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AI tool predicts certain GI cancers years in advance
TOPLINE:
and is more accurate than other tools, a large study suggests.
METHODOLOGY:
- Researchers performed a case-control study using data from the Veterans Affairs Central Cancer Registry.
- They identified 8,430 patients with EAC and 2,965 patients GCA; these patients were compared with more than 10 million control patients.
- K-ECAN uses basic information in the EHR to determine an individual’s future risk of developing EAC or GCA.
TAKEAWAY:
- With an area under the receiver operating characteristic of 0.77, K-ECAN demonstrated better discrimination than previously validated models and published guidelines.
- Using only data from 3 to 5 years prior to diagnosis only slightly diminished its accuracy (AUROC, 0.75).
- K-ECAN remained the most accurate tool when undersampling men to simulate a non-VHA population (AUROC, 0.85).
- Although gastroesophageal reflux disease (GERD) was strongly associated with EAC, it only contributed a small proportion of gain in information for prediction.
IN PRACTICE:
Because K-ECAN does not rely heavily on GERD symptoms to assess risk, it has the “potential to guide providers to increase appropriate uptake of screening. De-emphasizing GERD in decisions to offer screening could paradoxically increase appropriate uptake of screening for EAC and GCA,” the authors wrote.
SOURCE:
The study, with first author Joel H. Rubenstein, MD, with the LTC Charles S. Kettles VA Medical Center, Ann Arbor, Mich., was published online in Gastroenterology.
LIMITATIONS:
K-ECAN was developed and validated among U.S. veterans and needs to be validated in other populations.
DISCLOSURES:
Funding for the study was provided by the Department of Defense. Dr. Rubenstein has received research support from Lucid Diagnostics.
A version of this article first appeared on Medscape.com.
TOPLINE:
and is more accurate than other tools, a large study suggests.
METHODOLOGY:
- Researchers performed a case-control study using data from the Veterans Affairs Central Cancer Registry.
- They identified 8,430 patients with EAC and 2,965 patients GCA; these patients were compared with more than 10 million control patients.
- K-ECAN uses basic information in the EHR to determine an individual’s future risk of developing EAC or GCA.
TAKEAWAY:
- With an area under the receiver operating characteristic of 0.77, K-ECAN demonstrated better discrimination than previously validated models and published guidelines.
- Using only data from 3 to 5 years prior to diagnosis only slightly diminished its accuracy (AUROC, 0.75).
- K-ECAN remained the most accurate tool when undersampling men to simulate a non-VHA population (AUROC, 0.85).
- Although gastroesophageal reflux disease (GERD) was strongly associated with EAC, it only contributed a small proportion of gain in information for prediction.
IN PRACTICE:
Because K-ECAN does not rely heavily on GERD symptoms to assess risk, it has the “potential to guide providers to increase appropriate uptake of screening. De-emphasizing GERD in decisions to offer screening could paradoxically increase appropriate uptake of screening for EAC and GCA,” the authors wrote.
SOURCE:
The study, with first author Joel H. Rubenstein, MD, with the LTC Charles S. Kettles VA Medical Center, Ann Arbor, Mich., was published online in Gastroenterology.
LIMITATIONS:
K-ECAN was developed and validated among U.S. veterans and needs to be validated in other populations.
DISCLOSURES:
Funding for the study was provided by the Department of Defense. Dr. Rubenstein has received research support from Lucid Diagnostics.
A version of this article first appeared on Medscape.com.
TOPLINE:
and is more accurate than other tools, a large study suggests.
METHODOLOGY:
- Researchers performed a case-control study using data from the Veterans Affairs Central Cancer Registry.
- They identified 8,430 patients with EAC and 2,965 patients GCA; these patients were compared with more than 10 million control patients.
- K-ECAN uses basic information in the EHR to determine an individual’s future risk of developing EAC or GCA.
TAKEAWAY:
- With an area under the receiver operating characteristic of 0.77, K-ECAN demonstrated better discrimination than previously validated models and published guidelines.
- Using only data from 3 to 5 years prior to diagnosis only slightly diminished its accuracy (AUROC, 0.75).
- K-ECAN remained the most accurate tool when undersampling men to simulate a non-VHA population (AUROC, 0.85).
- Although gastroesophageal reflux disease (GERD) was strongly associated with EAC, it only contributed a small proportion of gain in information for prediction.
IN PRACTICE:
Because K-ECAN does not rely heavily on GERD symptoms to assess risk, it has the “potential to guide providers to increase appropriate uptake of screening. De-emphasizing GERD in decisions to offer screening could paradoxically increase appropriate uptake of screening for EAC and GCA,” the authors wrote.
SOURCE:
The study, with first author Joel H. Rubenstein, MD, with the LTC Charles S. Kettles VA Medical Center, Ann Arbor, Mich., was published online in Gastroenterology.
LIMITATIONS:
K-ECAN was developed and validated among U.S. veterans and needs to be validated in other populations.
DISCLOSURES:
Funding for the study was provided by the Department of Defense. Dr. Rubenstein has received research support from Lucid Diagnostics.
A version of this article first appeared on Medscape.com.
FROM GASTROENTEROLOGY
Delaying palliative chemo may improve QoL without affecting survival for asymptomatic patients
TOPLINE:
METHODOLOGY:
- Traditionally, chemotherapy is started immediately when advanced cancer is diagnosed, but delaying chemotherapy until symptoms start could improve QoL.
- To find out, investigators performed a meta-analysis of five studies that explored the timing of palliative chemotherapy. The analysis included three randomized trials in advanced colorectal cancer (CRC), one in advanced ovarian cancer, and a review of patients with stage IV gastric cancer.
- Of the 919 patients, treatment was delayed for 467 patients (50.8%) until symptoms started in the colorectal trials. It was delayed until tumor recurrence in the ovarian cancer trial, and it was delayed until a month or more had passed in the gastric cancer study, regardless of symptoms.
- QoL was assessed largely by the EORTC-QLQ-C30 questionnaire. Median follow-up ranged from 11 to 60 months.
TAKEAWAY:
- The researchers found no significant differences in overall survival between patients for whom chemotherapy was delayed and those for whom chemotherapy began immediately (pooled hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.90-1.22; P = .52).
- Median overall survival was 11.9 to 25.7 months with immediate treatment, vs. 9 to 27.1 months with delayed treatment.
- In the three studies that evaluated QoL, the findings suggested that QoL was largely better among patients whose treatment was delayed. In the CRC studies that assessed QoL, for instance, global health status in the delayed treatment group was higher than that in the immediate treatment group at almost all time points, but not significantly so.
- Rates of grade 3/4 toxicities, evaluated in two studies, did not differ significantly between the groups.
IN PRACTICE:
There is limited evidence on the optimal timing for starting chemotherapy for asymptomatic patients with advanced cancer. In these studies, delaying chemotherapy until symptoms occurred did not result in worse overall survival compared with immediate treatment and may have resulted in better QoL, the researchers concluded. They noted that for asymptomatic patients, delaying the start of systemic therapy should be discussed with the patient.
SOURCE:
The study, led by Simone Augustinus of the University of Amsterdam, was published online Aug. 17 in The Oncologist.
LIMITATIONS:
- Only three types of cancer were included in the analysis, and the findings may not be generalizable to other types of cancer.
- Some of the studies were older and employed out-of-date treatment regimens.
- QoL was only evaluated in three of five studies and could not be evaluated overall in the meta-analysis because of the different time points measured in each trial.
DISCLOSURES:
The study received no external funding. Two investigators have advisory, speaker, and/or research ties to Celgene, Novartis, AstraZeneca, and other companies.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Traditionally, chemotherapy is started immediately when advanced cancer is diagnosed, but delaying chemotherapy until symptoms start could improve QoL.
- To find out, investigators performed a meta-analysis of five studies that explored the timing of palliative chemotherapy. The analysis included three randomized trials in advanced colorectal cancer (CRC), one in advanced ovarian cancer, and a review of patients with stage IV gastric cancer.
- Of the 919 patients, treatment was delayed for 467 patients (50.8%) until symptoms started in the colorectal trials. It was delayed until tumor recurrence in the ovarian cancer trial, and it was delayed until a month or more had passed in the gastric cancer study, regardless of symptoms.
- QoL was assessed largely by the EORTC-QLQ-C30 questionnaire. Median follow-up ranged from 11 to 60 months.
TAKEAWAY:
- The researchers found no significant differences in overall survival between patients for whom chemotherapy was delayed and those for whom chemotherapy began immediately (pooled hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.90-1.22; P = .52).
- Median overall survival was 11.9 to 25.7 months with immediate treatment, vs. 9 to 27.1 months with delayed treatment.
- In the three studies that evaluated QoL, the findings suggested that QoL was largely better among patients whose treatment was delayed. In the CRC studies that assessed QoL, for instance, global health status in the delayed treatment group was higher than that in the immediate treatment group at almost all time points, but not significantly so.
- Rates of grade 3/4 toxicities, evaluated in two studies, did not differ significantly between the groups.
IN PRACTICE:
There is limited evidence on the optimal timing for starting chemotherapy for asymptomatic patients with advanced cancer. In these studies, delaying chemotherapy until symptoms occurred did not result in worse overall survival compared with immediate treatment and may have resulted in better QoL, the researchers concluded. They noted that for asymptomatic patients, delaying the start of systemic therapy should be discussed with the patient.
SOURCE:
The study, led by Simone Augustinus of the University of Amsterdam, was published online Aug. 17 in The Oncologist.
LIMITATIONS:
- Only three types of cancer were included in the analysis, and the findings may not be generalizable to other types of cancer.
- Some of the studies were older and employed out-of-date treatment regimens.
- QoL was only evaluated in three of five studies and could not be evaluated overall in the meta-analysis because of the different time points measured in each trial.
DISCLOSURES:
The study received no external funding. Two investigators have advisory, speaker, and/or research ties to Celgene, Novartis, AstraZeneca, and other companies.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Traditionally, chemotherapy is started immediately when advanced cancer is diagnosed, but delaying chemotherapy until symptoms start could improve QoL.
- To find out, investigators performed a meta-analysis of five studies that explored the timing of palliative chemotherapy. The analysis included three randomized trials in advanced colorectal cancer (CRC), one in advanced ovarian cancer, and a review of patients with stage IV gastric cancer.
- Of the 919 patients, treatment was delayed for 467 patients (50.8%) until symptoms started in the colorectal trials. It was delayed until tumor recurrence in the ovarian cancer trial, and it was delayed until a month or more had passed in the gastric cancer study, regardless of symptoms.
- QoL was assessed largely by the EORTC-QLQ-C30 questionnaire. Median follow-up ranged from 11 to 60 months.
TAKEAWAY:
- The researchers found no significant differences in overall survival between patients for whom chemotherapy was delayed and those for whom chemotherapy began immediately (pooled hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.90-1.22; P = .52).
- Median overall survival was 11.9 to 25.7 months with immediate treatment, vs. 9 to 27.1 months with delayed treatment.
- In the three studies that evaluated QoL, the findings suggested that QoL was largely better among patients whose treatment was delayed. In the CRC studies that assessed QoL, for instance, global health status in the delayed treatment group was higher than that in the immediate treatment group at almost all time points, but not significantly so.
