities,” she said. These can include impaired bowel, bladder, and sexual function, and an increase in late effects, such as increased risk of pelvic fractures and secondary cancers, as well as infertility and early menopause, and impaired bone marrow function.
This depressed bone marrow function can “become a problem for people going into chemotherapy into the future,” while infertility and early menopause are “a big deal because we’re seeing increasing diagnosis of rectal cancer in people before the age of 50 years.”
Dr. Schrag said that, since chemoradiotherapy became the standard of care, there has been “so much progress,” with better chemotherapy, better surgical techniques, and more screening, so we’re finding more tumors when they are smaller and easier to treat.”
The impetus for the PROSPECT trial, Dr. Schrag said, was therefore: “Could we use radiotherapy more selectively, and only give it to people who don’t respond to chemotherapy rather than giving [it] to everybody?”
The trial enrolled 1,128 patients with rectal cancer with clinically staged T2 node–positive, T3 node–negative, or T3 node–positive disease and who were candidates for sphincter-sparing surgery.
They were randomly assigned to receive either a modified chemotherapy regimen (n = 585) or standard chemoradiation (n = 543). The mean age of the patients was 57 years; 34.5% were female. The majority (85%) were White.
All patients then underwent surgery, with low anterior resection with total mesorectal excision.
The standard chemoradiotherapy consisted of pelvic radiotherapy at 50.4 Gy over 28 fractions alongside sensitizing chemotherapy with either fluorouracil or capecitabine.
The modified chemotherapy regimen consisted of mFOLFOX6, which included modified oxaliplatin with l-leucovorin, and bolus/continuous infusion of 5-fluorouracil.
Patients in the mFOLFOX6 group whose primary tumor decreased in size by at least 20% after the six cycles proceeded straight to surgery, while were rest given the chemoradiotherapy before surgery (9% ended up receiving chemoradiotherapy).
Postoperative adjuvant chemotherapy with six cycles in the mFOLFOX6 group, or eight cycles in the chemoradiotherapy group, was suggested but not mandated.
Dr. Schrag said in an interview that the team chose to use mFOLFOX6 because of their long experience in using it.
FOLFOX first became available in 2002, and randomized controlled trials showed that it was more effective than 5-fluorouracil alone in colon cancer trials.
She explained that locally advanced rectal cancer patients were “never included” in those trials because they were already receiving chemoradiotherapy, but that its use in metastatic rectal cancer, coupled with the data in colon cancer, led them to try it in the current setting.
“It’s also quite tolerable, it’s given every 2 weeks, and it’s familiar to oncologists everywhere,” Dr. Schrag added.
She noted that it’s “not risk free,” with an increased risk of neuropathy, “which is not a great side effect, but we’re able to modulate that.”
Trial results
After a median follow-up of 58 months, mFOLFOX6 was found to be noninferior to chemoradiotherapy for disease-free survival, at a hazard ratio for disease recurrence or death of 0.92 (P = .005 for noninferiority).
The 5-year disease-free survival was 80.8% in the mFOLFOX6 group and 78.6% among patients assigned to chemoradiotherapy, while 5-year overall survival was 89.5% versus 90.2%, at a nonsignificant HR for death of 1.04.
Rates of local recurrence at 5 years were low, at 1.8% with mFOLFOX6 and 1.6% with chemoradiotherapy.
Grade 3 or higher adverse effects were twice as common in the mFOLFOX6 group than among patients who received chemoradiotherapy, at 41% versus 22.8%, although the researchers noted that the treatment period was also twice as long in the chemotherapy arm.
The most common grade 3 or higher adverse effects with mFOLFOX6 were neutropenia (20.3%), pain (3.1%), and hypertension (2.9%), while those with chemoradiotherapy were lymphopenia (8.3%), diarrhea (6.4%), and hypertension (1.7%).
In terms of patient reported outcomes, patients receiving mFOLFOX6 reported lower rates of diarrhea and better overall bowel function during the neoadjuvant phase than those given chemoradiotherapy (P < .05 for all).
However, those assigned to chemoradiotherapy experienced lower rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting during treatment (P < .05 for all).
At 12-month postoperative follow-up, however, those differences had disappeared, and patients originally assigned to mFOLFOX6 had lower rates of fatigue and neuropathy, and better sexual function, than those given chemoradiotherapy (P < .05 for all).
“During the treatment itself, multiple symptoms were worse with chemotherapy, but a year after treatment ended, those symptoms resolved and the pattern flipped so that patients who received radiation exhibited lingering symptoms,” said coinvestigator Ethan Basch, MD, MSc, chief of medical oncology, and director of the cancer outcomes research program at University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill.
“Patients ideally will understand the potential impact of treatments on how they feel and function when making choices, so as oncologists we need to talk with our patients about their options and the consequences of those options,” he said in a statement.
The study was funded by the National Cancer Institute of the National Institutes of Health. Dr. Schrag reported relationships with Merck, JAMA, the American Association for Cancer Research, and Grail. Dr. Basch reported relationships with AstraZeneca, Navigating Cancer, Resilience Care, SIVAN Innovation, ASCO, Centers for Medicare & Medicaid Services, JAMA, the National Cancer Institute, and the Patient-Centered Outcomes Research Institute. Dr. Kunz reported relationships with Novartis, Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich. Dr. Gralow reported relationships with Genentech/Roche.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
Cross-border U.S.-Mexican collaboration drives up ALL survival
A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.
Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.
For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.
“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.
The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.
Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.
“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
‘Huge survival gap’
“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.
This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.
“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.
Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”
She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”
Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”
Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.
However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.
“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
Study details
Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.
In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.
The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.
“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.
This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.
Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.
Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.
Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
Impact of the collaboration
To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.
The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.
Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”
Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.
“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.
The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.
A version of this article first appeared on Medscape.com.
A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.
Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.
For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.
“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.
The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.
Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.
“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
‘Huge survival gap’
“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.
This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.
“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.
Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”
She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”
Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”
Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.
However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.
“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
Study details
Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.
In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.
The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.
“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.
This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.
Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.
Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.
Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
Impact of the collaboration
To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.
The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.
Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”
Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.
“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.
The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.
A version of this article first appeared on Medscape.com.
A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.
Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.
For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.
“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.
The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.
Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.
“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
‘Huge survival gap’
“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.
This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.
“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.
Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”
She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”
Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”
Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.
However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.
“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
Study details
Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.
In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.
The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.
“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.
This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.
Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.
Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.
Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
Impact of the collaboration
To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.
The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.
Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”
Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.
“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.
The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.
A version of this article first appeared on Medscape.com.
FROM ASCO 2023
Lomitapide shows promise in pediatric homozygous FH
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.
Intensive BP reduction after stroke recanalization harmful
MUNICH, GERMANY – 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 – 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 – 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.
AT ESOC 2023
Minimally invasive vs. open surgery in pancreatic cancer
, 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.
, 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.
, 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.
FROM ASCO 2023
Overweight in heterozygous FH tied to even higher CAD risk
MANNHEIM, GERMANY – – 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 – – 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 – – 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.
AT EAS 2023
Cardiopathy no basis for choosing anticoagulation in ESUS
MUNICH, GERMANY – 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 – 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 – 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.
FROM ESOC 2023
No added benefit from revascularization in low-risk CAS
MUNICH – , 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 – , 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 – , 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.
FROM ESOC 2023
Half of deaths from homozygous FH occur before age 32 years
MANNHEIM, GERMANY –
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 –
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 –
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.