User login
U.S. pulls COVID drug as Omicron subvariant spreads
F, the Omicron subvariant that now accounts for most new cases in the United States, The Associated Press reports.
The Food and Drug Administration announced that the antibody drug sotrovimab is no longer authorized to treat patients in U.S. states or territories. The decision was expected, as the FDA restricted the drug’s use across the country throughout March as BA.2 became dominant in certain regions, the AP reported.
The BA.2 subvariant now accounts for 72% of new COVID-19 cases sequenced by health authorities, according to the latest CDC data updated April 5. The FDA cited the CDC data in its reason for pulling back on the authorization of the drug.
The GlaxoSmithKline drug is the latest antibody medication to be pulled due to coronavirus mutations. In January, the FDA halted the use of antibody drugs from Regeneron and Eli Lilly because they didn’t work against the Omicron variant.
The FDA’s decision means that one antibody drug is still authorized for use against routine COVID-19 cases, the AP reported. A different Eli Lilly drug – bebtelovimab – still appears to work against BA.2.
Doctors can also prescribe antiviral pills, which typically affect the coronavirus spike protein and aren’t affected by mutations, to treat mild to moderate COVID-19, the AP reported. The authorized pills from Pfizer and Merck – Paxlovid and Lagevrio – have been shipped to pharmacy chains and medical clinics in hopes of getting them to patients early enough to work.
The federal government purchased nearly $2 billion worth of the GlaxoSmithKline drug and shipped more than 900,000 doses to states last fall, the AP reported. In March, the company announced that it was studying a higher dose that could be effective against BA.2, which would require FDA approval before resuming use in the United States.
The antibody drugs mimic the virus-blocking proteins found in the human body, the AP reported. They’re designed to attack a specific virus and need to be updated as the coronavirus mutates.
A version of this article first appeared on WebMD.com.
F, the Omicron subvariant that now accounts for most new cases in the United States, The Associated Press reports.
The Food and Drug Administration announced that the antibody drug sotrovimab is no longer authorized to treat patients in U.S. states or territories. The decision was expected, as the FDA restricted the drug’s use across the country throughout March as BA.2 became dominant in certain regions, the AP reported.
The BA.2 subvariant now accounts for 72% of new COVID-19 cases sequenced by health authorities, according to the latest CDC data updated April 5. The FDA cited the CDC data in its reason for pulling back on the authorization of the drug.
The GlaxoSmithKline drug is the latest antibody medication to be pulled due to coronavirus mutations. In January, the FDA halted the use of antibody drugs from Regeneron and Eli Lilly because they didn’t work against the Omicron variant.
The FDA’s decision means that one antibody drug is still authorized for use against routine COVID-19 cases, the AP reported. A different Eli Lilly drug – bebtelovimab – still appears to work against BA.2.
Doctors can also prescribe antiviral pills, which typically affect the coronavirus spike protein and aren’t affected by mutations, to treat mild to moderate COVID-19, the AP reported. The authorized pills from Pfizer and Merck – Paxlovid and Lagevrio – have been shipped to pharmacy chains and medical clinics in hopes of getting them to patients early enough to work.
The federal government purchased nearly $2 billion worth of the GlaxoSmithKline drug and shipped more than 900,000 doses to states last fall, the AP reported. In March, the company announced that it was studying a higher dose that could be effective against BA.2, which would require FDA approval before resuming use in the United States.
The antibody drugs mimic the virus-blocking proteins found in the human body, the AP reported. They’re designed to attack a specific virus and need to be updated as the coronavirus mutates.
A version of this article first appeared on WebMD.com.
F, the Omicron subvariant that now accounts for most new cases in the United States, The Associated Press reports.
The Food and Drug Administration announced that the antibody drug sotrovimab is no longer authorized to treat patients in U.S. states or territories. The decision was expected, as the FDA restricted the drug’s use across the country throughout March as BA.2 became dominant in certain regions, the AP reported.
The BA.2 subvariant now accounts for 72% of new COVID-19 cases sequenced by health authorities, according to the latest CDC data updated April 5. The FDA cited the CDC data in its reason for pulling back on the authorization of the drug.
The GlaxoSmithKline drug is the latest antibody medication to be pulled due to coronavirus mutations. In January, the FDA halted the use of antibody drugs from Regeneron and Eli Lilly because they didn’t work against the Omicron variant.
The FDA’s decision means that one antibody drug is still authorized for use against routine COVID-19 cases, the AP reported. A different Eli Lilly drug – bebtelovimab – still appears to work against BA.2.
Doctors can also prescribe antiviral pills, which typically affect the coronavirus spike protein and aren’t affected by mutations, to treat mild to moderate COVID-19, the AP reported. The authorized pills from Pfizer and Merck – Paxlovid and Lagevrio – have been shipped to pharmacy chains and medical clinics in hopes of getting them to patients early enough to work.
The federal government purchased nearly $2 billion worth of the GlaxoSmithKline drug and shipped more than 900,000 doses to states last fall, the AP reported. In March, the company announced that it was studying a higher dose that could be effective against BA.2, which would require FDA approval before resuming use in the United States.
The antibody drugs mimic the virus-blocking proteins found in the human body, the AP reported. They’re designed to attack a specific virus and need to be updated as the coronavirus mutates.
A version of this article first appeared on WebMD.com.
Novel medication tied to better quality of life in major depression
DENVER –
In a phase 3 trial that included more than 500 adult patients with MDD, those who received zuranolone for 14 days showed greater improvement at day 15 across numerous QoL outcomes, compared with their counterparts in the placebo group.
In addition, combined analysis of four zuranolone clinical trials showed “mental well-being and functioning improved to near general population norm levels” for the active-treatment group, reported the researchers, led by Anita H. Clayton, MD, chair and professor of psychiatry, University of Virginia, Charlottesville.
“Based on these integrated analyses, the benefit of treatment with zuranolone may extend beyond reduction in depressive symptoms to include potential improvement in quality of life and overall health, as perceived by patients,” they add.
The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
First oral formulation
Zuranolone represents the second entry in the new class of neuroactive steroid drugs, which modulate GABA-A receptor activity – but it would be the first to have an oral formulation. Brexanolone, which was approved by the Food and Drug Administration in 2019 for postpartum depression, is administered through continuous IV infusion over 60 hours.
As previously reported by this news organization, zuranolone improved depressive symptoms as early as day 3, achieving the primary endpoint of significantly greater reduction in scores on the 17-item Hamilton Rating Scale for Depression from baseline to day 15 versus placebo (P = .014).
In the new analysis, patient-reported measures of functional health and well-being were assessed in the WATERFALL trial. It included 266 patients with MDD who were treated with zuranolone 50 mg daily for 2 weeks and 268 patients with MDD who were treated with placebo.
The study used the Short Form–36 (SF-36v2), which covers a wide range of patient-reported measures, including physical function, bodily pain, general health, vitality, social function, and “role-emotional” symptoms.
Results showed that although the treatment and placebo groups had similar baseline SF-36v2 scores, those receiving zuranolone reported significantly greater improvements at day 15 in almost all of the assessment’s domains, including physical function (treatment difference, 0.8), general health (1.0), vitality (3.1), social functioning (1.1), and role-emotional symptoms (1.5; for all comparisons, P < .05). The only exceptions were in role-physical symptoms and bodily pain.
In measures that included physical function, bodily pain, and general health, the patients achieved improvements at day 15 that were consistent with normal levels, with the improvement in vitality considered clinically meaningful versus placebo.
Integrated data
In further analysis of integrated data from four zuranolone clinical trials in the NEST and LANDSCAPE programs for patients with MDD and postpartum depression, results showed similar improvements at day 15 for zuranolone in QoL and overall health across all of the SF-36v2 functioning and well-being domains (P <.05), with the exceptions of physical measure and bodily pain.
By day 42, all of the domains showed significantly greater improvement with zuranolone versus placebo (all, P <.05).
Among the strongest score improvements in the integrated trials were measures in social functioning, which improved from baseline scores of 29.66 to 42.82 on day 15 and to 43.59 on day 42.
Emotional domain scores improved from 24.43 at baseline to 39.13 on day 15 and to 39.82 on day 42. For mental health, the integrated scores for the zuranolone group improved from 27.13 at baseline to 42.40 on day 15 and 42.62 on day 42.
Of note, the baseline scores for mental health represented just 54.3% of those in the normal population; with the increase at day 15, the level was 84.8% of the normal population.
“Across four completed placebo-controlled NEST and LANDSCAPE clinical trials, patient reports of functional health and well-being as assessed by the SF-36v2 indicated substantial impairment at baseline compared to the population norm,” the researchers reported.
The improvements are especially important in light of the fact that in some patients with MDD, functional improvement is a top priority.
“Patients have often prioritized returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression,” the investigators wrote.
Zuranolone trials have shown that treatment-emergent adverse events (AEs) occur among about 60% of patients, versus about 44% with placebo. The most common AEs are somnolence, dizziness, headache, sedation, and diarrhea, with no increases in suicidal ideation or withdrawal.
The rates of severe AEs are low, and they are observed in about 3% of patients, versus 1.1% with placebo, the researchers noted.
Further, as opposed to serotonergic antidepressants such as SNRIs and SSRIs, zuranolone does not appear to have the undesirable side effects of decreased libido and sexual dysfunction, they added.
Clinically meaningful?
Andrew J. Cutler, MD, clinical associate professor of psychiatry at State University of New York, Syracuse, said the data are “very significant” for a number of reasons.
“We need more options to treat depression, especially ones with novel mechanisms of action and faster onset of efficacy, such as zuranolone,” said Dr. Cutler, who was not involved in the current study. He has coauthored other studies on zuranolone.
Regarding the study’s QoL outcomes, “while improvement in depressive symptoms is very important, what really matters to patients is improvement in function and quality of life,” Dr. Cutler noted.
Also commenting on the study, Jonathan E. Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences and professor of psychiatry, neuroscience, and pediatrics at Albert Einstein College of Medicine, New York, said the investigational drug could represent an important addition to the armamentarium for treating depression.
“Zuranolone has good oral bioavailability and would represent the first neuroactive steroid antidepressant available in oral form and, indeed, the first non–monoamine-based antidepressant available in oral form,” he said in an interview.
Dr. Alpert was not involved in the research and has no relationship with the drug’s development.
He noted that although there are modest differences between the patients who received zuranolone and those who received placebo in the trials, “this may have been related to high placebo response rates, which often complicate antidepressant trials.
“Further research is needed to determine whether differences between zuranolone and placebo are clinically meaningful, though the separation between drug and placebo on the primary endpoint, as well as some other measures, such as quality of life measures, is promising,” Dr. Alpert said.
However, he added that comparisons with other active antidepressants in terms of efficacy and tolerability remain to be seen.
“Given the large number of individuals with major depressive disorder who have incomplete response to or do not tolerate monoaminergic antidepressants, the development of agents that leverage novel nonmonoaminergic mechanisms is important,” Dr. Alpert concluded.
The study was funded by Sage Therapeutics and Biogen. Dr. Cutler has been involved in research of zuranolone for Sage Therapeutics. Dr. Alpert has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
DENVER –
In a phase 3 trial that included more than 500 adult patients with MDD, those who received zuranolone for 14 days showed greater improvement at day 15 across numerous QoL outcomes, compared with their counterparts in the placebo group.