- Rates of grade 3/4 toxicities, evaluated in two studies, did not differ significantly between the groups.
IN PRACTICE:
There is limited evidence on the optimal timing for starting chemotherapy for asymptomatic patients with advanced cancer. In these studies, delaying chemotherapy until symptoms occurred did not result in worse overall survival compared with immediate treatment and may have resulted in better QoL, the researchers concluded. They noted that for asymptomatic patients, delaying the start of systemic therapy should be discussed with the patient.
SOURCE:
The study, led by Simone Augustinus of the University of Amsterdam, was published online Aug. 17 in The Oncologist.
LIMITATIONS:
- Only three types of cancer were included in the analysis, and the findings may not be generalizable to other types of cancer.
- Some of the studies were older and employed out-of-date treatment regimens.
- QoL was only evaluated in three of five studies and could not be evaluated overall in the meta-analysis because of the different time points measured in each trial.
DISCLOSURES:
The study received no external funding. Two investigators have advisory, speaker, and/or research ties to Celgene, Novartis, AstraZeneca, and other companies.
A version of this article first appeared on Medscape.com.
FROM THE ONCOLOGIST
Hemophilia: Concizumab lessens bleeding, could expand treatment options
Concizumab (Novo Nordisk), a subcutaneous monoclonal antibody administered once daily, shows significant reductions in annualized bleeding rates in patients with hemophilia A or B with inhibitors, potentially representing the first subcutaneous treatment option for patients with hemophilia B with inhibitors.
“These results demonstrate the potential of concizumab as an efficacious treatment option for people living with hemophilia A or B with inhibitors – the latter a population with severely limited treatment options,” first author Tadashi Matsushita, MD, PhD, of the department of transfusion medicine, Nagoya (Japan) University Hospital, said in an interview regarding the study, published in the New England Journal of Medicine.
The results are from the prospective, multicenter, phase 3 explorer7 trial, involving 133 patients, including 80 with hemophilia A and 53 had hemophilia B, all with inhibitors, a complication of hemophilia therapy in which antibodies ‘inhibit’ clot formation and complicate standard treatment.
The patients, aged 12 or older and all receiving on-demand treatment with bypassing agents, were randomized to receive no prophylaxis for at least 24 weeks (n = 19) or concizumab prophylaxis for at least 32 weeks (n = 33), with the remaining patients nonrandomly assigned to two groups receiving concizumab prophylaxis for at least 24 weeks (n = 81).
For the primary endpoint of the estimated mean annualized bleeding rate, the rate in the no-prophylaxis group was 11.8 episodes versus just 1.7 episodes in the concizumab prophylaxis 32-week group (rate ratio, 0.14; P < .001).
The overall median annualized bleeding rate for patients in all three groups receiving concizumab was zero episodes.
Annualized rates of treated spontaneous, joint, and target joint bleeding episodes were also lower in the concizumab groups versus the no-prophylaxis group, with annualized rate ratios that were similar to the annualized rate ratio for the primary endpoint.
While similar annualized bleeding rates were observed in hemophilia subtypes, the study wasn’t powered to show superiority according the hemophilia A or B, the authors noted.
Plasma concentrations of concizumab remained stable over the course of the study.
There were no significant differences in terms of key secondary endpoints of change in bodily pain and physical functioning scores from the start of treatment to week 24.
Pause for safety
Treatment in the study was paused for 6 months from March 2020 to August 2020 following nonfatal thromboembolic events occurring in three patients receiving concizumab, including one in the explorer7 trial and two in the concurrent explorer8 trial, evaluating the drug in patients with hemophilia without inhibitors.
The authors wrote that the three patients had all received concomitant treatment for bleeding and had thrombotic risk factors including obesity and other comorbidities.
The trial resumed following mitigation measures that included revising the dosing regimen to include a 1–mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab. No further thromboembolic events were reported after the pause. Otherwise, adverse events were mainly low grade, with serious events being rare.
Option for hemophilia B important
Of the two disease types, hemophilia A is much more common, with an estimated prevalence in the United States of 12 cases per 100,000 males versus hemophilia B, which has a rate of only 3.7 cases per 100,000, according to the Centers for Disease Control and Prevention. Women make up only about 1% of cases with moderate to severe hemophilia.
A standard treatment of hemophilia A or B is prophylaxis with factor replacement therapies allow for improved clotting and reduced bleeding. However, one caveat is the need for intravenous injections, as often as once daily in some cases.
The development of inhibitors in response to replacement therapy may further necessitate the need for treatment with bypassing agents for breakthrough bleeding.
As an alternative, non–factor replacement therapies can promote coagulation, notably the factor VIII mimetic emicizumab, given by subcutaneous injection, and approved by the Food and Drug Administration in 2018 for patients with and without inhibitors.
Emicizumab is recommended by the World Federation on Hemophilia over bypassing agents as prophylaxis for patients with hemophilia A and persistent inhibitors.
Importantly, however, there are no effective prophylactic treatments or easily administered subcutaneous therapies available for hemophilia B with inhibitors, underscoring the potential importance of concizumab, which targets the tissue factor pathway inhibitor protein, linked to coagulation.
“Concizumab has the potential to become the first subcutaneous and first-in-class treatment for hemophilia B with inhibitors,” Dr. Matsushita said. “There are other therapies investigated for hemophilia B with and without inhibitors still in clinical development,” he noted.
FDA resubmission planned
In May, Novo Nordisk announced that the FDA had rejected its application for concizumab, requesting more information on the drug’s manufacturing process and its system for the monitoring and dosing of patients to ensure proper drug administration. In a statement, Novo Nordisk reported its plans to move ahead.
“Novo Nordisk has begun addressing the FDA’s feedback and is working closely with the FDA as plans for resubmission continue,” the company reported. “We are confident in the potential of concizumab to address a significant unmet need, particularly for people with hemophilia B with inhibitors who currently have limited prophylactic options and are committed to bringing this important treatment to people with hemophilia with inhibitors living in the U.S.A.”
Meanwhile in Canada, concizumab was approved in March 2023 for the treatment of adolescent and adult patients with hemophilia B with inhibitors and who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
The authors wrote that concizumab continues to be investigated across all hemophilia subtypes, including in the explorer10 study, which is evaluating the drug in children living with hemophilia A or B, with and without inhibitors.
The study was supported by Novo Nordisk. Dr. Matsushita reported speaking for and participating on a scientific advisory board of Novo Nordisk.
Concizumab (Novo Nordisk), a subcutaneous monoclonal antibody administered once daily, shows significant reductions in annualized bleeding rates in patients with hemophilia A or B with inhibitors, potentially representing the first subcutaneous treatment option for patients with hemophilia B with inhibitors.
“These results demonstrate the potential of concizumab as an efficacious treatment option for people living with hemophilia A or B with inhibitors – the latter a population with severely limited treatment options,” first author Tadashi Matsushita, MD, PhD, of the department of transfusion medicine, Nagoya (Japan) University Hospital, said in an interview regarding the study, published in the New England Journal of Medicine.
The results are from the prospective, multicenter, phase 3 explorer7 trial, involving 133 patients, including 80 with hemophilia A and 53 had hemophilia B, all with inhibitors, a complication of hemophilia therapy in which antibodies ‘inhibit’ clot formation and complicate standard treatment.
The patients, aged 12 or older and all receiving on-demand treatment with bypassing agents, were randomized to receive no prophylaxis for at least 24 weeks (n = 19) or concizumab prophylaxis for at least 32 weeks (n = 33), with the remaining patients nonrandomly assigned to two groups receiving concizumab prophylaxis for at least 24 weeks (n = 81).
For the primary endpoint of the estimated mean annualized bleeding rate, the rate in the no-prophylaxis group was 11.8 episodes versus just 1.7 episodes in the concizumab prophylaxis 32-week group (rate ratio, 0.14; P < .001).
The overall median annualized bleeding rate for patients in all three groups receiving concizumab was zero episodes.
Annualized rates of treated spontaneous, joint, and target joint bleeding episodes were also lower in the concizumab groups versus the no-prophylaxis group, with annualized rate ratios that were similar to the annualized rate ratio for the primary endpoint.
While similar annualized bleeding rates were observed in hemophilia subtypes, the study wasn’t powered to show superiority according the hemophilia A or B, the authors noted.
Plasma concentrations of concizumab remained stable over the course of the study.
There were no significant differences in terms of key secondary endpoints of change in bodily pain and physical functioning scores from the start of treatment to week 24.
Pause for safety
Treatment in the study was paused for 6 months from March 2020 to August 2020 following nonfatal thromboembolic events occurring in three patients receiving concizumab, including one in the explorer7 trial and two in the concurrent explorer8 trial, evaluating the drug in patients with hemophilia without inhibitors.
The authors wrote that the three patients had all received concomitant treatment for bleeding and had thrombotic risk factors including obesity and other comorbidities.
The trial resumed following mitigation measures that included revising the dosing regimen to include a 1–mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab. No further thromboembolic events were reported after the pause. Otherwise, adverse events were mainly low grade, with serious events being rare.
Option for hemophilia B important
Of the two disease types, hemophilia A is much more common, with an estimated prevalence in the United States of 12 cases per 100,000 males versus hemophilia B, which has a rate of only 3.7 cases per 100,000, according to the Centers for Disease Control and Prevention. Women make up only about 1% of cases with moderate to severe hemophilia.
A standard treatment of hemophilia A or B is prophylaxis with factor replacement therapies allow for improved clotting and reduced bleeding. However, one caveat is the need for intravenous injections, as often as once daily in some cases.
The development of inhibitors in response to replacement therapy may further necessitate the need for treatment with bypassing agents for breakthrough bleeding.
As an alternative, non–factor replacement therapies can promote coagulation, notably the factor VIII mimetic emicizumab, given by subcutaneous injection, and approved by the Food and Drug Administration in 2018 for patients with and without inhibitors.
Emicizumab is recommended by the World Federation on Hemophilia over bypassing agents as prophylaxis for patients with hemophilia A and persistent inhibitors.
Importantly, however, there are no effective prophylactic treatments or easily administered subcutaneous therapies available for hemophilia B with inhibitors, underscoring the potential importance of concizumab, which targets the tissue factor pathway inhibitor protein, linked to coagulation.
“Concizumab has the potential to become the first subcutaneous and first-in-class treatment for hemophilia B with inhibitors,” Dr. Matsushita said. “There are other therapies investigated for hemophilia B with and without inhibitors still in clinical development,” he noted.
FDA resubmission planned
In May, Novo Nordisk announced that the FDA had rejected its application for concizumab, requesting more information on the drug’s manufacturing process and its system for the monitoring and dosing of patients to ensure proper drug administration. In a statement, Novo Nordisk reported its plans to move ahead.
“Novo Nordisk has begun addressing the FDA’s feedback and is working closely with the FDA as plans for resubmission continue,” the company reported. “We are confident in the potential of concizumab to address a significant unmet need, particularly for people with hemophilia B with inhibitors who currently have limited prophylactic options and are committed to bringing this important treatment to people with hemophilia with inhibitors living in the U.S.A.”
Meanwhile in Canada, concizumab was approved in March 2023 for the treatment of adolescent and adult patients with hemophilia B with inhibitors and who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
The authors wrote that concizumab continues to be investigated across all hemophilia subtypes, including in the explorer10 study, which is evaluating the drug in children living with hemophilia A or B, with and without inhibitors.
The study was supported by Novo Nordisk. Dr. Matsushita reported speaking for and participating on a scientific advisory board of Novo Nordisk.
Concizumab (Novo Nordisk), a subcutaneous monoclonal antibody administered once daily, shows significant reductions in annualized bleeding rates in patients with hemophilia A or B with inhibitors, potentially representing the first subcutaneous treatment option for patients with hemophilia B with inhibitors.
“These results demonstrate the potential of concizumab as an efficacious treatment option for people living with hemophilia A or B with inhibitors – the latter a population with severely limited treatment options,” first author Tadashi Matsushita, MD, PhD, of the department of transfusion medicine, Nagoya (Japan) University Hospital, said in an interview regarding the study, published in the New England Journal of Medicine.
The results are from the prospective, multicenter, phase 3 explorer7 trial, involving 133 patients, including 80 with hemophilia A and 53 had hemophilia B, all with inhibitors, a complication of hemophilia therapy in which antibodies ‘inhibit’ clot formation and complicate standard treatment.
The patients, aged 12 or older and all receiving on-demand treatment with bypassing agents, were randomized to receive no prophylaxis for at least 24 weeks (n = 19) or concizumab prophylaxis for at least 32 weeks (n = 33), with the remaining patients nonrandomly assigned to two groups receiving concizumab prophylaxis for at least 24 weeks (n = 81).
For the primary endpoint of the estimated mean annualized bleeding rate, the rate in the no-prophylaxis group was 11.8 episodes versus just 1.7 episodes in the concizumab prophylaxis 32-week group (rate ratio, 0.14; P < .001).
The overall median annualized bleeding rate for patients in all three groups receiving concizumab was zero episodes.
Annualized rates of treated spontaneous, joint, and target joint bleeding episodes were also lower in the concizumab groups versus the no-prophylaxis group, with annualized rate ratios that were similar to the annualized rate ratio for the primary endpoint.
While similar annualized bleeding rates were observed in hemophilia subtypes, the study wasn’t powered to show superiority according the hemophilia A or B, the authors noted.
Plasma concentrations of concizumab remained stable over the course of the study.
There were no significant differences in terms of key secondary endpoints of change in bodily pain and physical functioning scores from the start of treatment to week 24.
Pause for safety
Treatment in the study was paused for 6 months from March 2020 to August 2020 following nonfatal thromboembolic events occurring in three patients receiving concizumab, including one in the explorer7 trial and two in the concurrent explorer8 trial, evaluating the drug in patients with hemophilia without inhibitors.
The authors wrote that the three patients had all received concomitant treatment for bleeding and had thrombotic risk factors including obesity and other comorbidities.
The trial resumed following mitigation measures that included revising the dosing regimen to include a 1–mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab. No further thromboembolic events were reported after the pause. Otherwise, adverse events were mainly low grade, with serious events being rare.
Option for hemophilia B important
Of the two disease types, hemophilia A is much more common, with an estimated prevalence in the United States of 12 cases per 100,000 males versus hemophilia B, which has a rate of only 3.7 cases per 100,000, according to the Centers for Disease Control and Prevention. Women make up only about 1% of cases with moderate to severe hemophilia.
A standard treatment of hemophilia A or B is prophylaxis with factor replacement therapies allow for improved clotting and reduced bleeding. However, one caveat is the need for intravenous injections, as often as once daily in some cases.
The development of inhibitors in response to replacement therapy may further necessitate the need for treatment with bypassing agents for breakthrough bleeding.
As an alternative, non–factor replacement therapies can promote coagulation, notably the factor VIII mimetic emicizumab, given by subcutaneous injection, and approved by the Food and Drug Administration in 2018 for patients with and without inhibitors.
Emicizumab is recommended by the World Federation on Hemophilia over bypassing agents as prophylaxis for patients with hemophilia A and persistent inhibitors.
Importantly, however, there are no effective prophylactic treatments or easily administered subcutaneous therapies available for hemophilia B with inhibitors, underscoring the potential importance of concizumab, which targets the tissue factor pathway inhibitor protein, linked to coagulation.
“Concizumab has the potential to become the first subcutaneous and first-in-class treatment for hemophilia B with inhibitors,” Dr. Matsushita said. “There are other therapies investigated for hemophilia B with and without inhibitors still in clinical development,” he noted.
FDA resubmission planned
In May, Novo Nordisk announced that the FDA had rejected its application for concizumab, requesting more information on the drug’s manufacturing process and its system for the monitoring and dosing of patients to ensure proper drug administration. In a statement, Novo Nordisk reported its plans to move ahead.
“Novo Nordisk has begun addressing the FDA’s feedback and is working closely with the FDA as plans for resubmission continue,” the company reported. “We are confident in the potential of concizumab to address a significant unmet need, particularly for people with hemophilia B with inhibitors who currently have limited prophylactic options and are committed to bringing this important treatment to people with hemophilia with inhibitors living in the U.S.A.”
Meanwhile in Canada, concizumab was approved in March 2023 for the treatment of adolescent and adult patients with hemophilia B with inhibitors and who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
The authors wrote that concizumab continues to be investigated across all hemophilia subtypes, including in the explorer10 study, which is evaluating the drug in children living with hemophilia A or B, with and without inhibitors.
The study was supported by Novo Nordisk. Dr. Matsushita reported speaking for and participating on a scientific advisory board of Novo Nordisk.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Dietary nitrates reduce contrast-induced nephropathy in ACS
AMSTERDAM –
In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.
The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.
The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.
“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.
He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.
At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.
However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.
“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
Dietary nitrates “make sense”
Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”
On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”
She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.
“We’re all going to get on beet juice after this,” she quipped.
Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.
Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.
“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”
Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.
“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.
“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.
A larger trial is now being planned.
The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.
He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.
“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
Replacing lost nitric oxide
In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.
The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.
“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”
The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.
“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
NITRATE-CIN study
NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.
To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m2 or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.
Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.
The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.
The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.
The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.
Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.
Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.
The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.
As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.
Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).
Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m2 (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.
At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.
Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.
While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.
“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”
In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.
She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”
Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.
The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AMSTERDAM –
In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.
The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.
The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.
“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.
He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.
At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.
However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.
“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
Dietary nitrates “make sense”
Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”
On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”
She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.
“We’re all going to get on beet juice after this,” she quipped.
Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.
Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.
“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”
Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.
“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.
“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.
A larger trial is now being planned.
The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.
He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.
“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
Replacing lost nitric oxide
In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.
The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.
“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”
The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.
“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
NITRATE-CIN study
NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.
To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m2 or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.
Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.
The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.
The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.
The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.
Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.
Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.
The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.
As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.
Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).
Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m2 (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.
At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.
Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.
While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.
“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”
In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.
She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”
Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.
The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AMSTERDAM –
In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.
The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.
The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.
“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.
He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.
At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.
However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.
“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
Dietary nitrates “make sense”
Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”
On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”
She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.
“We’re all going to get on beet juice after this,” she quipped.
Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.
Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.
“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”
Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.
“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.
“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.
A larger trial is now being planned.
The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.
He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.
“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
Replacing lost nitric oxide
In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.
The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.
“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”
The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.
“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
NITRATE-CIN study
NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.
To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m2 or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.
Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.
The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.
The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.
The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.
Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.
Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.
The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.
As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.
Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).
Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m2 (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.
At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.
Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.
While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.
“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”
In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.
She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”
Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.
The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT THE ESC CONGRESS 2023
Urine test shows promise for diagnosing urothelial carcinoma
, according to findings from a recent validation study.
The urinary comprehensive genomic profiling (uCGP) assay (UroAmp, Convergent Genomics) had a specificity of 95% and sensitivity of 90% for an initial diagnosis of urothelial carcinoma in patients with hematuria – identifying 95 of 100 people with urothelial carcinoma and 90 of 100 patients without the disease.
For patients under surveillance for urothelial cancer recurrence, the test was six times more accurate than traditional clinical risk factors for predicting recurrence.
“Considering its performance in multiple areas of urothelial carcinoma diagnosis and monitoring, uCGP shows great promise to enhance delivery of risk-stratified care,” Keyan Salari, MD, PhD, director of the prostate cancer genetics program at Massachusetts General Hospital in Boston, and colleagues wrote in a study published in Clinical Cancer Research.
“The idea is that this could be used as kind of a first-pass screening tool for patients with hematuria that could potentially obviate the need for undergoing imaging such as CT scans or cystoscopy,” Dr. Salari said in an interview.
The uCGP test is a next-generation sequencing assay that identifies mutations in 60 genes associated with bladder cancer. An earlier analysis evaluating the test as a potential screening tool focused on 10 key genes covered in the assay. The study found the test accurately predicted future bladder cancer in 66% of urine samples, including some that had been collected more than a decade prior to being tested.
In the current case-control study, Dr. Salari and colleagues used a total of 581 samples – 333 samples for classifying disease and developing algorithms for initial diagnosis, surveillance, and molecular-grade prediction, as well as 248 samples for blinded validation. The test’s performance was evaluated by calculating sensitivity, specificity, positive predictive value, and negative predictive value.
Overall, the test demonstrated a specificity of 95% and sensitivity of 90% for an initial urothelial carcinoma diagnosis, but performed even better for the most aggressive tumors, with 100% sensitivity for diagnosing high-grade urothelial carcinoma and muscle-invasive tumors.
On the diagnosis front, the test had a positive predictive value of 88% and a negative predictive value of 99%.
Among patients under surveillance, the test predicted the risk of recurrence significantly better than standard clinical risk factors (hazard ratio, 6.2). The test demonstrated a positive predictive value similar to that observed for cytology (45% vs. 42%) but a much higher sensitivity (79% vs. 25%). The test also demonstrated a negative predictive value of 91% for recurrence.
The molecular-grade algorithm performed well, with a positive predictive value for high-grade disease of 88% and a specificity of 95% in the validation cohort.
Overall, “uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients,” the authors concluded. The test is not currently reimbursed by Medicare, but negotiations with third-party payers are reportedly underway.
The study was supported by the National Cancer Institute. Dr. Salari reported grants from Convergent Genomics during the conduct of the study as well as grants from Urology Care Foundation and Prostate Cancer Foundation, and personal fees from OrigiMed outside the submitted work. Several coauthors are employees and stockholders of Convergent Genomics.
A version of this article first appeared on Medscape.com.
, according to findings from a recent validation study.
The urinary comprehensive genomic profiling (uCGP) assay (UroAmp, Convergent Genomics) had a specificity of 95% and sensitivity of 90% for an initial diagnosis of urothelial carcinoma in patients with hematuria – identifying 95 of 100 people with urothelial carcinoma and 90 of 100 patients without the disease.
For patients under surveillance for urothelial cancer recurrence, the test was six times more accurate than traditional clinical risk factors for predicting recurrence.