In addition, combined analysis of four zuranolone clinical trials showed “mental well-being and functioning improved to near general population norm levels” for the active-treatment group, reported the researchers, led by Anita H. Clayton, MD, chair and professor of psychiatry, University of Virginia, Charlottesville.
“Based on these integrated analyses, the benefit of treatment with zuranolone may extend beyond reduction in depressive symptoms to include potential improvement in quality of life and overall health, as perceived by patients,” they add.
The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
First oral formulation
Zuranolone represents the second entry in the new class of neuroactive steroid drugs, which modulate GABA-A receptor activity – but it would be the first to have an oral formulation. Brexanolone, which was approved by the Food and Drug Administration in 2019 for postpartum depression, is administered through continuous IV infusion over 60 hours.
As previously reported by this news organization, zuranolone improved depressive symptoms as early as day 3, achieving the primary endpoint of significantly greater reduction in scores on the 17-item Hamilton Rating Scale for Depression from baseline to day 15 versus placebo (P = .014).
In the new analysis, patient-reported measures of functional health and well-being were assessed in the WATERFALL trial. It included 266 patients with MDD who were treated with zuranolone 50 mg daily for 2 weeks and 268 patients with MDD who were treated with placebo.
The study used the Short Form–36 (SF-36v2), which covers a wide range of patient-reported measures, including physical function, bodily pain, general health, vitality, social function, and “role-emotional” symptoms.
Results showed that although the treatment and placebo groups had similar baseline SF-36v2 scores, those receiving zuranolone reported significantly greater improvements at day 15 in almost all of the assessment’s domains, including physical function (treatment difference, 0.8), general health (1.0), vitality (3.1), social functioning (1.1), and role-emotional symptoms (1.5; for all comparisons, P < .05). The only exceptions were in role-physical symptoms and bodily pain.
In measures that included physical function, bodily pain, and general health, the patients achieved improvements at day 15 that were consistent with normal levels, with the improvement in vitality considered clinically meaningful versus placebo.
Integrated data
In further analysis of integrated data from four zuranolone clinical trials in the NEST and LANDSCAPE programs for patients with MDD and postpartum depression, results showed similar improvements at day 15 for zuranolone in QoL and overall health across all of the SF-36v2 functioning and well-being domains (P <.05), with the exceptions of physical measure and bodily pain.
By day 42, all of the domains showed significantly greater improvement with zuranolone versus placebo (all, P <.05).
Among the strongest score improvements in the integrated trials were measures in social functioning, which improved from baseline scores of 29.66 to 42.82 on day 15 and to 43.59 on day 42.
Emotional domain scores improved from 24.43 at baseline to 39.13 on day 15 and to 39.82 on day 42. For mental health, the integrated scores for the zuranolone group improved from 27.13 at baseline to 42.40 on day 15 and 42.62 on day 42.
Of note, the baseline scores for mental health represented just 54.3% of those in the normal population; with the increase at day 15, the level was 84.8% of the normal population.
“Across four completed placebo-controlled NEST and LANDSCAPE clinical trials, patient reports of functional health and well-being as assessed by the SF-36v2 indicated substantial impairment at baseline compared to the population norm,” the researchers reported.
The improvements are especially important in light of the fact that in some patients with MDD, functional improvement is a top priority.
“Patients have often prioritized returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression,” the investigators wrote.
Zuranolone trials have shown that treatment-emergent adverse events (AEs) occur among about 60% of patients, versus about 44% with placebo. The most common AEs are somnolence, dizziness, headache, sedation, and diarrhea, with no increases in suicidal ideation or withdrawal.
The rates of severe AEs are low, and they are observed in about 3% of patients, versus 1.1% with placebo, the researchers noted.
Further, as opposed to serotonergic antidepressants such as SNRIs and SSRIs, zuranolone does not appear to have the undesirable side effects of decreased libido and sexual dysfunction, they added.
Clinically meaningful?
Andrew J. Cutler, MD, clinical associate professor of psychiatry at State University of New York, Syracuse, said the data are “very significant” for a number of reasons.
“We need more options to treat depression, especially ones with novel mechanisms of action and faster onset of efficacy, such as zuranolone,” said Dr. Cutler, who was not involved in the current study. He has coauthored other studies on zuranolone.
Regarding the study’s QoL outcomes, “while improvement in depressive symptoms is very important, what really matters to patients is improvement in function and quality of life,” Dr. Cutler noted.
Also commenting on the study, Jonathan E. Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences and professor of psychiatry, neuroscience, and pediatrics at Albert Einstein College of Medicine, New York, said the investigational drug could represent an important addition to the armamentarium for treating depression.
“Zuranolone has good oral bioavailability and would represent the first neuroactive steroid antidepressant available in oral form and, indeed, the first non–monoamine-based antidepressant available in oral form,” he said in an interview.
Dr. Alpert was not involved in the research and has no relationship with the drug’s development.
He noted that although there are modest differences between the patients who received zuranolone and those who received placebo in the trials, “this may have been related to high placebo response rates, which often complicate antidepressant trials.
“Further research is needed to determine whether differences between zuranolone and placebo are clinically meaningful, though the separation between drug and placebo on the primary endpoint, as well as some other measures, such as quality of life measures, is promising,” Dr. Alpert said.
However, he added that comparisons with other active antidepressants in terms of efficacy and tolerability remain to be seen.
“Given the large number of individuals with major depressive disorder who have incomplete response to or do not tolerate monoaminergic antidepressants, the development of agents that leverage novel nonmonoaminergic mechanisms is important,” Dr. Alpert concluded.
The study was funded by Sage Therapeutics and Biogen. Dr. Cutler has been involved in research of zuranolone for Sage Therapeutics. Dr. Alpert has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
DENVER –
In a phase 3 trial that included more than 500 adult patients with MDD, those who received zuranolone for 14 days showed greater improvement at day 15 across numerous QoL outcomes, compared with their counterparts in the placebo group.
In addition, combined analysis of four zuranolone clinical trials showed “mental well-being and functioning improved to near general population norm levels” for the active-treatment group, reported the researchers, led by Anita H. Clayton, MD, chair and professor of psychiatry, University of Virginia, Charlottesville.
“Based on these integrated analyses, the benefit of treatment with zuranolone may extend beyond reduction in depressive symptoms to include potential improvement in quality of life and overall health, as perceived by patients,” they add.
The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
First oral formulation
Zuranolone represents the second entry in the new class of neuroactive steroid drugs, which modulate GABA-A receptor activity – but it would be the first to have an oral formulation. Brexanolone, which was approved by the Food and Drug Administration in 2019 for postpartum depression, is administered through continuous IV infusion over 60 hours.
As previously reported by this news organization, zuranolone improved depressive symptoms as early as day 3, achieving the primary endpoint of significantly greater reduction in scores on the 17-item Hamilton Rating Scale for Depression from baseline to day 15 versus placebo (P = .014).
In the new analysis, patient-reported measures of functional health and well-being were assessed in the WATERFALL trial. It included 266 patients with MDD who were treated with zuranolone 50 mg daily for 2 weeks and 268 patients with MDD who were treated with placebo.
The study used the Short Form–36 (SF-36v2), which covers a wide range of patient-reported measures, including physical function, bodily pain, general health, vitality, social function, and “role-emotional” symptoms.
Results showed that although the treatment and placebo groups had similar baseline SF-36v2 scores, those receiving zuranolone reported significantly greater improvements at day 15 in almost all of the assessment’s domains, including physical function (treatment difference, 0.8), general health (1.0), vitality (3.1), social functioning (1.1), and role-emotional symptoms (1.5; for all comparisons, P < .05). The only exceptions were in role-physical symptoms and bodily pain.
In measures that included physical function, bodily pain, and general health, the patients achieved improvements at day 15 that were consistent with normal levels, with the improvement in vitality considered clinically meaningful versus placebo.
Integrated data
In further analysis of integrated data from four zuranolone clinical trials in the NEST and LANDSCAPE programs for patients with MDD and postpartum depression, results showed similar improvements at day 15 for zuranolone in QoL and overall health across all of the SF-36v2 functioning and well-being domains (P <.05), with the exceptions of physical measure and bodily pain.
By day 42, all of the domains showed significantly greater improvement with zuranolone versus placebo (all, P <.05).
Among the strongest score improvements in the integrated trials were measures in social functioning, which improved from baseline scores of 29.66 to 42.82 on day 15 and to 43.59 on day 42.
Emotional domain scores improved from 24.43 at baseline to 39.13 on day 15 and to 39.82 on day 42. For mental health, the integrated scores for the zuranolone group improved from 27.13 at baseline to 42.40 on day 15 and 42.62 on day 42.
Of note, the baseline scores for mental health represented just 54.3% of those in the normal population; with the increase at day 15, the level was 84.8% of the normal population.
“Across four completed placebo-controlled NEST and LANDSCAPE clinical trials, patient reports of functional health and well-being as assessed by the SF-36v2 indicated substantial impairment at baseline compared to the population norm,” the researchers reported.
The improvements are especially important in light of the fact that in some patients with MDD, functional improvement is a top priority.
“Patients have often prioritized returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression,” the investigators wrote.
Zuranolone trials have shown that treatment-emergent adverse events (AEs) occur among about 60% of patients, versus about 44% with placebo. The most common AEs are somnolence, dizziness, headache, sedation, and diarrhea, with no increases in suicidal ideation or withdrawal.
The rates of severe AEs are low, and they are observed in about 3% of patients, versus 1.1% with placebo, the researchers noted.
Further, as opposed to serotonergic antidepressants such as SNRIs and SSRIs, zuranolone does not appear to have the undesirable side effects of decreased libido and sexual dysfunction, they added.
Clinically meaningful?
Andrew J. Cutler, MD, clinical associate professor of psychiatry at State University of New York, Syracuse, said the data are “very significant” for a number of reasons.
“We need more options to treat depression, especially ones with novel mechanisms of action and faster onset of efficacy, such as zuranolone,” said Dr. Cutler, who was not involved in the current study. He has coauthored other studies on zuranolone.
Regarding the study’s QoL outcomes, “while improvement in depressive symptoms is very important, what really matters to patients is improvement in function and quality of life,” Dr. Cutler noted.
Also commenting on the study, Jonathan E. Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences and professor of psychiatry, neuroscience, and pediatrics at Albert Einstein College of Medicine, New York, said the investigational drug could represent an important addition to the armamentarium for treating depression.
“Zuranolone has good oral bioavailability and would represent the first neuroactive steroid antidepressant available in oral form and, indeed, the first non–monoamine-based antidepressant available in oral form,” he said in an interview.
Dr. Alpert was not involved in the research and has no relationship with the drug’s development.
He noted that although there are modest differences between the patients who received zuranolone and those who received placebo in the trials, “this may have been related to high placebo response rates, which often complicate antidepressant trials.
“Further research is needed to determine whether differences between zuranolone and placebo are clinically meaningful, though the separation between drug and placebo on the primary endpoint, as well as some other measures, such as quality of life measures, is promising,” Dr. Alpert said.
However, he added that comparisons with other active antidepressants in terms of efficacy and tolerability remain to be seen.
“Given the large number of individuals with major depressive disorder who have incomplete response to or do not tolerate monoaminergic antidepressants, the development of agents that leverage novel nonmonoaminergic mechanisms is important,” Dr. Alpert concluded.