“Considering its performance in multiple areas of urothelial carcinoma diagnosis and monitoring, uCGP shows great promise to enhance delivery of risk-stratified care,” Keyan Salari, MD, PhD, director of the prostate cancer genetics program at Massachusetts General Hospital in Boston, and colleagues wrote in a study published in Clinical Cancer Research.
“The idea is that this could be used as kind of a first-pass screening tool for patients with hematuria that could potentially obviate the need for undergoing imaging such as CT scans or cystoscopy,” Dr. Salari said in an interview.
The uCGP test is a next-generation sequencing assay that identifies mutations in 60 genes associated with bladder cancer. An earlier analysis evaluating the test as a potential screening tool focused on 10 key genes covered in the assay. The study found the test accurately predicted future bladder cancer in 66% of urine samples, including some that had been collected more than a decade prior to being tested.
In the current case-control study, Dr. Salari and colleagues used a total of 581 samples – 333 samples for classifying disease and developing algorithms for initial diagnosis, surveillance, and molecular-grade prediction, as well as 248 samples for blinded validation. The test’s performance was evaluated by calculating sensitivity, specificity, positive predictive value, and negative predictive value.
Overall, the test demonstrated a specificity of 95% and sensitivity of 90% for an initial urothelial carcinoma diagnosis, but performed even better for the most aggressive tumors, with 100% sensitivity for diagnosing high-grade urothelial carcinoma and muscle-invasive tumors.
On the diagnosis front, the test had a positive predictive value of 88% and a negative predictive value of 99%.
Among patients under surveillance, the test predicted the risk of recurrence significantly better than standard clinical risk factors (hazard ratio, 6.2). The test demonstrated a positive predictive value similar to that observed for cytology (45% vs. 42%) but a much higher sensitivity (79% vs. 25%). The test also demonstrated a negative predictive value of 91% for recurrence.
The molecular-grade algorithm performed well, with a positive predictive value for high-grade disease of 88% and a specificity of 95% in the validation cohort.
Overall, “uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients,” the authors concluded. The test is not currently reimbursed by Medicare, but negotiations with third-party payers are reportedly underway.
The study was supported by the National Cancer Institute. Dr. Salari reported grants from Convergent Genomics during the conduct of the study as well as grants from Urology Care Foundation and Prostate Cancer Foundation, and personal fees from OrigiMed outside the submitted work. Several coauthors are employees and stockholders of Convergent Genomics.
A version of this article first appeared on Medscape.com.
, according to findings from a recent validation study.
The urinary comprehensive genomic profiling (uCGP) assay (UroAmp, Convergent Genomics) had a specificity of 95% and sensitivity of 90% for an initial diagnosis of urothelial carcinoma in patients with hematuria – identifying 95 of 100 people with urothelial carcinoma and 90 of 100 patients without the disease.
For patients under surveillance for urothelial cancer recurrence, the test was six times more accurate than traditional clinical risk factors for predicting recurrence.
“Considering its performance in multiple areas of urothelial carcinoma diagnosis and monitoring, uCGP shows great promise to enhance delivery of risk-stratified care,” Keyan Salari, MD, PhD, director of the prostate cancer genetics program at Massachusetts General Hospital in Boston, and colleagues wrote in a study published in Clinical Cancer Research.
“The idea is that this could be used as kind of a first-pass screening tool for patients with hematuria that could potentially obviate the need for undergoing imaging such as CT scans or cystoscopy,” Dr. Salari said in an interview.
The uCGP test is a next-generation sequencing assay that identifies mutations in 60 genes associated with bladder cancer. An earlier analysis evaluating the test as a potential screening tool focused on 10 key genes covered in the assay. The study found the test accurately predicted future bladder cancer in 66% of urine samples, including some that had been collected more than a decade prior to being tested.
In the current case-control study, Dr. Salari and colleagues used a total of 581 samples – 333 samples for classifying disease and developing algorithms for initial diagnosis, surveillance, and molecular-grade prediction, as well as 248 samples for blinded validation. The test’s performance was evaluated by calculating sensitivity, specificity, positive predictive value, and negative predictive value.
Overall, the test demonstrated a specificity of 95% and sensitivity of 90% for an initial urothelial carcinoma diagnosis, but performed even better for the most aggressive tumors, with 100% sensitivity for diagnosing high-grade urothelial carcinoma and muscle-invasive tumors.
On the diagnosis front, the test had a positive predictive value of 88% and a negative predictive value of 99%.
Among patients under surveillance, the test predicted the risk of recurrence significantly better than standard clinical risk factors (hazard ratio, 6.2). The test demonstrated a positive predictive value similar to that observed for cytology (45% vs. 42%) but a much higher sensitivity (79% vs. 25%). The test also demonstrated a negative predictive value of 91% for recurrence.
The molecular-grade algorithm performed well, with a positive predictive value for high-grade disease of 88% and a specificity of 95% in the validation cohort.
Overall, “uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients,” the authors concluded. The test is not currently reimbursed by Medicare, but negotiations with third-party payers are reportedly underway.
The study was supported by the National Cancer Institute. Dr. Salari reported grants from Convergent Genomics during the conduct of the study as well as grants from Urology Care Foundation and Prostate Cancer Foundation, and personal fees from OrigiMed outside the submitted work. Several coauthors are employees and stockholders of Convergent Genomics.
A version of this article first appeared on Medscape.com.
FROM CLINICAL CANCER RESEARCH
Medicare announces 10 drugs targeted for price cuts in 2026
People on Medicare may in 2026 see prices drop for 10 medicines, including pricey diabetes, cancer, blood clot, and arthritis treatments, if advocates for federal drug-price negotiations can implement their plans amid tough opposition.
It’s unclear at this time, though, how these negotiations will play out. The Chamber of Commerce has sided with pharmaceutical companies in bids to block direct Medicare negotiation of drug prices. Many influential Republicans in Congress oppose this plan, which has deep support from both Democrats and AARP.
While facing strong opposition to negotiations, the Centers for Medicare & Medicaid Services sought in its announcement to illustrate the high costs of the selected medicines.
CMS provided data on total Part D costs for selected medicines for the period from June 2022 to May 2023, along with tallies of the number of people taking these drugs. The 10 selected medicines are as follows:
- Eliquis (generic name: apixaban), used to prevent and treat serious blood clots. It is taken by about 3.7 million people through Part D plans. The estimated cost is $16.4 billion.
- Jardiance (generic name: empagliflozin), used for diabetes and heart failure. It is taken by almost 1.6 million people through Part D plans. The estimated cost is $7.06 billion.
- Xarelto (generic name: rivaroxaban), used for blood clots. It is taken by about 1.3 million people through Part D plans. The estimated cost is $6 billion.
- Januvia (generic name: sitagliptin), used for diabetes. It is taken by about 869,00 people through Part D plans. The estimated cost is $4.1 billion.
- Farxiga (generic name: dapagliflozin), used for diabetes, heart failure, and chronic kidney disease. It is taken by about 799,000 people through Part D plans. The estimated cost is almost $3.3 billion.
- Entresto (generic name: sacubitril/valsartan), used to treat heart failure. It is taken by 587,000 people through Part D plans. The estimated cost is $2.9 billion.
- Enbrel( generic name: etanercept), used for rheumatoid arthritis, psoriasis, and psoriatic arthritis. It is taken by 48,000 people through Part D plans. The estimated cost is $2.8 billion.
- Imbruvica (generic name: ibrutinib), used to treat some blood cancers. It is taken by about 20,000 people in Part D plans. The estimated cost is $2.7 billion.
- Stelara (generic name: ustekinumab), used to treat plaque psoriasis, psoriatic arthritis, or certain bowel conditions (Crohn’s disease, ulcerative colitis). It is used by about 22,000 people through Part D plans. The estimated cost is $2.6 billion.
- Fiasp; Fiasp FlexTouch; Fiasp PenFill; NovoLog; NovoLog FlexPen; NovoLog PenFill. These are forms of insulin used to treat diabetes. They are used by about 777,000 people through Part D plans. The estimated cost is $2.6 billion.
A vocal critic of Medicare drug negotiations, Joel White, president of the Council for Affordable Health Coverage, called the announcement of the 10 drugs selected for negotiation “a hollow victory lap.” A former Republican staffer on the House Ways and Means Committee, Mr. White aided with the development of the Medicare Part D plans and has kept tabs on the pharmacy programs since its launch in 2006.
“No one’s costs will go down now or for years because of this announcement” about Part D negotiations, Mr. White said in a statement.
According to its website, CAHC includes among its members the American Academy of Ophthalmology as well as some patient groups, drugmakers, such as Johnson & Johnson, and insurers and industry groups, such as the National Association of Manufacturers.
Separately, the influential Chamber of Commerce is making a strong push to at least delay the implementation of the Medicare Part D drug negotiations. On Aug. 28, the chamber released a letter sent to the Biden administration, raising concerns about a “rush” to implement the provisions of the Inflation Reduction Act.
The chamber also has filed suit to challenge the drug negotiation provisions of the Inflation Reduction Act, requesting that the court issue a preliminary injunction by Oct. 1, 2023.
Other pending legal challenges to direct Medicare drug negotiations include suits filed by Merck, Bristol-Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, and AstraZeneca, according to an email from Pharmaceutical Research and Manufacturers of America. PhRMA also said it is a party to a case.
In addition, the three congressional Republicans with most direct influence over Medicare policy issued on Aug. 29 a joint statement outlining their objections to the planned negotiations on drug prices.
This drug-negotiation proposal is “an unworkable, legally dubious scheme that will lead to higher prices for new drugs coming to market, stifle the development of new cures, and destroy jobs,” said House Energy and Commerce Committee Chair Cathy McMorris Rodgers (R-Wash.), House Ways and Means Committee Chair Jason Smith (R-Mo.), and Senate Finance Committee Ranking Member Mike Crapo (R-Idaho).
Democrats were equally firm and vocal in their support of the negotiations. Senate Finance Chairman Ron Wyden (D-Ore.) issued a statement on Aug. 29 that said the release of the list of the 10 drugs selected for Medicare drug negotiations is part of a “seismic shift in the relationship between Big Pharma, the federal government, and seniors who are counting on lower prices.
“I will be following the negotiation process closely and will fight any attempt by Big Pharma to undo or undermine the progress that’s been made,” Mr. Wyden said.
In addition, AARP issued a statement of its continued support for Medicare drug negotiations.
“The No. 1 reason seniors skip or ration their prescriptions is because they can’t afford them. This must stop,” said AARP executive vice president and chief advocacy and engagement officer Nancy LeaMond in the statement. “The big drug companies and their allies continue suing to overturn the Medicare drug price negotiation program to keep up their price gouging. We can’t allow seniors to be Big Pharma’s cash machine anymore.”
A version of this article first appeared on Medscape.com.
People on Medicare may in 2026 see prices drop for 10 medicines, including pricey diabetes, cancer, blood clot, and arthritis treatments, if advocates for federal drug-price negotiations can implement their plans amid tough opposition.
It’s unclear at this time, though, how these negotiations will play out. The Chamber of Commerce has sided with pharmaceutical companies in bids to block direct Medicare negotiation of drug prices. Many influential Republicans in Congress oppose this plan, which has deep support from both Democrats and AARP.
While facing strong opposition to negotiations, the Centers for Medicare & Medicaid Services sought in its announcement to illustrate the high costs of the selected medicines.
CMS provided data on total Part D costs for selected medicines for the period from June 2022 to May 2023, along with tallies of the number of people taking these drugs. The 10 selected medicines are as follows:
- Eliquis (generic name: apixaban), used to prevent and treat serious blood clots. It is taken by about 3.7 million people through Part D plans. The estimated cost is $16.4 billion.
- Jardiance (generic name: empagliflozin), used for diabetes and heart failure. It is taken by almost 1.6 million people through Part D plans. The estimated cost is $7.06 billion.
- Xarelto (generic name: rivaroxaban), used for blood clots. It is taken by about 1.3 million people through Part D plans. The estimated cost is $6 billion.
- Januvia (generic name: sitagliptin), used for diabetes. It is taken by about 869,00 people through Part D plans. The estimated cost is $4.1 billion.
- Farxiga (generic name: dapagliflozin), used for diabetes, heart failure, and chronic kidney disease. It is taken by about 799,000 people through Part D plans. The estimated cost is almost $3.3 billion.
- Entresto (generic name: sacubitril/valsartan), used to treat heart failure. It is taken by 587,000 people through Part D plans. The estimated cost is $2.9 billion.
- Enbrel( generic name: etanercept), used for rheumatoid arthritis, psoriasis, and psoriatic arthritis. It is taken by 48,000 people through Part D plans. The estimated cost is $2.8 billion.
- Imbruvica (generic name: ibrutinib), used to treat some blood cancers. It is taken by about 20,000 people in Part D plans. The estimated cost is $2.7 billion.
- Stelara (generic name: ustekinumab), used to treat plaque psoriasis, psoriatic arthritis, or certain bowel conditions (Crohn’s disease, ulcerative colitis). It is used by about 22,000 people through Part D plans. The estimated cost is $2.6 billion.
- Fiasp; Fiasp FlexTouch; Fiasp PenFill; NovoLog; NovoLog FlexPen; NovoLog PenFill. These are forms of insulin used to treat diabetes. They are used by about 777,000 people through Part D plans. The estimated cost is $2.6 billion.
A vocal critic of Medicare drug negotiations, Joel White, president of the Council for Affordable Health Coverage, called the announcement of the 10 drugs selected for negotiation “a hollow victory lap.” A former Republican staffer on the House Ways and Means Committee, Mr. White aided with the development of the Medicare Part D plans and has kept tabs on the pharmacy programs since its launch in 2006.
“No one’s costs will go down now or for years because of this announcement” about Part D negotiations, Mr. White said in a statement.
According to its website, CAHC includes among its members the American Academy of Ophthalmology as well as some patient groups, drugmakers, such as Johnson & Johnson, and insurers and industry groups, such as the National Association of Manufacturers.
Separately, the influential Chamber of Commerce is making a strong push to at least delay the implementation of the Medicare Part D drug negotiations. On Aug. 28, the chamber released a letter sent to the Biden administration, raising concerns about a “rush” to implement the provisions of the Inflation Reduction Act.
The chamber also has filed suit to challenge the drug negotiation provisions of the Inflation Reduction Act, requesting that the court issue a preliminary injunction by Oct. 1, 2023.
Other pending legal challenges to direct Medicare drug negotiations include suits filed by Merck, Bristol-Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, and AstraZeneca, according to an email from Pharmaceutical Research and Manufacturers of America. PhRMA also said it is a party to a case.
In addition, the three congressional Republicans with most direct influence over Medicare policy issued on Aug. 29 a joint statement outlining their objections to the planned negotiations on drug prices.
This drug-negotiation proposal is “an unworkable, legally dubious scheme that will lead to higher prices for new drugs coming to market, stifle the development of new cures, and destroy jobs,” said House Energy and Commerce Committee Chair Cathy McMorris Rodgers (R-Wash.), House Ways and Means Committee Chair Jason Smith (R-Mo.), and Senate Finance Committee Ranking Member Mike Crapo (R-Idaho).
Democrats were equally firm and vocal in their support of the negotiations. Senate Finance Chairman Ron Wyden (D-Ore.) issued a statement on Aug. 29 that said the release of the list of the 10 drugs selected for Medicare drug negotiations is part of a “seismic shift in the relationship between Big Pharma, the federal government, and seniors who are counting on lower prices.
“I will be following the negotiation process closely and will fight any attempt by Big Pharma to undo or undermine the progress that’s been made,” Mr. Wyden said.
In addition, AARP issued a statement of its continued support for Medicare drug negotiations.
“The No. 1 reason seniors skip or ration their prescriptions is because they can’t afford them. This must stop,” said AARP executive vice president and chief advocacy and engagement officer Nancy LeaMond in the statement. “The big drug companies and their allies continue suing to overturn the Medicare drug price negotiation program to keep up their price gouging. We can’t allow seniors to be Big Pharma’s cash machine anymore.”
A version of this article first appeared on Medscape.com.
People on Medicare may in 2026 see prices drop for 10 medicines, including pricey diabetes, cancer, blood clot, and arthritis treatments, if advocates for federal drug-price negotiations can implement their plans amid tough opposition.
It’s unclear at this time, though, how these negotiations will play out. The Chamber of Commerce has sided with pharmaceutical companies in bids to block direct Medicare negotiation of drug prices. Many influential Republicans in Congress oppose this plan, which has deep support from both Democrats and AARP.
While facing strong opposition to negotiations, the Centers for Medicare & Medicaid Services sought in its announcement to illustrate the high costs of the selected medicines.
CMS provided data on total Part D costs for selected medicines for the period from June 2022 to May 2023, along with tallies of the number of people taking these drugs. The 10 selected medicines are as follows:
- Eliquis (generic name: apixaban), used to prevent and treat serious blood clots. It is taken by about 3.7 million people through Part D plans. The estimated cost is $16.4 billion.
- Jardiance (generic name: empagliflozin), used for diabetes and heart failure. It is taken by almost 1.6 million people through Part D plans. The estimated cost is $7.06 billion.
- Xarelto (generic name: rivaroxaban), used for blood clots. It is taken by about 1.3 million people through Part D plans. The estimated cost is $6 billion.
- Januvia (generic name: sitagliptin), used for diabetes. It is taken by about 869,00 people through Part D plans. The estimated cost is $4.1 billion.
- Farxiga (generic name: dapagliflozin), used for diabetes, heart failure, and chronic kidney disease. It is taken by about 799,000 people through Part D plans. The estimated cost is almost $3.3 billion.
- Entresto (generic name: sacubitril/valsartan), used to treat heart failure. It is taken by 587,000 people through Part D plans. The estimated cost is $2.9 billion.
- Enbrel( generic name: etanercept), used for rheumatoid arthritis, psoriasis, and psoriatic arthritis. It is taken by 48,000 people through Part D plans. The estimated cost is $2.8 billion.
- Imbruvica (generic name: ibrutinib), used to treat some blood cancers. It is taken by about 20,000 people in Part D plans. The estimated cost is $2.7 billion.
- Stelara (generic name: ustekinumab), used to treat plaque psoriasis, psoriatic arthritis, or certain bowel conditions (Crohn’s disease, ulcerative colitis). It is used by about 22,000 people through Part D plans. The estimated cost is $2.6 billion.
- Fiasp; Fiasp FlexTouch; Fiasp PenFill; NovoLog; NovoLog FlexPen; NovoLog PenFill. These are forms of insulin used to treat diabetes. They are used by about 777,000 people through Part D plans. The estimated cost is $2.6 billion.
A vocal critic of Medicare drug negotiations, Joel White, president of the Council for Affordable Health Coverage, called the announcement of the 10 drugs selected for negotiation “a hollow victory lap.” A former Republican staffer on the House Ways and Means Committee, Mr. White aided with the development of the Medicare Part D plans and has kept tabs on the pharmacy programs since its launch in 2006.
“No one’s costs will go down now or for years because of this announcement” about Part D negotiations, Mr. White said in a statement.
According to its website, CAHC includes among its members the American Academy of Ophthalmology as well as some patient groups, drugmakers, such as Johnson & Johnson, and insurers and industry groups, such as the National Association of Manufacturers.
Separately, the influential Chamber of Commerce is making a strong push to at least delay the implementation of the Medicare Part D drug negotiations. On Aug. 28, the chamber released a letter sent to the Biden administration, raising concerns about a “rush” to implement the provisions of the Inflation Reduction Act.
The chamber also has filed suit to challenge the drug negotiation provisions of the Inflation Reduction Act, requesting that the court issue a preliminary injunction by Oct. 1, 2023.
Other pending legal challenges to direct Medicare drug negotiations include suits filed by Merck, Bristol-Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, and AstraZeneca, according to an email from Pharmaceutical Research and Manufacturers of America. PhRMA also said it is a party to a case.
In addition, the three congressional Republicans with most direct influence over Medicare policy issued on Aug. 29 a joint statement outlining their objections to the planned negotiations on drug prices.
This drug-negotiation proposal is “an unworkable, legally dubious scheme that will lead to higher prices for new drugs coming to market, stifle the development of new cures, and destroy jobs,” said House Energy and Commerce Committee Chair Cathy McMorris Rodgers (R-Wash.), House Ways and Means Committee Chair Jason Smith (R-Mo.), and Senate Finance Committee Ranking Member Mike Crapo (R-Idaho).
Democrats were equally firm and vocal in their support of the negotiations. Senate Finance Chairman Ron Wyden (D-Ore.) issued a statement on Aug. 29 that said the release of the list of the 10 drugs selected for Medicare drug negotiations is part of a “seismic shift in the relationship between Big Pharma, the federal government, and seniors who are counting on lower prices.
“I will be following the negotiation process closely and will fight any attempt by Big Pharma to undo or undermine the progress that’s been made,” Mr. Wyden said.
In addition, AARP issued a statement of its continued support for Medicare drug negotiations.
“The No. 1 reason seniors skip or ration their prescriptions is because they can’t afford them. This must stop,” said AARP executive vice president and chief advocacy and engagement officer Nancy LeaMond in the statement. “The big drug companies and their allies continue suing to overturn the Medicare drug price negotiation program to keep up their price gouging. We can’t allow seniors to be Big Pharma’s cash machine anymore.”
A version of this article first appeared on Medscape.com.
No link between most cancers and depression/anxiety: Study
from a large, individual participant data meta-analysis.
An exception was for lung and smoking-related cancers, but key covariates appeared to explain the relationship between depression, anxiety, and these cancer types, the investigators reported.
The findings challenge a common theory that depression and anxiety increase cancer risk and should “change current thinking,” they argue.
“Our results may come as a relief to many patients with cancer who believe their diagnosis is attributed to previous anxiety or depression,” first author Lonneke A. van Tuijl, PhD, of the University of Groningen and Utrecht University, the Netherlands, noted in a press release.
Analyses included data from up to nearly 320,000 individuals from the 18 prospective cohorts included in the international Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. The cohorts are from studies conducted in the Netherlands, United Kingdom, Norway, and Canada, and included 25,803 patients with cancer. During follow-up of up to 26 years and more than 3.2 million person-years, depression and anxiety symptoms and diagnoses showed no association with overall breast, prostate, colorectal, and alcohol-related cancers (hazard ratios, 0.98-1.05).