The study was funded by Sage Therapeutics and Biogen. Dr. Cutler has been involved in research of zuranolone for Sage Therapeutics. Dr. Alpert has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ADAA 2022
Pembro provides DFS benefit in early NSCLC
Adjuvant pembrolizumab significantly improves disease-free survival (DFS) compared to placebo in patients with early-stage non–small cell lung cancer (NSCLC) who have undergone complete resection, according to findings from the phase 3 PEARLS/KEYNOTE-091 (PEARLS) study.
Patients in the pembrolizumab arm demonstrated median DFS nearly 12 months longer than those in the placebo arm (53.6 vs. 42.0 months). Investigators observed a DFS benefit for patients with any programmed death-ligand 1 (PD-L1) expression.
“We believe that pembrolizumab has the potential to become a new adjuvant treatment option for patient with [stage IB to IIIA] non–small cell lung cancer following complete resection and adjuvant chemotherapy when recommended,” concluded first author Luis Paz-Ares, MD, chair of the clinical research unit at Hospital Universitario 12 de Octubre, CNIO & Universidad Complutense, Madrid. “Pembrolizumab provided a benefit regardless of pathological stage and PD-L1 progression subgroup.”
The findings were presented by Dr. Paz-Ares at the European Society for Medical Oncology (ESMO) March virtual plenary session and published March 17 in Annals of Oncology.
Pembrolizumab is the standard treatment for patients with advanced NSCLC, but its efficacy in early-stage disease remains unclear. To determine whether patients with early-stage disease benefit from pembrolizumab, Dr. Paz-Ares and colleagues randomized 1,177 adults with stage IB, II, or IIIA NSCLC to 200 mg of pembrolizumab (n = 590) or placebo (n = 587) every 3 weeks.
All patients had Eastern Cooperative Oncology Group performance status of 0-1, and any level of PD-L1 expression. Of the study participants, 168 in the pembrolizumab arm and 165 in the placebo arm had PD-L1 expression and a tumor proportion score (TPS) of at least 50%.
Overall, patients receiving pembrolizumab had a DFS of 53.6 months compared to 42.0 months in the placebo arm (hazard ratio [HR], 0.76; P = .0014). The DFS benefit was generally consistent across patients with PD-L1 TPS <1%, 1%-49%, and ≥50%. In the subset of patients with PD-L1 TPS ≥50%, a slightly higher percentage of patients in the pembrolizumab group demonstrated DFS at 18 months (71.7% vs. 70.2%), but the difference did not reach statistical significance (HR, 0.82; P = .14).
Overall survival (OS) at 18 months was 91.7% in the treatment arm and 91.3% in the placebo arm (HR, 0.87; P = .17), but the data were immature.
“The disease-free survival benefit was observed across most prespecified subgroups,” Dr. Paz-Ares said.
No new safety concerns were raised. Grade 3 or greater adverse events occurred in 34.1% of patients in the treatment arm and 25.8% in the placebo arm. Adverse events led to discontinuation in 19.8% of patients receiving pembrolizumab and 5.9% of patients in the placebo group.
Invited discussant Martin Reck, MD, said these findings represent forward progress. “We do see many patients with distant relapse, which indicates that we have to improve our control of the systemic relapse,” said Dr. Reck, head of the department of thoracic oncology and the clinical trial department at the Lungen Clinic Grosshansdorf, Germany.
Prior data provide a rationale for using immune checkpoint inhibition in early-stage NSCLC, and both the PEARLS study and the IMpower010 trial evaluating atezolizumab in a similar setting have demonstrated relevant improvements in DFS.
“I think we are entering the times of perioperative immunotherapies. We are seeing the first signals of efficacy for adjuvant immunotherapy in two large, randomized trials,” Dr. Reck said.
Based on the PEARLS trial results, Dr. Reck said that PD-L1 appears to have predictive and prognostic value but noted that “several other clinical trials say PD-L1 expression is a poor prognostic marker” for sensitivity to immune checkpoint inhibitor. Given this potential inconsistency, Dr. Reck called for further follow-up in this patient population and for studies in larger groups of patients to further delineate the role of PD-L1 as well as EGFR mutations and adjuvant chemotherapy in patients with early NSCLC.
The PEARLS study was funded by Merck Sharp & Dohme Corp. Dr. Paz-Ares and Dr. Reck disclosed numerous relationships with pharmaceutical companies.
Adjuvant pembrolizumab significantly improves disease-free survival (DFS) compared to placebo in patients with early-stage non–small cell lung cancer (NSCLC) who have undergone complete resection, according to findings from the phase 3 PEARLS/KEYNOTE-091 (PEARLS) study.
Patients in the pembrolizumab arm demonstrated median DFS nearly 12 months longer than those in the placebo arm (53.6 vs. 42.0 months). Investigators observed a DFS benefit for patients with any programmed death-ligand 1 (PD-L1) expression.
“We believe that pembrolizumab has the potential to become a new adjuvant treatment option for patient with [stage IB to IIIA] non–small cell lung cancer following complete resection and adjuvant chemotherapy when recommended,” concluded first author Luis Paz-Ares, MD, chair of the clinical research unit at Hospital Universitario 12 de Octubre, CNIO & Universidad Complutense, Madrid. “Pembrolizumab provided a benefit regardless of pathological stage and PD-L1 progression subgroup.”
The findings were presented by Dr. Paz-Ares at the European Society for Medical Oncology (ESMO) March virtual plenary session and published March 17 in Annals of Oncology.
Pembrolizumab is the standard treatment for patients with advanced NSCLC, but its efficacy in early-stage disease remains unclear. To determine whether patients with early-stage disease benefit from pembrolizumab, Dr. Paz-Ares and colleagues randomized 1,177 adults with stage IB, II, or IIIA NSCLC to 200 mg of pembrolizumab (n = 590) or placebo (n = 587) every 3 weeks.
All patients had Eastern Cooperative Oncology Group performance status of 0-1, and any level of PD-L1 expression. Of the study participants, 168 in the pembrolizumab arm and 165 in the placebo arm had PD-L1 expression and a tumor proportion score (TPS) of at least 50%.
Overall, patients receiving pembrolizumab had a DFS of 53.6 months compared to 42.0 months in the placebo arm (hazard ratio [HR], 0.76; P = .0014). The DFS benefit was generally consistent across patients with PD-L1 TPS <1%, 1%-49%, and ≥50%. In the subset of patients with PD-L1 TPS ≥50%, a slightly higher percentage of patients in the pembrolizumab group demonstrated DFS at 18 months (71.7% vs. 70.2%), but the difference did not reach statistical significance (HR, 0.82; P = .14).
Overall survival (OS) at 18 months was 91.7% in the treatment arm and 91.3% in the placebo arm (HR, 0.87; P = .17), but the data were immature.
“The disease-free survival benefit was observed across most prespecified subgroups,” Dr. Paz-Ares said.
No new safety concerns were raised. Grade 3 or greater adverse events occurred in 34.1% of patients in the treatment arm and 25.8% in the placebo arm. Adverse events led to discontinuation in 19.8% of patients receiving pembrolizumab and 5.9% of patients in the placebo group.
Invited discussant Martin Reck, MD, said these findings represent forward progress. “We do see many patients with distant relapse, which indicates that we have to improve our control of the systemic relapse,” said Dr. Reck, head of the department of thoracic oncology and the clinical trial department at the Lungen Clinic Grosshansdorf, Germany.
Prior data provide a rationale for using immune checkpoint inhibition in early-stage NSCLC, and both the PEARLS study and the IMpower010 trial evaluating atezolizumab in a similar setting have demonstrated relevant improvements in DFS.
“I think we are entering the times of perioperative immunotherapies. We are seeing the first signals of efficacy for adjuvant immunotherapy in two large, randomized trials,” Dr. Reck said.
Based on the PEARLS trial results, Dr. Reck said that PD-L1 appears to have predictive and prognostic value but noted that “several other clinical trials say PD-L1 expression is a poor prognostic marker” for sensitivity to immune checkpoint inhibitor. Given this potential inconsistency, Dr. Reck called for further follow-up in this patient population and for studies in larger groups of patients to further delineate the role of PD-L1 as well as EGFR mutations and adjuvant chemotherapy in patients with early NSCLC.
The PEARLS study was funded by Merck Sharp & Dohme Corp. Dr. Paz-Ares and Dr. Reck disclosed numerous relationships with pharmaceutical companies.
Adjuvant pembrolizumab significantly improves disease-free survival (DFS) compared to placebo in patients with early-stage non–small cell lung cancer (NSCLC) who have undergone complete resection, according to findings from the phase 3 PEARLS/KEYNOTE-091 (PEARLS) study.
Patients in the pembrolizumab arm demonstrated median DFS nearly 12 months longer than those in the placebo arm (53.6 vs. 42.0 months). Investigators observed a DFS benefit for patients with any programmed death-ligand 1 (PD-L1) expression.
“We believe that pembrolizumab has the potential to become a new adjuvant treatment option for patient with [stage IB to IIIA] non–small cell lung cancer following complete resection and adjuvant chemotherapy when recommended,” concluded first author Luis Paz-Ares, MD, chair of the clinical research unit at Hospital Universitario 12 de Octubre, CNIO & Universidad Complutense, Madrid. “Pembrolizumab provided a benefit regardless of pathological stage and PD-L1 progression subgroup.”
The findings were presented by Dr. Paz-Ares at the European Society for Medical Oncology (ESMO) March virtual plenary session and published March 17 in Annals of Oncology.
Pembrolizumab is the standard treatment for patients with advanced NSCLC, but its efficacy in early-stage disease remains unclear. To determine whether patients with early-stage disease benefit from pembrolizumab, Dr. Paz-Ares and colleagues randomized 1,177 adults with stage IB, II, or IIIA NSCLC to 200 mg of pembrolizumab (n = 590) or placebo (n = 587) every 3 weeks.
All patients had Eastern Cooperative Oncology Group performance status of 0-1, and any level of PD-L1 expression. Of the study participants, 168 in the pembrolizumab arm and 165 in the placebo arm had PD-L1 expression and a tumor proportion score (TPS) of at least 50%.
Overall, patients receiving pembrolizumab had a DFS of 53.6 months compared to 42.0 months in the placebo arm (hazard ratio [HR], 0.76; P = .0014). The DFS benefit was generally consistent across patients with PD-L1 TPS <1%, 1%-49%, and ≥50%. In the subset of patients with PD-L1 TPS ≥50%, a slightly higher percentage of patients in the pembrolizumab group demonstrated DFS at 18 months (71.7% vs. 70.2%), but the difference did not reach statistical significance (HR, 0.82; P = .14).
Overall survival (OS) at 18 months was 91.7% in the treatment arm and 91.3% in the placebo arm (HR, 0.87; P = .17), but the data were immature.
“The disease-free survival benefit was observed across most prespecified subgroups,” Dr. Paz-Ares said.
No new safety concerns were raised. Grade 3 or greater adverse events occurred in 34.1% of patients in the treatment arm and 25.8% in the placebo arm. Adverse events led to discontinuation in 19.8% of patients receiving pembrolizumab and 5.9% of patients in the placebo group.
Invited discussant Martin Reck, MD, said these findings represent forward progress. “We do see many patients with distant relapse, which indicates that we have to improve our control of the systemic relapse,” said Dr. Reck, head of the department of thoracic oncology and the clinical trial department at the Lungen Clinic Grosshansdorf, Germany.
Prior data provide a rationale for using immune checkpoint inhibition in early-stage NSCLC, and both the PEARLS study and the IMpower010 trial evaluating atezolizumab in a similar setting have demonstrated relevant improvements in DFS.
“I think we are entering the times of perioperative immunotherapies. We are seeing the first signals of efficacy for adjuvant immunotherapy in two large, randomized trials,” Dr. Reck said.
Based on the PEARLS trial results, Dr. Reck said that PD-L1 appears to have predictive and prognostic value but noted that “several other clinical trials say PD-L1 expression is a poor prognostic marker” for sensitivity to immune checkpoint inhibitor. Given this potential inconsistency, Dr. Reck called for further follow-up in this patient population and for studies in larger groups of patients to further delineate the role of PD-L1 as well as EGFR mutations and adjuvant chemotherapy in patients with early NSCLC.
The PEARLS study was funded by Merck Sharp & Dohme Corp. Dr. Paz-Ares and Dr. Reck disclosed numerous relationships with pharmaceutical companies.
FROM THE ESMO MARCH PLENARY
Adding immunotherapy to chemo in lung cancer improves patient outcomes, new data show
according to an analysis presented at the annual European Lung Cancer Congress (ELCC) on March 30.
“Overall, it is very clear that chemotherapy plus immunotherapy prolongs the time to symptom deterioration and actually improves symptoms” in this patient population, said study discussant Luis Paz-Ares, MD, PhD, chair of medical oncology at the Hospital Universitario 12 de Octubre, Madrid, who was not involved in the research.
Last September, investigators reported efficacy outcomes from the phase 3 POSEIDON trial, which randomized 1,013 patients with EGFR/ALK wild-type mNSCLC to one of three first-line options: chemotherapy alone, chemotherapy plus the checkpoint inhibitor durvalumab, or chemotherapy plus two check-point inhibitors, durvalumab and tremelimumab. The analysis showed improved progression-free survival in both immunotherapy arms as well as a significant 2.3-month overall survival advantage with dual immunotherapy and a nonsignificant 1.6-month advantage with single agent durvalumab.
At the ELCC meeting, study presenter and lead investigator Edward Garon, MD, reported the latest data on the trial’s secondary endpoints: patient-reported outcomes. Global health status, functioning, and symptom scores were assessed using two questionnaires, the EORTC QLQ-C30 and EORTC QLQ-LC13.
Overall, Dr. Garon and colleagues reported a longer time to deterioration in all three areas – global health status, functioning, and symptoms – for patients who received immunotherapy versus chemotherapy alone, with similar results in both immunotherapy arms.
Time to deterioration in global health status, for instance, was a median of about 8 months on both immunotherapy regimens versus 5.6 months with chemotherapy alone. The positive findings held for many patient-reported treatment side effects, including dyspnea, hemoptysis, nausea/vomiting, and insomnia, but the benefits of adding immunotherapy weren’t always statistically significant.
Adding one or both checkpoint inhibitors to chemotherapy “improved efficacy while delaying deterioration in symptoms, functioning, and [health-related quality of life] versus chemotherapy alone in patients with mNSCLC,” concluded Dr. Garon, a thoracic medical oncologist at the University of California, Los Angeles. Plus, he added, “the pattern was observed across nearly all prespecified symptoms and domains of interest.”
According to study discussant Dr. Paz-Ares, “the data seem to be very consistent with all the trials asking similar questions.” The important thing here is figuring out the ideal candidates for dual inhibitor therapy, he said.
With positive efficacy and patient-reported outcomes for single and dual immunotherapy in this trial, it’s a “relatively straightforward” decision to add immunotherapy to chemotherapy for patients with mNSCLC, Massimo Di Maio, a medical oncologist at the University of Turin, Italy, said in an editorial on the ELCC’s news site.
However, that’s not always the case for every cancer type, which makes patient-reported outcomes “crucial” for determining the right treatment for each patient. Some might opt for a modest survival benefit regardless of the side effects, while others might favor a less toxic approach, even it means not living quite as long, he said.
The problem, he stressed, is that trials often release efficacy data well before patient-reported outcomes, which makes weighing the benefits and risks of a treat-ment option more difficult. The delay between efficacy and patient-reported outcome data was about 6 months in the POSEIDON trial.
“Timing is key when it comes to using [patient reported outcomes] for decision-making in oncology,” Dr. Di Maio said. “In fact, to enable a full assessment of a treatment, results should be published concurrently with the efficacy and safety data. Unfortunately, this is generally not the case.”
POSEIDON was funded by AstraZeneca, which markets durvalumab and is developing tremelimumab. Dr. Garon reported grants from the company. Dr. Paz-Ares reported honoraria and institutional research grants from AstraZeneca. Dr. Di Maio is a consultant for AstraZeneca and reported receiving honoraria and personal fees from the company.
according to an analysis presented at the annual European Lung Cancer Congress (ELCC) on March 30.
“Overall, it is very clear that chemotherapy plus immunotherapy prolongs the time to symptom deterioration and actually improves symptoms” in this patient population, said study discussant Luis Paz-Ares, MD, PhD, chair of medical oncology at the Hospital Universitario 12 de Octubre, Madrid, who was not involved in the research.
Last September, investigators reported efficacy outcomes from the phase 3 POSEIDON trial, which randomized 1,013 patients with EGFR/ALK wild-type mNSCLC to one of three first-line options: chemotherapy alone, chemotherapy plus the checkpoint inhibitor durvalumab, or chemotherapy plus two check-point inhibitors, durvalumab and tremelimumab. The analysis showed improved progression-free survival in both immunotherapy arms as well as a significant 2.3-month overall survival advantage with dual immunotherapy and a nonsignificant 1.6-month advantage with single agent durvalumab.
At the ELCC meeting, study presenter and lead investigator Edward Garon, MD, reported the latest data on the trial’s secondary endpoints: patient-reported outcomes. Global health status, functioning, and symptom scores were assessed using two questionnaires, the EORTC QLQ-C30 and EORTC QLQ-LC13.
Overall, Dr. Garon and colleagues reported a longer time to deterioration in all three areas – global health status, functioning, and symptoms – for patients who received immunotherapy versus chemotherapy alone, with similar results in both immunotherapy arms.
Time to deterioration in global health status, for instance, was a median of about 8 months on both immunotherapy regimens versus 5.6 months with chemotherapy alone. The positive findings held for many patient-reported treatment side effects, including dyspnea, hemoptysis, nausea/vomiting, and insomnia, but the benefits of adding immunotherapy weren’t always statistically significant.
Adding one or both checkpoint inhibitors to chemotherapy “improved efficacy while delaying deterioration in symptoms, functioning, and [health-related quality of life] versus chemotherapy alone in patients with mNSCLC,” concluded Dr. Garon, a thoracic medical oncologist at the University of California, Los Angeles. Plus, he added, “the pattern was observed across nearly all prespecified symptoms and domains of interest.”
According to study discussant Dr. Paz-Ares, “the data seem to be very consistent with all the trials asking similar questions.” The important thing here is figuring out the ideal candidates for dual inhibitor therapy, he said.
With positive efficacy and patient-reported outcomes for single and dual immunotherapy in this trial, it’s a “relatively straightforward” decision to add immunotherapy to chemotherapy for patients with mNSCLC, Massimo Di Maio, a medical oncologist at the University of Turin, Italy, said in an editorial on the ELCC’s news site.
However, that’s not always the case for every cancer type, which makes patient-reported outcomes “crucial” for determining the right treatment for each patient. Some might opt for a modest survival benefit regardless of the side effects, while others might favor a less toxic approach, even it means not living quite as long, he said.
The problem, he stressed, is that trials often release efficacy data well before patient-reported outcomes, which makes weighing the benefits and risks of a treat-ment option more difficult. The delay between efficacy and patient-reported outcome data was about 6 months in the POSEIDON trial.
“Timing is key when it comes to using [patient reported outcomes] for decision-making in oncology,” Dr. Di Maio said. “In fact, to enable a full assessment of a treatment, results should be published concurrently with the efficacy and safety data. Unfortunately, this is generally not the case.”
POSEIDON was funded by AstraZeneca, which markets durvalumab and is developing tremelimumab. Dr. Garon reported grants from the company. Dr. Paz-Ares reported honoraria and institutional research grants from AstraZeneca. Dr. Di Maio is a consultant for AstraZeneca and reported receiving honoraria and personal fees from the company.
according to an analysis presented at the annual European Lung Cancer Congress (ELCC) on March 30.
“Overall, it is very clear that chemotherapy plus immunotherapy prolongs the time to symptom deterioration and actually improves symptoms” in this patient population, said study discussant Luis Paz-Ares, MD, PhD, chair of medical oncology at the Hospital Universitario 12 de Octubre, Madrid, who was not involved in the research.
Last September, investigators reported efficacy outcomes from the phase 3 POSEIDON trial, which randomized 1,013 patients with EGFR/ALK wild-type mNSCLC to one of three first-line options: chemotherapy alone, chemotherapy plus the checkpoint inhibitor durvalumab, or chemotherapy plus two check-point inhibitors, durvalumab and tremelimumab. The analysis showed improved progression-free survival in both immunotherapy arms as well as a significant 2.3-month overall survival advantage with dual immunotherapy and a nonsignificant 1.6-month advantage with single agent durvalumab.
At the ELCC meeting, study presenter and lead investigator Edward Garon, MD, reported the latest data on the trial’s secondary endpoints: patient-reported outcomes. Global health status, functioning, and symptom scores were assessed using two questionnaires, the EORTC QLQ-C30 and EORTC QLQ-LC13.
Overall, Dr. Garon and colleagues reported a longer time to deterioration in all three areas – global health status, functioning, and symptoms – for patients who received immunotherapy versus chemotherapy alone, with similar results in both immunotherapy arms.
Time to deterioration in global health status, for instance, was a median of about 8 months on both immunotherapy regimens versus 5.6 months with chemotherapy alone. The positive findings held for many patient-reported treatment side effects, including dyspnea, hemoptysis, nausea/vomiting, and insomnia, but the benefits of adding immunotherapy weren’t always statistically significant.
Adding one or both checkpoint inhibitors to chemotherapy “improved efficacy while delaying deterioration in symptoms, functioning, and [health-related quality of life] versus chemotherapy alone in patients with mNSCLC,” concluded Dr. Garon, a thoracic medical oncologist at the University of California, Los Angeles. Plus, he added, “the pattern was observed across nearly all prespecified symptoms and domains of interest.”
According to study discussant Dr. Paz-Ares, “the data seem to be very consistent with all the trials asking similar questions.” The important thing here is figuring out the ideal candidates for dual inhibitor therapy, he said.
With positive efficacy and patient-reported outcomes for single and dual immunotherapy in this trial, it’s a “relatively straightforward” decision to add immunotherapy to chemotherapy for patients with mNSCLC, Massimo Di Maio, a medical oncologist at the University of Turin, Italy, said in an editorial on the ELCC’s news site.
However, that’s not always the case for every cancer type, which makes patient-reported outcomes “crucial” for determining the right treatment for each patient. Some might opt for a modest survival benefit regardless of the side effects, while others might favor a less toxic approach, even it means not living quite as long, he said.