For the specific cancer types, the investigators “found no evidence for an association between depression or anxiety and the incidence of colorectal cancer (HRs, 0.88-1.13), prostate cancer (HRs, 0.97-1.17), or alcohol-related cancers (HRs, 0.97-1.06).”
“For breast cancer, all pooled HRs were consistently negative but mean pooled HRs were close to 1 (HRs, 0.92-0.98) and the upper limit of the 95% confidence intervals all exceeded 1 (with the exception of anxiety symptoms),” they noted.
An increase in risk observed between depression and anxiety symptoms and diagnoses and lung cancer (HRs, 1.12-1.60) and smoking-related cancers (HRs, 1.06-1.60), in minimally adjusted models, was substantially attenuated after adjusting for known risk factors such as smoking, alcohol use, and body mass index (HRs, 1.04-1.08), the investigators reported.
The findings were published online in Cancer.
“Depression and anxiety have long been hypothesized to increase the risk for cancer. It is thought that the increased cancer risk can occur via several pathways, including health behaviors, or by influencing mutation, viral oncogenes, cell proliferation, or DNA repair,” the authors explained, noting that “[c]onclusions drawn in meta-analyses vary greatly, with some supporting an association between depression, anxiety, and cancer incidence and others finding no or a negligible association.”
The current findings “may help health professionals to alleviate feelings of guilt and self-blame in patients with cancer who attribute their diagnosis to previous depression or anxiety,” they said, noting that the findings “also underscore the importance of addressing tobacco smoking and other unhealthy behaviors – including those that may develop as a result of anxiety or depression.”
“However, further research is needed to understand exactly how depression, anxiety, health behaviors, and lung cancer are related,” said Dr. Tuijl.
Dr. Tuijl has received grants and travel support from the Dutch Cancer Society (KWF).
from a large, individual participant data meta-analysis.
An exception was for lung and smoking-related cancers, but key covariates appeared to explain the relationship between depression, anxiety, and these cancer types, the investigators reported.
The findings challenge a common theory that depression and anxiety increase cancer risk and should “change current thinking,” they argue.
“Our results may come as a relief to many patients with cancer who believe their diagnosis is attributed to previous anxiety or depression,” first author Lonneke A. van Tuijl, PhD, of the University of Groningen and Utrecht University, the Netherlands, noted in a press release.
Analyses included data from up to nearly 320,000 individuals from the 18 prospective cohorts included in the international Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. The cohorts are from studies conducted in the Netherlands, United Kingdom, Norway, and Canada, and included 25,803 patients with cancer. During follow-up of up to 26 years and more than 3.2 million person-years, depression and anxiety symptoms and diagnoses showed no association with overall breast, prostate, colorectal, and alcohol-related cancers (hazard ratios, 0.98-1.05).
For the specific cancer types, the investigators “found no evidence for an association between depression or anxiety and the incidence of colorectal cancer (HRs, 0.88-1.13), prostate cancer (HRs, 0.97-1.17), or alcohol-related cancers (HRs, 0.97-1.06).”
“For breast cancer, all pooled HRs were consistently negative but mean pooled HRs were close to 1 (HRs, 0.92-0.98) and the upper limit of the 95% confidence intervals all exceeded 1 (with the exception of anxiety symptoms),” they noted.
An increase in risk observed between depression and anxiety symptoms and diagnoses and lung cancer (HRs, 1.12-1.60) and smoking-related cancers (HRs, 1.06-1.60), in minimally adjusted models, was substantially attenuated after adjusting for known risk factors such as smoking, alcohol use, and body mass index (HRs, 1.04-1.08), the investigators reported.
The findings were published online in Cancer.
“Depression and anxiety have long been hypothesized to increase the risk for cancer. It is thought that the increased cancer risk can occur via several pathways, including health behaviors, or by influencing mutation, viral oncogenes, cell proliferation, or DNA repair,” the authors explained, noting that “[c]onclusions drawn in meta-analyses vary greatly, with some supporting an association between depression, anxiety, and cancer incidence and others finding no or a negligible association.”
The current findings “may help health professionals to alleviate feelings of guilt and self-blame in patients with cancer who attribute their diagnosis to previous depression or anxiety,” they said, noting that the findings “also underscore the importance of addressing tobacco smoking and other unhealthy behaviors – including those that may develop as a result of anxiety or depression.”
“However, further research is needed to understand exactly how depression, anxiety, health behaviors, and lung cancer are related,” said Dr. Tuijl.
Dr. Tuijl has received grants and travel support from the Dutch Cancer Society (KWF).
from a large, individual participant data meta-analysis.
An exception was for lung and smoking-related cancers, but key covariates appeared to explain the relationship between depression, anxiety, and these cancer types, the investigators reported.
The findings challenge a common theory that depression and anxiety increase cancer risk and should “change current thinking,” they argue.
“Our results may come as a relief to many patients with cancer who believe their diagnosis is attributed to previous anxiety or depression,” first author Lonneke A. van Tuijl, PhD, of the University of Groningen and Utrecht University, the Netherlands, noted in a press release.
Analyses included data from up to nearly 320,000 individuals from the 18 prospective cohorts included in the international Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. The cohorts are from studies conducted in the Netherlands, United Kingdom, Norway, and Canada, and included 25,803 patients with cancer. During follow-up of up to 26 years and more than 3.2 million person-years, depression and anxiety symptoms and diagnoses showed no association with overall breast, prostate, colorectal, and alcohol-related cancers (hazard ratios, 0.98-1.05).
For the specific cancer types, the investigators “found no evidence for an association between depression or anxiety and the incidence of colorectal cancer (HRs, 0.88-1.13), prostate cancer (HRs, 0.97-1.17), or alcohol-related cancers (HRs, 0.97-1.06).”
“For breast cancer, all pooled HRs were consistently negative but mean pooled HRs were close to 1 (HRs, 0.92-0.98) and the upper limit of the 95% confidence intervals all exceeded 1 (with the exception of anxiety symptoms),” they noted.
An increase in risk observed between depression and anxiety symptoms and diagnoses and lung cancer (HRs, 1.12-1.60) and smoking-related cancers (HRs, 1.06-1.60), in minimally adjusted models, was substantially attenuated after adjusting for known risk factors such as smoking, alcohol use, and body mass index (HRs, 1.04-1.08), the investigators reported.
The findings were published online in Cancer.
“Depression and anxiety have long been hypothesized to increase the risk for cancer. It is thought that the increased cancer risk can occur via several pathways, including health behaviors, or by influencing mutation, viral oncogenes, cell proliferation, or DNA repair,” the authors explained, noting that “[c]onclusions drawn in meta-analyses vary greatly, with some supporting an association between depression, anxiety, and cancer incidence and others finding no or a negligible association.”
The current findings “may help health professionals to alleviate feelings of guilt and self-blame in patients with cancer who attribute their diagnosis to previous depression or anxiety,” they said, noting that the findings “also underscore the importance of addressing tobacco smoking and other unhealthy behaviors – including those that may develop as a result of anxiety or depression.”
“However, further research is needed to understand exactly how depression, anxiety, health behaviors, and lung cancer are related,” said Dr. Tuijl.
Dr. Tuijl has received grants and travel support from the Dutch Cancer Society (KWF).
FROM CANCER
PTSD: Written exposure therapy matches prolonged exposure therapy
Investigators also found that participants randomly assigned to receive WET were significantly less likely to drop out of treatment than those receiving PE.
Written exposure therapy involves writing about thoughts and feelings during a specific traumatic event during five supervised, 30-minute sessions and discussing the writing process with the therapist supervising the sessions.
In the latter sessions, the participant talks about how the event affected them.
“Clinicians should consider using WET in their practices as some clients would prefer a shorter treatment approach, and it may be the only option for some clients – for instance, those who have limited time for therapy and may not be able to do a longer treatment,” study investigator Denise Sloan, PhD, said in an interview.
She also noted that WET is covered by insurance and that “most providers I know indicate that they list it as CBT [cognitive-behavioral therapy] code to insurance companies.”
Sloan is senior clinician investigator of the National Center for PTSD at VA Boston Healthcare System and professor of psychiatry at Boston University.
The findings were published online in JAMA Psychiatry.
High attrition rates
The disadvantage to the three major types of therapy used most often to treat PTSD in veterans – eye movement desensitization and reprocessing, cognitive processing therapy (CPT), and PE – are the dropout rates, that range from 18% to as high as 50%.
Prior studies have shown that WET is briefer and just as effective as CPT, but investigators noted that it had never been tested against PE in a randomized clinical trial.
To find out how the two types of therapy compare, Dr. Sloan and associates randomized 178 veterans with PTSD from three VA centers – Boston; Charleston, S.C.; and Madison, Wisc. – to receive either WET or PE.
PE consisted of 8-15 90-minute therapy sessions during which participants imagine the most distressing aspect of their traumatic memory, and between sessions, they confront the people, places, or situations they have been avoiding because of the trauma.
The investigators used the Structured Clinical Interview for DSM-5 at baseline to screen participants at high risk for suicide, comorbid substance use disorder, and unstable bipolar disorder, who were excluded from the study.
At baseline, 10, 20, and 30 weeks after the first treatment session, the investigators measured the severity of each patient’s PTSD symptoms with the Clinician-Administered PTSD Scale for DSM-5, which has a range of 0 (no PTSD symptoms) to 80 (most severe PTSD symptoms).
Of the 178 veterans, 134 were men, and their mean age was 45 years. The majority (63%) was White, while 21% were Black.
The researchers found that study participants were not significantly more likely to meet PTSD diagnostic criteria in the WET or PE conditions at any assessment.
WET briefer, better retention
Investigators noted the largest difference in PTSD scores in favor of WET at the 10-month assessment: The mean score for those receiving WET was 27.7, and the mean score for those receiving PE was 30.1 (odds ratio, 0.72; 95% CI, 0.35-1.46).
Among those who finished treatment, the mean number of treatment sessions was 12.5 for PE and 6 for WET.
Participants assigned to receive PE were significantly more likely to drop out of the study prematurely; 32 (35.6%) dropped out, compared with 11 (12.5%) participants assigned to WET.
Notably, of the 32 participants who dropped out of PE, 30 did so by session 7, so the increased dropout in PE was not related to the greater number of sessions, the investigators noted.
They added that findings could have been limited by stressors related to the global COVID-19 pandemic, which was taking place during the treatment, and the fact that all of the participants were veterans, which could limit the generalizability of the findings.
In an editorial, Charles Taylor, PhD, and Murray Stein, MD, MPH, both from the department of psychiatry at the University of California, San Diego, wrote that “WET achieved comparable reductions in PTSD symptoms through fewer sessions, shorter duration sessions, less therapist involvement, and no explicit prescription of homework.
“These findings should galvanize the psychotherapy field to design parsimonious treatments from the start, systematically testing the effects of different dose parameters,” they concluded.
The study was supported by the VA. Dr. Sloan reported receiving royalty payments for the published Written Exposure Therapy manual from the American Psychological Association outside the submitted work.
A version of this article appeared on Medscape.com.