The problem, he stressed, is that trials often release efficacy data well before patient-reported outcomes, which makes weighing the benefits and risks of a treat-ment option more difficult. The delay between efficacy and patient-reported outcome data was about 6 months in the POSEIDON trial.
“Timing is key when it comes to using [patient reported outcomes] for decision-making in oncology,” Dr. Di Maio said. “In fact, to enable a full assessment of a treatment, results should be published concurrently with the efficacy and safety data. Unfortunately, this is generally not the case.”
POSEIDON was funded by AstraZeneca, which markets durvalumab and is developing tremelimumab. Dr. Garon reported grants from the company. Dr. Paz-Ares reported honoraria and institutional research grants from AstraZeneca. Dr. Di Maio is a consultant for AstraZeneca and reported receiving honoraria and personal fees from the company.
FROM ELCC 2022
Anticoagulation not routinely needed after TAVR: ADAPT-TAVR
In patients undergoing transcatheter aortic valve replacement (TAVR), the incidence of leaflet thrombosis was numerically lower in those treated with the anticoagulant edoxaban for 6 months after the procedure than in those who received dual antiplatelet therapy, although the difference was not statistically significant, in the ADAPT-TAVR study.
There was no difference in new cerebral thromboembolism or neurologic/neurocognitive function between the two groups in the study.
Also, there was no significant relation between subclinical leaflet thrombosis and increased risk for cerebral thromboembolism and neurologic dysfunction.
The ADAPT-TAVR trial was presented April 4 at the American College of Cardiology (ACC) 2022 Scientific Session by Duk-Woo Park, MD, Asan Medical Center, Seoul, South Korea. It was simultaneously published online in Circulation.
“The key messages from this study are that subclinical leaflet thrombosis has not been proven to affect clinical outcomes for patients undergoing valve replacement and that in patients in whom leaflet thrombosis causes no symptoms or complications, its presence should not dictate the type of antithrombotic therapy that patients receive following the implantation of an artificial heart valve,” Dr. Park said.
“These findings do not support the routine use of computed tomography scans to detect subclinical leaflet thrombosis,” he added.
Commenting on the study at an ACC press conference, Megan Coylewright, MD, director of the Structural Heart Program at Erlanger Health System, Chattanooga, Tennessee, said: “Oftentimes when studies are negative, we’re disappointed. In this case, I think we are pleased that the study is negative because it suggests we do not have to expose our TAVR patients to anticoagulation for benefit.”
Dr. Coylewright explained that the ADAPT-TAVR study was asking whether clots form on the valve, as defined by CT.
“We are worried about that for two reasons: could that clot cause a stroke, and could that clot cause the valve to break down over time. This study looked at the first issue. And it found that there was some clot build up on the valve, but that it wasn’t significantly different between the anticoagulant and dual antiplatelet groups. And there was no correlation with embolic events, she noted.
“It shows how fast our field moves. In the U.S. now, we are using aspirin alone at 81 mg for patients who do not have an indication for oral anticoagulation after TAVR. We are moving away from dual antiplatelet therapy because the bleeding risk is so bad,” Dr. Coylewright said.
In his presentation, Dr. Park explained that it is believed that oral anticoagulants are more effective than antiplatelet therapy at reducing subclinical leaflet thrombosis, but it is not known whether there is a causal association between subclinical leaflet thrombosis and cerebral embolism, or whether oral anticoagulation can reduce cerebral embolism related to subclinical leaflet thrombosis.
The ADAPT-TAVR was conducted to look at these issues. The open-label randomized trial was conducted in five centers in Hong Kong, South Korea, and Taiwan.
For the study, 229 patients who had undergone successful TAVR and did not have an indication for anticoagulation were randomized to edoxaban 60 mg once daily, edoxaban 30 mg once daily for patients needing a reduced dose, or dual antiplatelet therapy for 6 months.
The primary endpoint was an incidence of leaflet thrombosis on four-dimensional CT at 6 months.
Results showed a strong trend toward a lower incidence of leaflet thrombosis in the edoxaban groups than in the dual antiplatelet group (9.8% vs. 18.4%; P = .076).
There was a nonsignificant difference in the percentage of patients with new cerebral lesions identified on brain MRI between the edoxaban and dual antiplatelet groups (25.0% vs. 20.2%).
The percentage of patients with worsening of neurologic and neurocognitive function was not different among the groups.
The incidence of any or major bleeding events was not different between two therapies.
There was also no significant association of the presence or extent of leaflet thrombosis with new cerebral lesions or change of neurologic or neurocognitive function.
Dr. Park noted that the trial had several limitations, including an open-label design, use of surrogate imaging outcomes for the primary outcome, and the relatively short follow-up period, so the study was underpowered to detect any meaningful differences in clinical efficacy and safety outcomes. The results should thus be considered hypothesis-generating, highlighting the need for further research, he added.
The long-term effect of leaflet thrombosis or different antithrombotic strategies on bioprosthetic valve durability is still unknown, Dr. Park said.
He also pointed out that the findings cannot be directly extrapolated to patients with an established indication for oral anticoagulant therapy.
The ADAPT-TAVR trial was an investigator-initiated trial and was funded by the CardioVascular Research Foundation (Seoul, Korea) and Daiichi Sankyo Korea.
A version of this article first appeared on Medscape.com.
In patients undergoing transcatheter aortic valve replacement (TAVR), the incidence of leaflet thrombosis was numerically lower in those treated with the anticoagulant edoxaban for 6 months after the procedure than in those who received dual antiplatelet therapy, although the difference was not statistically significant, in the ADAPT-TAVR study.
There was no difference in new cerebral thromboembolism or neurologic/neurocognitive function between the two groups in the study.
Also, there was no significant relation between subclinical leaflet thrombosis and increased risk for cerebral thromboembolism and neurologic dysfunction.
The ADAPT-TAVR trial was presented April 4 at the American College of Cardiology (ACC) 2022 Scientific Session by Duk-Woo Park, MD, Asan Medical Center, Seoul, South Korea. It was simultaneously published online in Circulation.
“The key messages from this study are that subclinical leaflet thrombosis has not been proven to affect clinical outcomes for patients undergoing valve replacement and that in patients in whom leaflet thrombosis causes no symptoms or complications, its presence should not dictate the type of antithrombotic therapy that patients receive following the implantation of an artificial heart valve,” Dr. Park said.
“These findings do not support the routine use of computed tomography scans to detect subclinical leaflet thrombosis,” he added.
Commenting on the study at an ACC press conference, Megan Coylewright, MD, director of the Structural Heart Program at Erlanger Health System, Chattanooga, Tennessee, said: “Oftentimes when studies are negative, we’re disappointed. In this case, I think we are pleased that the study is negative because it suggests we do not have to expose our TAVR patients to anticoagulation for benefit.”
Dr. Coylewright explained that the ADAPT-TAVR study was asking whether clots form on the valve, as defined by CT.
“We are worried about that for two reasons: could that clot cause a stroke, and could that clot cause the valve to break down over time. This study looked at the first issue. And it found that there was some clot build up on the valve, but that it wasn’t significantly different between the anticoagulant and dual antiplatelet groups. And there was no correlation with embolic events, she noted.
“It shows how fast our field moves. In the U.S. now, we are using aspirin alone at 81 mg for patients who do not have an indication for oral anticoagulation after TAVR. We are moving away from dual antiplatelet therapy because the bleeding risk is so bad,” Dr. Coylewright said.
In his presentation, Dr. Park explained that it is believed that oral anticoagulants are more effective than antiplatelet therapy at reducing subclinical leaflet thrombosis, but it is not known whether there is a causal association between subclinical leaflet thrombosis and cerebral embolism, or whether oral anticoagulation can reduce cerebral embolism related to subclinical leaflet thrombosis.
The ADAPT-TAVR was conducted to look at these issues. The open-label randomized trial was conducted in five centers in Hong Kong, South Korea, and Taiwan.
For the study, 229 patients who had undergone successful TAVR and did not have an indication for anticoagulation were randomized to edoxaban 60 mg once daily, edoxaban 30 mg once daily for patients needing a reduced dose, or dual antiplatelet therapy for 6 months.
The primary endpoint was an incidence of leaflet thrombosis on four-dimensional CT at 6 months.
Results showed a strong trend toward a lower incidence of leaflet thrombosis in the edoxaban groups than in the dual antiplatelet group (9.8% vs. 18.4%; P = .076).
There was a nonsignificant difference in the percentage of patients with new cerebral lesions identified on brain MRI between the edoxaban and dual antiplatelet groups (25.0% vs. 20.2%).
The percentage of patients with worsening of neurologic and neurocognitive function was not different among the groups.
The incidence of any or major bleeding events was not different between two therapies.
There was also no significant association of the presence or extent of leaflet thrombosis with new cerebral lesions or change of neurologic or neurocognitive function.
Dr. Park noted that the trial had several limitations, including an open-label design, use of surrogate imaging outcomes for the primary outcome, and the relatively short follow-up period, so the study was underpowered to detect any meaningful differences in clinical efficacy and safety outcomes. The results should thus be considered hypothesis-generating, highlighting the need for further research, he added.
The long-term effect of leaflet thrombosis or different antithrombotic strategies on bioprosthetic valve durability is still unknown, Dr. Park said.
He also pointed out that the findings cannot be directly extrapolated to patients with an established indication for oral anticoagulant therapy.
The ADAPT-TAVR trial was an investigator-initiated trial and was funded by the CardioVascular Research Foundation (Seoul, Korea) and Daiichi Sankyo Korea.
A version of this article first appeared on Medscape.com.
In patients undergoing transcatheter aortic valve replacement (TAVR), the incidence of leaflet thrombosis was numerically lower in those treated with the anticoagulant edoxaban for 6 months after the procedure than in those who received dual antiplatelet therapy, although the difference was not statistically significant, in the ADAPT-TAVR study.
There was no difference in new cerebral thromboembolism or neurologic/neurocognitive function between the two groups in the study.
Also, there was no significant relation between subclinical leaflet thrombosis and increased risk for cerebral thromboembolism and neurologic dysfunction.
The ADAPT-TAVR trial was presented April 4 at the American College of Cardiology (ACC) 2022 Scientific Session by Duk-Woo Park, MD, Asan Medical Center, Seoul, South Korea. It was simultaneously published online in Circulation.
“The key messages from this study are that subclinical leaflet thrombosis has not been proven to affect clinical outcomes for patients undergoing valve replacement and that in patients in whom leaflet thrombosis causes no symptoms or complications, its presence should not dictate the type of antithrombotic therapy that patients receive following the implantation of an artificial heart valve,” Dr. Park said.
“These findings do not support the routine use of computed tomography scans to detect subclinical leaflet thrombosis,” he added.
Commenting on the study at an ACC press conference, Megan Coylewright, MD, director of the Structural Heart Program at Erlanger Health System, Chattanooga, Tennessee, said: “Oftentimes when studies are negative, we’re disappointed. In this case, I think we are pleased that the study is negative because it suggests we do not have to expose our TAVR patients to anticoagulation for benefit.”
Dr. Coylewright explained that the ADAPT-TAVR study was asking whether clots form on the valve, as defined by CT.
“We are worried about that for two reasons: could that clot cause a stroke, and could that clot cause the valve to break down over time. This study looked at the first issue. And it found that there was some clot build up on the valve, but that it wasn’t significantly different between the anticoagulant and dual antiplatelet groups. And there was no correlation with embolic events, she noted.
“It shows how fast our field moves. In the U.S. now, we are using aspirin alone at 81 mg for patients who do not have an indication for oral anticoagulation after TAVR. We are moving away from dual antiplatelet therapy because the bleeding risk is so bad,” Dr. Coylewright said.
In his presentation, Dr. Park explained that it is believed that oral anticoagulants are more effective than antiplatelet therapy at reducing subclinical leaflet thrombosis, but it is not known whether there is a causal association between subclinical leaflet thrombosis and cerebral embolism, or whether oral anticoagulation can reduce cerebral embolism related to subclinical leaflet thrombosis.
The ADAPT-TAVR was conducted to look at these issues. The open-label randomized trial was conducted in five centers in Hong Kong, South Korea, and Taiwan.
For the study, 229 patients who had undergone successful TAVR and did not have an indication for anticoagulation were randomized to edoxaban 60 mg once daily, edoxaban 30 mg once daily for patients needing a reduced dose, or dual antiplatelet therapy for 6 months.
The primary endpoint was an incidence of leaflet thrombosis on four-dimensional CT at 6 months.
Results showed a strong trend toward a lower incidence of leaflet thrombosis in the edoxaban groups than in the dual antiplatelet group (9.8% vs. 18.4%; P = .076).
There was a nonsignificant difference in the percentage of patients with new cerebral lesions identified on brain MRI between the edoxaban and dual antiplatelet groups (25.0% vs. 20.2%).
The percentage of patients with worsening of neurologic and neurocognitive function was not different among the groups.
The incidence of any or major bleeding events was not different between two therapies.
There was also no significant association of the presence or extent of leaflet thrombosis with new cerebral lesions or change of neurologic or neurocognitive function.
Dr. Park noted that the trial had several limitations, including an open-label design, use of surrogate imaging outcomes for the primary outcome, and the relatively short follow-up period, so the study was underpowered to detect any meaningful differences in clinical efficacy and safety outcomes. The results should thus be considered hypothesis-generating, highlighting the need for further research, he added.
The long-term effect of leaflet thrombosis or different antithrombotic strategies on bioprosthetic valve durability is still unknown, Dr. Park said.
He also pointed out that the findings cannot be directly extrapolated to patients with an established indication for oral anticoagulant therapy.
The ADAPT-TAVR trial was an investigator-initiated trial and was funded by the CardioVascular Research Foundation (Seoul, Korea) and Daiichi Sankyo Korea.
A version of this article first appeared on Medscape.com.
CDC recommends hep B vaccination for most adults
It also added that adults aged 60 years or older without known risk factors for hepatitis B may get vaccinated.
The agency earlier recommended the vaccination for all infants and children under the age of 19 years and for adults aged 60 years or older with known risk factors.
The CDC said it wants to expand vaccinations because, after decades of progress, the number of new hepatitis B infections is increasing among adults. Acute hepatitis B infections among adults lead to chronic hepatitis B disease in an estimated 2%-6% of cases, and can result in cirrhosis, liver cancer, and death.
Among adults aged 40-49 years, the rate of cases increased from 1.9 per 100,000 people in 2011 to 2.7 per 100,000 in 2019. Among adults aged 50-59 years, the rate increased during this period from 1.1 to 1.6 per 100,000.
Most adults aren’t vaccinated. Among adults aged 19 years or older, only 30.0% reported that they’d received at least the three recommended doses of the vaccine. The rate was 40.3% for adults aged 19-49 years, and 19.1% for adults aged 50 years or older.
Hepatitis B infection rates are particularly elevated among African Americans.
Even among adults with chronic liver disease, the vaccination rate is only 33.0%. And, among travelers to countries where the virus has been endemic since 1995, only 38.9% were vaccinated.
In a 2018 survey of internal medicine and family physicians, 68% said their patients had not told them about risk factors, making it difficult to assess whether the patients needed the vaccine according to the recommendations at the time. These risk factors include injection drug use, incarceration, and multiple sex partners, experiences the patients may not have been willing to discuss.
CDC researchers calculated that universal adult hepatitis B vaccination would cost $153,000 for every quality-adjusted life-year (QALY) gained. For adults aged 19-59 years, a QALY would cost $117,000 because infections are more prevalent in that age group.
The CDC specified that it intends its new guidelines to prompt physicians to offer the vaccine to adults aged 60 years or older rather than wait for them to request it.
The Food and Drug Administration has approved both three-dose and two-dose hepatitis B vaccines, with evidence showing similar seroprotection and adverse events.
People who have already completed their vaccination or have a history of hepatitis B infection should only receive additional vaccinations in specific cases, as detailed in the CDC’s 2018 recommendations.
A version of this article first appeared on Medscape.com.
It also added that adults aged 60 years or older without known risk factors for hepatitis B may get vaccinated.
The agency earlier recommended the vaccination for all infants and children under the age of 19 years and for adults aged 60 years or older with known risk factors.
The CDC said it wants to expand vaccinations because, after decades of progress, the number of new hepatitis B infections is increasing among adults. Acute hepatitis B infections among adults lead to chronic hepatitis B disease in an estimated 2%-6% of cases, and can result in cirrhosis, liver cancer, and death.
Among adults aged 40-49 years, the rate of cases increased from 1.9 per 100,000 people in 2011 to 2.7 per 100,000 in 2019. Among adults aged 50-59 years, the rate increased during this period from 1.1 to 1.6 per 100,000.
Most adults aren’t vaccinated. Among adults aged 19 years or older, only 30.0% reported that they’d received at least the three recommended doses of the vaccine. The rate was 40.3% for adults aged 19-49 years, and 19.1% for adults aged 50 years or older.
Hepatitis B infection rates are particularly elevated among African Americans.
Even among adults with chronic liver disease, the vaccination rate is only 33.0%. And, among travelers to countries where the virus has been endemic since 1995, only 38.9% were vaccinated.
In a 2018 survey of internal medicine and family physicians, 68% said their patients had not told them about risk factors, making it difficult to assess whether the patients needed the vaccine according to the recommendations at the time. These risk factors include injection drug use, incarceration, and multiple sex partners, experiences the patients may not have been willing to discuss.
CDC researchers calculated that universal adult hepatitis B vaccination would cost $153,000 for every quality-adjusted life-year (QALY) gained. For adults aged 19-59 years, a QALY would cost $117,000 because infections are more prevalent in that age group.
The CDC specified that it intends its new guidelines to prompt physicians to offer the vaccine to adults aged 60 years or older rather than wait for them to request it.
The Food and Drug Administration has approved both three-dose and two-dose hepatitis B vaccines, with evidence showing similar seroprotection and adverse events.
People who have already completed their vaccination or have a history of hepatitis B infection should only receive additional vaccinations in specific cases, as detailed in the CDC’s 2018 recommendations.
A version of this article first appeared on Medscape.com.
It also added that adults aged 60 years or older without known risk factors for hepatitis B may get vaccinated.
The agency earlier recommended the vaccination for all infants and children under the age of 19 years and for adults aged 60 years or older with known risk factors.
The CDC said it wants to expand vaccinations because, after decades of progress, the number of new hepatitis B infections is increasing among adults. Acute hepatitis B infections among adults lead to chronic hepatitis B disease in an estimated 2%-6% of cases, and can result in cirrhosis, liver cancer, and death.
Among adults aged 40-49 years, the rate of cases increased from 1.9 per 100,000 people in 2011 to 2.7 per 100,000 in 2019. Among adults aged 50-59 years, the rate increased during this period from 1.1 to 1.6 per 100,000.
Most adults aren’t vaccinated. Among adults aged 19 years or older, only 30.0% reported that they’d received at least the three recommended doses of the vaccine. The rate was 40.3% for adults aged 19-49 years, and 19.1% for adults aged 50 years or older.
Hepatitis B infection rates are particularly elevated among African Americans.
Even among adults with chronic liver disease, the vaccination rate is only 33.0%. And, among travelers to countries where the virus has been endemic since 1995, only 38.9% were vaccinated.
In a 2018 survey of internal medicine and family physicians, 68% said their patients had not told them about risk factors, making it difficult to assess whether the patients needed the vaccine according to the recommendations at the time. These risk factors include injection drug use, incarceration, and multiple sex partners, experiences the patients may not have been willing to discuss.
CDC researchers calculated that universal adult hepatitis B vaccination would cost $153,000 for every quality-adjusted life-year (QALY) gained. For adults aged 19-59 years, a QALY would cost $117,000 because infections are more prevalent in that age group.
The CDC specified that it intends its new guidelines to prompt physicians to offer the vaccine to adults aged 60 years or older rather than wait for them to request it.
The Food and Drug Administration has approved both three-dose and two-dose hepatitis B vaccines, with evidence showing similar seroprotection and adverse events.
People who have already completed their vaccination or have a history of hepatitis B infection should only receive additional vaccinations in specific cases, as detailed in the CDC’s 2018 recommendations.
A version of this article first appeared on Medscape.com.
FROM THE MMWR
New HF guidelines feature ‘quad’ therapy, tweaked terminology
The new heart failure (HF) guidelines released by three North American societies had a lot of catching up to do given the significant, even paradigm-shifting, additions to available treatment options in the last few years.
The landscape now includes both new and repurposed drug therapies that benefit almost without regard to ejection fraction (EF), and evidence-based urgency to engage patients early on with at least four core medication classes, so-called quadruple therapy.
The guideline document offers a roadmap for navigating those key issues and many others and uses some creative tactics. They include the introduction of generalist-friendly labels for the traditional but obscurely named four stages of HF severity that, it is hoped, will have wider reach and expand the use of effective therapies.
It introduces additional disease-staging terminology that characterizes the syndrome as a continuum:
- “At risk for HF” for stage A, applied to asymptomatic patients with risk factors such as diabetes or hypertension but no known cardiac changes.
- “Pre-HF” for stage B, which adds cardiac structural changes or elevated natriuretic peptides, still in the absence of symptoms.
- “Symptomatic HF” for stage C, that is, structural disease with current or previous symptoms.
- “Advanced HF” for stage D, characterized by severe debilitating symptoms or repeated hospitalizations even with guideline-directed medical therapy (GDMT).
The new terms should be “easier for primary care physicians as well as nonspecialists” to remember and use effectively “and easier to translate to the patients,” compared with the solely alphabetical staging labels appearing in the guidelines for more than 15 years, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, said in an interview.
An emphasis on “at risk for HF” and “pre-HF” in the new document may help efforts to expand primary prevention of HF and management of preclinical HF. The guideline, Dr. Bozkurt said, includes specific treatment recommendations for those early stages.
The document also updates and sometimes introduces “recommendations for advanced heart failure, acute heart failure, and comorbidities – specifically for atrial fibrillation, iron deficiency, sleep apnea, coronary artery disease, and valvular heart disease,” Dr. Bozkurt observed, as well as for cardiomyopathy and HF related to pregnancy and cancer chemotherapy. “So, it’s a very comprehensive guideline.”