Investigators also found that participants randomly assigned to receive WET were significantly less likely to drop out of treatment than those receiving PE.
Written exposure therapy involves writing about thoughts and feelings during a specific traumatic event during five supervised, 30-minute sessions and discussing the writing process with the therapist supervising the sessions.
In the latter sessions, the participant talks about how the event affected them.
“Clinicians should consider using WET in their practices as some clients would prefer a shorter treatment approach, and it may be the only option for some clients – for instance, those who have limited time for therapy and may not be able to do a longer treatment,” study investigator Denise Sloan, PhD, said in an interview.
She also noted that WET is covered by insurance and that “most providers I know indicate that they list it as CBT [cognitive-behavioral therapy] code to insurance companies.”
Sloan is senior clinician investigator of the National Center for PTSD at VA Boston Healthcare System and professor of psychiatry at Boston University.
The findings were published online in JAMA Psychiatry.
High attrition rates
The disadvantage to the three major types of therapy used most often to treat PTSD in veterans – eye movement desensitization and reprocessing, cognitive processing therapy (CPT), and PE – are the dropout rates, that range from 18% to as high as 50%.
Prior studies have shown that WET is briefer and just as effective as CPT, but investigators noted that it had never been tested against PE in a randomized clinical trial.
To find out how the two types of therapy compare, Dr. Sloan and associates randomized 178 veterans with PTSD from three VA centers – Boston; Charleston, S.C.; and Madison, Wisc. – to receive either WET or PE.
PE consisted of 8-15 90-minute therapy sessions during which participants imagine the most distressing aspect of their traumatic memory, and between sessions, they confront the people, places, or situations they have been avoiding because of the trauma.
The investigators used the Structured Clinical Interview for DSM-5 at baseline to screen participants at high risk for suicide, comorbid substance use disorder, and unstable bipolar disorder, who were excluded from the study.
At baseline, 10, 20, and 30 weeks after the first treatment session, the investigators measured the severity of each patient’s PTSD symptoms with the Clinician-Administered PTSD Scale for DSM-5, which has a range of 0 (no PTSD symptoms) to 80 (most severe PTSD symptoms).
Of the 178 veterans, 134 were men, and their mean age was 45 years. The majority (63%) was White, while 21% were Black.
The researchers found that study participants were not significantly more likely to meet PTSD diagnostic criteria in the WET or PE conditions at any assessment.
WET briefer, better retention
Investigators noted the largest difference in PTSD scores in favor of WET at the 10-month assessment: The mean score for those receiving WET was 27.7, and the mean score for those receiving PE was 30.1 (odds ratio, 0.72; 95% CI, 0.35-1.46).
Among those who finished treatment, the mean number of treatment sessions was 12.5 for PE and 6 for WET.
Participants assigned to receive PE were significantly more likely to drop out of the study prematurely; 32 (35.6%) dropped out, compared with 11 (12.5%) participants assigned to WET.
Notably, of the 32 participants who dropped out of PE, 30 did so by session 7, so the increased dropout in PE was not related to the greater number of sessions, the investigators noted.
They added that findings could have been limited by stressors related to the global COVID-19 pandemic, which was taking place during the treatment, and the fact that all of the participants were veterans, which could limit the generalizability of the findings.
In an editorial, Charles Taylor, PhD, and Murray Stein, MD, MPH, both from the department of psychiatry at the University of California, San Diego, wrote that “WET achieved comparable reductions in PTSD symptoms through fewer sessions, shorter duration sessions, less therapist involvement, and no explicit prescription of homework.
“These findings should galvanize the psychotherapy field to design parsimonious treatments from the start, systematically testing the effects of different dose parameters,” they concluded.
The study was supported by the VA. Dr. Sloan reported receiving royalty payments for the published Written Exposure Therapy manual from the American Psychological Association outside the submitted work.
A version of this article appeared on Medscape.com.
Investigators also found that participants randomly assigned to receive WET were significantly less likely to drop out of treatment than those receiving PE.
Written exposure therapy involves writing about thoughts and feelings during a specific traumatic event during five supervised, 30-minute sessions and discussing the writing process with the therapist supervising the sessions.
In the latter sessions, the participant talks about how the event affected them.
“Clinicians should consider using WET in their practices as some clients would prefer a shorter treatment approach, and it may be the only option for some clients – for instance, those who have limited time for therapy and may not be able to do a longer treatment,” study investigator Denise Sloan, PhD, said in an interview.
She also noted that WET is covered by insurance and that “most providers I know indicate that they list it as CBT [cognitive-behavioral therapy] code to insurance companies.”
Sloan is senior clinician investigator of the National Center for PTSD at VA Boston Healthcare System and professor of psychiatry at Boston University.
The findings were published online in JAMA Psychiatry.
High attrition rates
The disadvantage to the three major types of therapy used most often to treat PTSD in veterans – eye movement desensitization and reprocessing, cognitive processing therapy (CPT), and PE – are the dropout rates, that range from 18% to as high as 50%.
Prior studies have shown that WET is briefer and just as effective as CPT, but investigators noted that it had never been tested against PE in a randomized clinical trial.
To find out how the two types of therapy compare, Dr. Sloan and associates randomized 178 veterans with PTSD from three VA centers – Boston; Charleston, S.C.; and Madison, Wisc. – to receive either WET or PE.
PE consisted of 8-15 90-minute therapy sessions during which participants imagine the most distressing aspect of their traumatic memory, and between sessions, they confront the people, places, or situations they have been avoiding because of the trauma.
The investigators used the Structured Clinical Interview for DSM-5 at baseline to screen participants at high risk for suicide, comorbid substance use disorder, and unstable bipolar disorder, who were excluded from the study.
At baseline, 10, 20, and 30 weeks after the first treatment session, the investigators measured the severity of each patient’s PTSD symptoms with the Clinician-Administered PTSD Scale for DSM-5, which has a range of 0 (no PTSD symptoms) to 80 (most severe PTSD symptoms).
Of the 178 veterans, 134 were men, and their mean age was 45 years. The majority (63%) was White, while 21% were Black.
The researchers found that study participants were not significantly more likely to meet PTSD diagnostic criteria in the WET or PE conditions at any assessment.
WET briefer, better retention
Investigators noted the largest difference in PTSD scores in favor of WET at the 10-month assessment: The mean score for those receiving WET was 27.7, and the mean score for those receiving PE was 30.1 (odds ratio, 0.72; 95% CI, 0.35-1.46).
Among those who finished treatment, the mean number of treatment sessions was 12.5 for PE and 6 for WET.
Participants assigned to receive PE were significantly more likely to drop out of the study prematurely; 32 (35.6%) dropped out, compared with 11 (12.5%) participants assigned to WET.
Notably, of the 32 participants who dropped out of PE, 30 did so by session 7, so the increased dropout in PE was not related to the greater number of sessions, the investigators noted.
They added that findings could have been limited by stressors related to the global COVID-19 pandemic, which was taking place during the treatment, and the fact that all of the participants were veterans, which could limit the generalizability of the findings.
In an editorial, Charles Taylor, PhD, and Murray Stein, MD, MPH, both from the department of psychiatry at the University of California, San Diego, wrote that “WET achieved comparable reductions in PTSD symptoms through fewer sessions, shorter duration sessions, less therapist involvement, and no explicit prescription of homework.
“These findings should galvanize the psychotherapy field to design parsimonious treatments from the start, systematically testing the effects of different dose parameters,” they concluded.
The study was supported by the VA. Dr. Sloan reported receiving royalty payments for the published Written Exposure Therapy manual from the American Psychological Association outside the submitted work.
A version of this article appeared on Medscape.com.
FROM JAMA PSYCHIATRY
CTE common among young athletes in largest brain donor study
Analysis of brain tissue from athletes who were exposed to RHIs and died before the age of 30 revealed neuropathological evidence of shrinkage of the brain and microscopic changes that indicate a breach of the blood-brain barrier. The case series also identified the first known American female athlete with CTE.
Nearly all of those with CTE had a mild form of the disease and 71% played only at the amateur level in youth, high school, or college sports.
“A lot of people think CTE is a result of high-level, professional play such as football, ice hockey, and boxing, but it can affect amateur athletes and can affect people at a young age,” lead author Ann McKee, MD, professor of neurology and pathology and director of the Chronic Traumatic Encephalopathy Center at Boston University, said in an interview.
The findings were published online in JAMA Neurology.
A rare look
Brain donation at younger ages is rare, so most of what is known about CTE comes from studies in older athletes.
“We’ve always known that young people could develop this disease early after just amateur high school, youth, and college exposure, but this is the largest study of donor brains at this age,” Dr. McKee said.
The case series included 152 brains of athletes who played contact sports, experienced RHIs, and died before age 30. The tissues are part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank and were donated between February 2008 and September 2022.
Researchers reviewed the donors’ medical records and conducted retrospective interviews with the donors’ next of kin to assess cognitive symptoms, mood disturbances, and neurobehavioral issues.
Donors died between the ages of 13 and 29 years, 92.8% were male and 73% were White. In 57.2% of the cases, suicide was the cause of death, with no difference between those with or without CTE.
CTE was neuropathologically diagnosed in 41.4% of athletes, using diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke.
More than 95% had mild CTE. Diagnosis was associated with older age (mean difference, 3.92 years; P < .001) and significantly more years of exposure to contact sports (11.6 vs. 8.8 years).
Among those with CTE, 71.4% played amateur sports, including football (60.9%), soccer (17.2%), hockey (7.8%), and wrestling (7%).
The cohort includes the first known American female athlete with CTE. Recruiting female brain donors has always been a challenge, Dr. McKee said. In this study, females comprised about 7% of the entire cohort and tended to be younger and play fewer years of a sport, compared with their male counterparts. All of that could lower their risk for CTE, Dr. McKee said.
“We don’t have enough brain donations to make any comments about differences between the genders, but we’ve always known that women can develop CTE,” she said. “It’s been reported after domestic violence and in an autistic woman who was a headbanger, so it was just a matter of time before we found our first case.”
Early stage of CTE?
Neuropathological analysis revealed neuronal p-tau aggregates in all CTE cases, a hallmark of the disease.
Young athletes with CTE had significantly more ventricular dilatation, suggesting atrophy or shrinkage of the brain, and more cavum septum pellucidum.
“I was surprised that even at this very young age group we could see structural changes to the gross pathology,” Dr. McKee said.
Investigators also found evidence of perivascular macrophages in the deep white matter, a microscopic change that correlated with CTE and years of play and indicates a breach of the blood-brain barrier that could allow pro-inflammatory molecules to enter the brain, setting up a neuroinflammatory response.
“Neuroinflammation is a very early change after repetitive head impacts, as well as in CTE,” Dr. McKee said. “This may be one of the mechanisms by which the inflammation starts, meaning microvascular injury might be an integral part of the pathogenesis of CTE.”
A message for clinicians
All athletes had symptoms of mood and neurobehavioral dysfunction common in people with RHIs. There were no significant differences in those clinical symptoms based on CTE diagnosis, which is likely related to the retrospective nature of the clinical evaluations, Dr. McKee said.
While the study leaves many questions about CTE in younger athletes unanswered, there is a message for clinicians and for patients in the findings, she said.