Dr. Bozkurt is vice chair of the guideline writing committee and helped introduce the guideline at the annual scientific sessions of the American College of Cardiology. The document, developed by the ACC, the American Heart Association, and the Heart Failure Society of America, was published April 1, 2022, in the societies’ flagship journals, Journal of the American College of Cardiology, Circulation, and the Journal of Cardiac Failure, respectively. It replaces the 2013 guideline from the ACC and AHA and the ACC/AHA/HFSA–focused update from 2017.
“We really need to treat early, and then we need to treat appropriately,” Douglas L. Mann, MD, Washington University in St. Louis, said in an interview. Dr. Mann, who was not involved in development of the new guideline, said he is “enthusiastic” about the new staging terminology.
“I think it makes it easier to convey the message that these people do need medicines, will benefit from medicines, and in some cases heart failure can be preventable,” he said. “I’m in favor of anything that simplifies it and makes it more readily interpretable by busy doctors who aren’t specialists.”
With the new staging terminology and in other ways, the guideline seems to appreciate cardiomyopathy as a journey from preclinical to advanced symptomatic stages – the preclinical “at-risk” stage tightening focus on primary prevention – and updated thinking on classification of HF by EF.
For example, there is new consideration of “HF with improved ejection fraction” (HFimpEF), which suggests the patient may be evolving from HF with reduced EF (HFrEF) to HF with EF that is preserved or mildly reduced, or vice versa.
With HFimpEF, which identifies patients previously with an EF of 40% or lower that improves to beyond 40% at follow-up testing, patients should continue on the medications they had been previously taking for HFrEF, Dr. Bozkurt said.
Patients at risk for HF, in stage A by the older terminology, are characterized by one or more significant HF risk factors, such as hypertension, diabetes, or coronary disease, as they have been in prior guidelines. But the new document, Dr. Bozkurt observed, adds genetic cardiomyopathies and exposure to cardiotoxic agents to the list.
Perhaps surprisingly, the guideline also includes elevated natriuretic peptides as an indicator of “at risk for HF,” with implications for screening. The evidence suggests that, “for patients who are at risk for heart failure, natriuretic peptide-based screening, followed by team-based care, can prevent development of left ventricular dysfunction in heart failure,” Dr. Bozkurt said.
Persons at risk for HF realistically encompass a huge swath of the population given the world prevalence of high blood pressure, obesity, and diabetes. Management of stage A, therefore, focuses on established tenets of primary cardiovascular prevention, such as weight and BP control, exercise, and healthy dietary choices.
They may well be eligible for treatment with sodium-glucose transporter 2 (SGLT2) inhibitors, which have been “game changers,” Dr. Mann said. “Now you can give them to diabetics and it’s going to prevent heart failure and [cardiovascular] events. We didn’t have a drug like that before, so I think that places a lot of emphasis on aggressive treatment of diabetes.”
For patients with symptomatic HF, the document touts multidisciplinary care and early initiation of drugs from each of four drug classes. Such quadruple therapy includes an SGLT2 inhibitor along with a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin system (RAS) inhibitor: the “core foundational therapies” for patients with HFrEF, Dr. Bozkurt observed.
Of note, she said, the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan (Entresto, Novartis) is the preferred RAS inhibitor. But “if the ARNI cannot be used, then use ACE inhibitors.” If the patient is intolerant of ACE inhibitors because of cough or angioedema, then the choice should be an angiotensin-receptor blocker.
“We have very effective therapies offering survival and morbidity benefits as well as improvements in quality of life and reverse remodeling,” Dr. Bozkurt observed. “The most important message is that optimization of therapies, including all of these medication classes, saves lives.”
The guideline also includes, for the first time, a series of “value statements” on cost-effectiveness of different therapies that assign a “high-value” rating to MRAs, hydralazine, and isosorbide dinitrate in otherwise optimally treated self-identified African Americans, and device therapy in appropriately selected patients. The statements hold SGLT2 inhibitors in chronic symptomatic HF and cardiac transplantation in advanced GDMT-resistant HF to be of “intermediate” value.
The value statements, Dr. Bozkurt noted, “are included throughout the document when there is evidence; when there is a high-quality cost-effectiveness study published.”
Dr. Bozkurt disclosed receiving honoraria or consulting fees from Amgen, AstraZeneca, Baxter International, Bristol-Myers Squibb, Sanofi-Aventis, scPharmaceuticals, and Vifor Pharma; serving on a data safety monitoring board for LivaNova USA; and holding other relationships with Abbott Laboratories and Relypsa. Dr. Mann disclosed receiving honoraria or consulting fees from MyoKardia, Novartis, and Novo Nordisk.
A version of this article first appeared on Medscape.com.
The new heart failure (HF) guidelines released by three North American societies had a lot of catching up to do given the significant, even paradigm-shifting, additions to available treatment options in the last few years.
The landscape now includes both new and repurposed drug therapies that benefit almost without regard to ejection fraction (EF), and evidence-based urgency to engage patients early on with at least four core medication classes, so-called quadruple therapy.
The guideline document offers a roadmap for navigating those key issues and many others and uses some creative tactics. They include the introduction of generalist-friendly labels for the traditional but obscurely named four stages of HF severity that, it is hoped, will have wider reach and expand the use of effective therapies.
It introduces additional disease-staging terminology that characterizes the syndrome as a continuum:
- “At risk for HF” for stage A, applied to asymptomatic patients with risk factors such as diabetes or hypertension but no known cardiac changes.
- “Pre-HF” for stage B, which adds cardiac structural changes or elevated natriuretic peptides, still in the absence of symptoms.
- “Symptomatic HF” for stage C, that is, structural disease with current or previous symptoms.
- “Advanced HF” for stage D, characterized by severe debilitating symptoms or repeated hospitalizations even with guideline-directed medical therapy (GDMT).
The new terms should be “easier for primary care physicians as well as nonspecialists” to remember and use effectively “and easier to translate to the patients,” compared with the solely alphabetical staging labels appearing in the guidelines for more than 15 years, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, said in an interview.
An emphasis on “at risk for HF” and “pre-HF” in the new document may help efforts to expand primary prevention of HF and management of preclinical HF. The guideline, Dr. Bozkurt said, includes specific treatment recommendations for those early stages.
The document also updates and sometimes introduces “recommendations for advanced heart failure, acute heart failure, and comorbidities – specifically for atrial fibrillation, iron deficiency, sleep apnea, coronary artery disease, and valvular heart disease,” Dr. Bozkurt observed, as well as for cardiomyopathy and HF related to pregnancy and cancer chemotherapy. “So, it’s a very comprehensive guideline.”
Dr. Bozkurt is vice chair of the guideline writing committee and helped introduce the guideline at the annual scientific sessions of the American College of Cardiology. The document, developed by the ACC, the American Heart Association, and the Heart Failure Society of America, was published April 1, 2022, in the societies’ flagship journals, Journal of the American College of Cardiology, Circulation, and the Journal of Cardiac Failure, respectively. It replaces the 2013 guideline from the ACC and AHA and the ACC/AHA/HFSA–focused update from 2017.
“We really need to treat early, and then we need to treat appropriately,” Douglas L. Mann, MD, Washington University in St. Louis, said in an interview. Dr. Mann, who was not involved in development of the new guideline, said he is “enthusiastic” about the new staging terminology.
“I think it makes it easier to convey the message that these people do need medicines, will benefit from medicines, and in some cases heart failure can be preventable,” he said. “I’m in favor of anything that simplifies it and makes it more readily interpretable by busy doctors who aren’t specialists.”
With the new staging terminology and in other ways, the guideline seems to appreciate cardiomyopathy as a journey from preclinical to advanced symptomatic stages – the preclinical “at-risk” stage tightening focus on primary prevention – and updated thinking on classification of HF by EF.
For example, there is new consideration of “HF with improved ejection fraction” (HFimpEF), which suggests the patient may be evolving from HF with reduced EF (HFrEF) to HF with EF that is preserved or mildly reduced, or vice versa.
With HFimpEF, which identifies patients previously with an EF of 40% or lower that improves to beyond 40% at follow-up testing, patients should continue on the medications they had been previously taking for HFrEF, Dr. Bozkurt said.
Patients at risk for HF, in stage A by the older terminology, are characterized by one or more significant HF risk factors, such as hypertension, diabetes, or coronary disease, as they have been in prior guidelines. But the new document, Dr. Bozkurt observed, adds genetic cardiomyopathies and exposure to cardiotoxic agents to the list.
Perhaps surprisingly, the guideline also includes elevated natriuretic peptides as an indicator of “at risk for HF,” with implications for screening. The evidence suggests that, “for patients who are at risk for heart failure, natriuretic peptide-based screening, followed by team-based care, can prevent development of left ventricular dysfunction in heart failure,” Dr. Bozkurt said.
Persons at risk for HF realistically encompass a huge swath of the population given the world prevalence of high blood pressure, obesity, and diabetes. Management of stage A, therefore, focuses on established tenets of primary cardiovascular prevention, such as weight and BP control, exercise, and healthy dietary choices.
They may well be eligible for treatment with sodium-glucose transporter 2 (SGLT2) inhibitors, which have been “game changers,” Dr. Mann said. “Now you can give them to diabetics and it’s going to prevent heart failure and [cardiovascular] events. We didn’t have a drug like that before, so I think that places a lot of emphasis on aggressive treatment of diabetes.”
For patients with symptomatic HF, the document touts multidisciplinary care and early initiation of drugs from each of four drug classes. Such quadruple therapy includes an SGLT2 inhibitor along with a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin system (RAS) inhibitor: the “core foundational therapies” for patients with HFrEF, Dr. Bozkurt observed.
Of note, she said, the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan (Entresto, Novartis) is the preferred RAS inhibitor. But “if the ARNI cannot be used, then use ACE inhibitors.” If the patient is intolerant of ACE inhibitors because of cough or angioedema, then the choice should be an angiotensin-receptor blocker.
“We have very effective therapies offering survival and morbidity benefits as well as improvements in quality of life and reverse remodeling,” Dr. Bozkurt observed. “The most important message is that optimization of therapies, including all of these medication classes, saves lives.”
The guideline also includes, for the first time, a series of “value statements” on cost-effectiveness of different therapies that assign a “high-value” rating to MRAs, hydralazine, and isosorbide dinitrate in otherwise optimally treated self-identified African Americans, and device therapy in appropriately selected patients. The statements hold SGLT2 inhibitors in chronic symptomatic HF and cardiac transplantation in advanced GDMT-resistant HF to be of “intermediate” value.
The value statements, Dr. Bozkurt noted, “are included throughout the document when there is evidence; when there is a high-quality cost-effectiveness study published.”
Dr. Bozkurt disclosed receiving honoraria or consulting fees from Amgen, AstraZeneca, Baxter International, Bristol-Myers Squibb, Sanofi-Aventis, scPharmaceuticals, and Vifor Pharma; serving on a data safety monitoring board for LivaNova USA; and holding other relationships with Abbott Laboratories and Relypsa. Dr. Mann disclosed receiving honoraria or consulting fees from MyoKardia, Novartis, and Novo Nordisk.
A version of this article first appeared on Medscape.com.
The new heart failure (HF) guidelines released by three North American societies had a lot of catching up to do given the significant, even paradigm-shifting, additions to available treatment options in the last few years.
The landscape now includes both new and repurposed drug therapies that benefit almost without regard to ejection fraction (EF), and evidence-based urgency to engage patients early on with at least four core medication classes, so-called quadruple therapy.