For clinicians, it’s important to note that “this young population of amateur athletes can be very symptomatic, and in all likelihood, a lot of these symptoms are reversible with proper care and management,” Dr. McKee said.
“For individual athletes, it’s important to note that 58% of this cohort did not have CTE, so just because you have these symptoms is not an indication that you have a neurodegenerative disease,” she added.
The study was funded by Andlinger Foundation, the National Football League, Mac Parkman Foundation, National Operating Committee on Standards for Athletic Equipment, and the Nick and Lynn Buoniconti Foundation, World Wrestling Entertainment, Alzheimer’s Association, National Institutes of Health, Concussion Legacy Foundation, U.S. Department of Defense and the U.S. Department of Veterans Affairs. Dr. McKee is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the NIH and Department of Veteran Affairs and other funding from the Buoniconti Foundation and Mac Parkman Foundation during the conduct of the study.
A version of this article appeared on Medscape.com.
Analysis of brain tissue from athletes who were exposed to RHIs and died before the age of 30 revealed neuropathological evidence of shrinkage of the brain and microscopic changes that indicate a breach of the blood-brain barrier. The case series also identified the first known American female athlete with CTE.
Nearly all of those with CTE had a mild form of the disease and 71% played only at the amateur level in youth, high school, or college sports.
“A lot of people think CTE is a result of high-level, professional play such as football, ice hockey, and boxing, but it can affect amateur athletes and can affect people at a young age,” lead author Ann McKee, MD, professor of neurology and pathology and director of the Chronic Traumatic Encephalopathy Center at Boston University, said in an interview.
The findings were published online in JAMA Neurology.
A rare look
Brain donation at younger ages is rare, so most of what is known about CTE comes from studies in older athletes.
“We’ve always known that young people could develop this disease early after just amateur high school, youth, and college exposure, but this is the largest study of donor brains at this age,” Dr. McKee said.
The case series included 152 brains of athletes who played contact sports, experienced RHIs, and died before age 30. The tissues are part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank and were donated between February 2008 and September 2022.
Researchers reviewed the donors’ medical records and conducted retrospective interviews with the donors’ next of kin to assess cognitive symptoms, mood disturbances, and neurobehavioral issues.
Donors died between the ages of 13 and 29 years, 92.8% were male and 73% were White. In 57.2% of the cases, suicide was the cause of death, with no difference between those with or without CTE.
CTE was neuropathologically diagnosed in 41.4% of athletes, using diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke.
More than 95% had mild CTE. Diagnosis was associated with older age (mean difference, 3.92 years; P < .001) and significantly more years of exposure to contact sports (11.6 vs. 8.8 years).
Among those with CTE, 71.4% played amateur sports, including football (60.9%), soccer (17.2%), hockey (7.8%), and wrestling (7%).
The cohort includes the first known American female athlete with CTE. Recruiting female brain donors has always been a challenge, Dr. McKee said. In this study, females comprised about 7% of the entire cohort and tended to be younger and play fewer years of a sport, compared with their male counterparts. All of that could lower their risk for CTE, Dr. McKee said.
“We don’t have enough brain donations to make any comments about differences between the genders, but we’ve always known that women can develop CTE,” she said. “It’s been reported after domestic violence and in an autistic woman who was a headbanger, so it was just a matter of time before we found our first case.”
Early stage of CTE?
Neuropathological analysis revealed neuronal p-tau aggregates in all CTE cases, a hallmark of the disease.
Young athletes with CTE had significantly more ventricular dilatation, suggesting atrophy or shrinkage of the brain, and more cavum septum pellucidum.
“I was surprised that even at this very young age group we could see structural changes to the gross pathology,” Dr. McKee said.
Investigators also found evidence of perivascular macrophages in the deep white matter, a microscopic change that correlated with CTE and years of play and indicates a breach of the blood-brain barrier that could allow pro-inflammatory molecules to enter the brain, setting up a neuroinflammatory response.
“Neuroinflammation is a very early change after repetitive head impacts, as well as in CTE,” Dr. McKee said. “This may be one of the mechanisms by which the inflammation starts, meaning microvascular injury might be an integral part of the pathogenesis of CTE.”
A message for clinicians
All athletes had symptoms of mood and neurobehavioral dysfunction common in people with RHIs. There were no significant differences in those clinical symptoms based on CTE diagnosis, which is likely related to the retrospective nature of the clinical evaluations, Dr. McKee said.
While the study leaves many questions about CTE in younger athletes unanswered, there is a message for clinicians and for patients in the findings, she said.
For clinicians, it’s important to note that “this young population of amateur athletes can be very symptomatic, and in all likelihood, a lot of these symptoms are reversible with proper care and management,” Dr. McKee said.
“For individual athletes, it’s important to note that 58% of this cohort did not have CTE, so just because you have these symptoms is not an indication that you have a neurodegenerative disease,” she added.
The study was funded by Andlinger Foundation, the National Football League, Mac Parkman Foundation, National Operating Committee on Standards for Athletic Equipment, and the Nick and Lynn Buoniconti Foundation, World Wrestling Entertainment, Alzheimer’s Association, National Institutes of Health, Concussion Legacy Foundation, U.S. Department of Defense and the U.S. Department of Veterans Affairs. Dr. McKee is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the NIH and Department of Veteran Affairs and other funding from the Buoniconti Foundation and Mac Parkman Foundation during the conduct of the study.
A version of this article appeared on Medscape.com.
Analysis of brain tissue from athletes who were exposed to RHIs and died before the age of 30 revealed neuropathological evidence of shrinkage of the brain and microscopic changes that indicate a breach of the blood-brain barrier. The case series also identified the first known American female athlete with CTE.
Nearly all of those with CTE had a mild form of the disease and 71% played only at the amateur level in youth, high school, or college sports.
“A lot of people think CTE is a result of high-level, professional play such as football, ice hockey, and boxing, but it can affect amateur athletes and can affect people at a young age,” lead author Ann McKee, MD, professor of neurology and pathology and director of the Chronic Traumatic Encephalopathy Center at Boston University, said in an interview.
The findings were published online in JAMA Neurology.
A rare look
Brain donation at younger ages is rare, so most of what is known about CTE comes from studies in older athletes.
“We’ve always known that young people could develop this disease early after just amateur high school, youth, and college exposure, but this is the largest study of donor brains at this age,” Dr. McKee said.
The case series included 152 brains of athletes who played contact sports, experienced RHIs, and died before age 30. The tissues are part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank and were donated between February 2008 and September 2022.
Researchers reviewed the donors’ medical records and conducted retrospective interviews with the donors’ next of kin to assess cognitive symptoms, mood disturbances, and neurobehavioral issues.
Donors died between the ages of 13 and 29 years, 92.8% were male and 73% were White. In 57.2% of the cases, suicide was the cause of death, with no difference between those with or without CTE.
CTE was neuropathologically diagnosed in 41.4% of athletes, using diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke.
More than 95% had mild CTE. Diagnosis was associated with older age (mean difference, 3.92 years; P < .001) and significantly more years of exposure to contact sports (11.6 vs. 8.8 years).
Among those with CTE, 71.4% played amateur sports, including football (60.9%), soccer (17.2%), hockey (7.8%), and wrestling (7%).
The cohort includes the first known American female athlete with CTE. Recruiting female brain donors has always been a challenge, Dr. McKee said. In this study, females comprised about 7% of the entire cohort and tended to be younger and play fewer years of a sport, compared with their male counterparts. All of that could lower their risk for CTE, Dr. McKee said.
“We don’t have enough brain donations to make any comments about differences between the genders, but we’ve always known that women can develop CTE,” she said. “It’s been reported after domestic violence and in an autistic woman who was a headbanger, so it was just a matter of time before we found our first case.”
Early stage of CTE?
Neuropathological analysis revealed neuronal p-tau aggregates in all CTE cases, a hallmark of the disease.
Young athletes with CTE had significantly more ventricular dilatation, suggesting atrophy or shrinkage of the brain, and more cavum septum pellucidum.
“I was surprised that even at this very young age group we could see structural changes to the gross pathology,” Dr. McKee said.
Investigators also found evidence of perivascular macrophages in the deep white matter, a microscopic change that correlated with CTE and years of play and indicates a breach of the blood-brain barrier that could allow pro-inflammatory molecules to enter the brain, setting up a neuroinflammatory response.
“Neuroinflammation is a very early change after repetitive head impacts, as well as in CTE,” Dr. McKee said. “This may be one of the mechanisms by which the inflammation starts, meaning microvascular injury might be an integral part of the pathogenesis of CTE.”
A message for clinicians
All athletes had symptoms of mood and neurobehavioral dysfunction common in people with RHIs. There were no significant differences in those clinical symptoms based on CTE diagnosis, which is likely related to the retrospective nature of the clinical evaluations, Dr. McKee said.
While the study leaves many questions about CTE in younger athletes unanswered, there is a message for clinicians and for patients in the findings, she said.
For clinicians, it’s important to note that “this young population of amateur athletes can be very symptomatic, and in all likelihood, a lot of these symptoms are reversible with proper care and management,” Dr. McKee said.
“For individual athletes, it’s important to note that 58% of this cohort did not have CTE, so just because you have these symptoms is not an indication that you have a neurodegenerative disease,” she added.
The study was funded by Andlinger Foundation, the National Football League, Mac Parkman Foundation, National Operating Committee on Standards for Athletic Equipment, and the Nick and Lynn Buoniconti Foundation, World Wrestling Entertainment, Alzheimer’s Association, National Institutes of Health, Concussion Legacy Foundation, U.S. Department of Defense and the U.S. Department of Veterans Affairs. Dr. McKee is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the NIH and Department of Veteran Affairs and other funding from the Buoniconti Foundation and Mac Parkman Foundation during the conduct of the study.
A version of this article appeared on Medscape.com.
Traditional Chinese medicine improves outcomes in HFrEF
When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.
reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.
Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).
The results were presented at the annual congress of the European Society of Cardiology.
Hard endpoints pursued in rigorous design
There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).
In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.
Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.
In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.
The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.
At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
Death and hospitalization reduced 22%
By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).
The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).
However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).
All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).
Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
Overlap of drug benefits suspected
Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.
Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.
However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.
“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.
Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.
She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.
“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.
Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.
A version of this article appeared on Medscape.com.
When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.
reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.
Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).
The results were presented at the annual congress of the European Society of Cardiology.
Hard endpoints pursued in rigorous design
There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).
In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.
Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.
In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.
The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.
At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
Death and hospitalization reduced 22%
By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).
The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).
However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).
All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).
Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
Overlap of drug benefits suspected
Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.
Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.
However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.
“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.
Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.
She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.
“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.
Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.
A version of this article appeared on Medscape.com.
When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.
reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.
Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).
The results were presented at the annual congress of the European Society of Cardiology.
Hard endpoints pursued in rigorous design
There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).
In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.
Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.
In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.
The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.
At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
Death and hospitalization reduced 22%
By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).
The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).
However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).
All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).
Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
Overlap of drug benefits suspected
Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.
Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.
However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.
“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.
Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.
She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.
“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.
Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.
A version of this article appeared on Medscape.com.
FROM ESC CONGRESS 2023