The guideline document offers a roadmap for navigating those key issues and many others and uses some creative tactics. They include the introduction of generalist-friendly labels for the traditional but obscurely named four stages of HF severity that, it is hoped, will have wider reach and expand the use of effective therapies.
It introduces additional disease-staging terminology that characterizes the syndrome as a continuum:
- “At risk for HF” for stage A, applied to asymptomatic patients with risk factors such as diabetes or hypertension but no known cardiac changes.
- “Pre-HF” for stage B, which adds cardiac structural changes or elevated natriuretic peptides, still in the absence of symptoms.
- “Symptomatic HF” for stage C, that is, structural disease with current or previous symptoms.
- “Advanced HF” for stage D, characterized by severe debilitating symptoms or repeated hospitalizations even with guideline-directed medical therapy (GDMT).
The new terms should be “easier for primary care physicians as well as nonspecialists” to remember and use effectively “and easier to translate to the patients,” compared with the solely alphabetical staging labels appearing in the guidelines for more than 15 years, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, said in an interview.
An emphasis on “at risk for HF” and “pre-HF” in the new document may help efforts to expand primary prevention of HF and management of preclinical HF. The guideline, Dr. Bozkurt said, includes specific treatment recommendations for those early stages.
The document also updates and sometimes introduces “recommendations for advanced heart failure, acute heart failure, and comorbidities – specifically for atrial fibrillation, iron deficiency, sleep apnea, coronary artery disease, and valvular heart disease,” Dr. Bozkurt observed, as well as for cardiomyopathy and HF related to pregnancy and cancer chemotherapy. “So, it’s a very comprehensive guideline.”
Dr. Bozkurt is vice chair of the guideline writing committee and helped introduce the guideline at the annual scientific sessions of the American College of Cardiology. The document, developed by the ACC, the American Heart Association, and the Heart Failure Society of America, was published April 1, 2022, in the societies’ flagship journals, Journal of the American College of Cardiology, Circulation, and the Journal of Cardiac Failure, respectively. It replaces the 2013 guideline from the ACC and AHA and the ACC/AHA/HFSA–focused update from 2017.
“We really need to treat early, and then we need to treat appropriately,” Douglas L. Mann, MD, Washington University in St. Louis, said in an interview. Dr. Mann, who was not involved in development of the new guideline, said he is “enthusiastic” about the new staging terminology.
“I think it makes it easier to convey the message that these people do need medicines, will benefit from medicines, and in some cases heart failure can be preventable,” he said. “I’m in favor of anything that simplifies it and makes it more readily interpretable by busy doctors who aren’t specialists.”
With the new staging terminology and in other ways, the guideline seems to appreciate cardiomyopathy as a journey from preclinical to advanced symptomatic stages – the preclinical “at-risk” stage tightening focus on primary prevention – and updated thinking on classification of HF by EF.
For example, there is new consideration of “HF with improved ejection fraction” (HFimpEF), which suggests the patient may be evolving from HF with reduced EF (HFrEF) to HF with EF that is preserved or mildly reduced, or vice versa.
With HFimpEF, which identifies patients previously with an EF of 40% or lower that improves to beyond 40% at follow-up testing, patients should continue on the medications they had been previously taking for HFrEF, Dr. Bozkurt said.
Patients at risk for HF, in stage A by the older terminology, are characterized by one or more significant HF risk factors, such as hypertension, diabetes, or coronary disease, as they have been in prior guidelines. But the new document, Dr. Bozkurt observed, adds genetic cardiomyopathies and exposure to cardiotoxic agents to the list.
Perhaps surprisingly, the guideline also includes elevated natriuretic peptides as an indicator of “at risk for HF,” with implications for screening. The evidence suggests that, “for patients who are at risk for heart failure, natriuretic peptide-based screening, followed by team-based care, can prevent development of left ventricular dysfunction in heart failure,” Dr. Bozkurt said.
Persons at risk for HF realistically encompass a huge swath of the population given the world prevalence of high blood pressure, obesity, and diabetes. Management of stage A, therefore, focuses on established tenets of primary cardiovascular prevention, such as weight and BP control, exercise, and healthy dietary choices.
They may well be eligible for treatment with sodium-glucose transporter 2 (SGLT2) inhibitors, which have been “game changers,” Dr. Mann said. “Now you can give them to diabetics and it’s going to prevent heart failure and [cardiovascular] events. We didn’t have a drug like that before, so I think that places a lot of emphasis on aggressive treatment of diabetes.”
For patients with symptomatic HF, the document touts multidisciplinary care and early initiation of drugs from each of four drug classes. Such quadruple therapy includes an SGLT2 inhibitor along with a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin system (RAS) inhibitor: the “core foundational therapies” for patients with HFrEF, Dr. Bozkurt observed.
Of note, she said, the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan (Entresto, Novartis) is the preferred RAS inhibitor. But “if the ARNI cannot be used, then use ACE inhibitors.” If the patient is intolerant of ACE inhibitors because of cough or angioedema, then the choice should be an angiotensin-receptor blocker.
“We have very effective therapies offering survival and morbidity benefits as well as improvements in quality of life and reverse remodeling,” Dr. Bozkurt observed. “The most important message is that optimization of therapies, including all of these medication classes, saves lives.”
The guideline also includes, for the first time, a series of “value statements” on cost-effectiveness of different therapies that assign a “high-value” rating to MRAs, hydralazine, and isosorbide dinitrate in otherwise optimally treated self-identified African Americans, and device therapy in appropriately selected patients. The statements hold SGLT2 inhibitors in chronic symptomatic HF and cardiac transplantation in advanced GDMT-resistant HF to be of “intermediate” value.
The value statements, Dr. Bozkurt noted, “are included throughout the document when there is evidence; when there is a high-quality cost-effectiveness study published.”
Dr. Bozkurt disclosed receiving honoraria or consulting fees from Amgen, AstraZeneca, Baxter International, Bristol-Myers Squibb, Sanofi-Aventis, scPharmaceuticals, and Vifor Pharma; serving on a data safety monitoring board for LivaNova USA; and holding other relationships with Abbott Laboratories and Relypsa. Dr. Mann disclosed receiving honoraria or consulting fees from MyoKardia, Novartis, and Novo Nordisk.
A version of this article first appeared on Medscape.com.
FROM ACC 2022
SCORED: Sotagliflozin shows robust MACE benefit
WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.
In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.
Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.
Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.
Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
An early MACE benefit and a stroke benefit
“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.
The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.
Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.
MACE results ‘heterogeneous’ from SGLT2 inhibitors
Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.
“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.
“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.
Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.
An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.
During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:
- The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
- The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
- The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m2, an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
- And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).
SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.
In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.
Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.
Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.
Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
An early MACE benefit and a stroke benefit
“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.
The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.
Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.
MACE results ‘heterogeneous’ from SGLT2 inhibitors
Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.
“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.
“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.
Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.
An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.
During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:
- The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
- The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
- The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m2, an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
- And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).
SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.
In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.
Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.
Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.
Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
An early MACE benefit and a stroke benefit
“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.
The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.
Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.
MACE results ‘heterogeneous’ from SGLT2 inhibitors
Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.
“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.
“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.
Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.
An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.
During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:
- The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
- The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
- The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m2, an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
- And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).
SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
AT ACC 2022
Hypertension control during pregnancy validated in major trial
Pregnant women with even mild hypertension should receive blood pressure–lowering medications to reduce the likelihood of adverse outcomes for the mother and the child, according to a large, open-label, randomized trial.
“Treating to the blood pressure goal in this study reduced the risk of adverse events associated with pregnancy but did not impair fetal growth,” Alan T. Tita, MD, PhD, associate dean for Global and Women’s Health, University of Alabama, Birmingham, reported at the annual scientific sessions of the American College of Cardiology.
The question of whether to treat chronic hypertension during pregnancy has been “an international controversy for decades,” said Dr. Tita, who led the investigator-initiated Chronic Hypertension and Pregnancy (CHAP) trial.
For the composite primary outcome of severe preeclampsia, medically indicated preterm birth at less than 35 weeks of gestation, placental abruption, or fetal/neonatal death, the treatment of hypertension versus no treatment showed a relative risk reduction of 18% (30.2% vs. 37%, (hazard ratio, 0.82; P < .001).
Small for gestational age is primary safety endpoint
An increase in preeclampsia risk in women whose fetus was small for gestational age (SGA), a theoretical consequence of reductions in arterial pressure, was not seen. The rate of SGA, defined as below the 10th percentile, was slightly higher in the treatment group (11.2% vs. 10.4%), but the difference did not approach significance (P = 0.76).
By answering this long-pending question, the CHAP data are “practice changing,” declared an ACC-invited commentator, Athena Poppas, MD, chief of cardiology and director of the Lifespan Cardiovascular Institute, Providence, R.I. She agreed that the need for treatment of mild chronic hypertension has been a dilemma for clinicians that is now acceptably resolved.
In this trial, 2,408 pregnant women with chronic mild hypertension defined as a blood pressure of 160/90 mm Hg were randomized to treatment with a goal blood pressure of less than 140/90 mm Hg or no treatment unless the blood pressure rose to at least 160/105. All women had singleton pregnancies. Enrollment before 23 weeks of gestation was required. Severe hypertension (at least 160/105 mm Hg) was an exclusion criterion, as were several comorbidities, such as kidney disease.
Combination therapy accepted for <140/90 mm Hg goal
The beta-blocker labetalol or the calcium channel blocker nifedipine as single agents were the preferred antihypertensive medications in the protocol, but other medications were permitted. To reach the blood pressure goal, the single-agent therapy was titrated to the maximum dose before starting a second agent.
After randomization the systolic and diastolic blood pressures fell in both groups, but they fell more and remained consistently lower in the active treatment group, particularly during the first 20 weeks after randomization, according to graphs displayed by Dr. Tita. Over the course of the study, the mean diastolic blood pressures were 129.5 and 132.6 mm Hg in the active treatment and control groups, respectively, while the systolic pressures were 79.1 vs. 81.5 mm Hg.
When the components of the primary outcome were evaluated separately, the greatest advantage of treatment was the reduction in the rate of severe eclampsia (23.3% vs. 29.1%; HR, 0.80: 95% confidence interval, 0.70-0.92) and preterm birth (12.2% vs. 16.7%; HR, 0.73: 95% CI, 0.60-0.89).
Across a large array of subgroups, including those with or without diabetes and those treated before or after 14 weeks of gestation, there was a consistent advantage for treatment, even if not statistically different. It is notable that 48% of patients were Black and 35% had a body mass index of at least 40. The active treatment was favored across all groups stratified by these characteristics.
Although the incidences of placental abruption (1.7% on treatment vs. 1.9% without) and fetal or neonatal death (3.5% vs. 4.3%) were lower in the active treatment group, they were uncommon events in both arms of the study. The differences did not reach statistical significance.
Maternal morbidity rates lower on treatment
Severe SGA, which was defined as below the 5th percentile, was also numerically but not significantly higher in the control arm than in the group receiving treatment (5.1% vs. 5.5%), but the incidence of composite adverse maternal events was numerically lower (2.1% vs. 2.8%). The incidences of all components of maternal morbidity, such as maternal death (0.1% vs. 0.2%) pulmonary edema (0.4% vs. 0.9%), heart failure (0.1% vs. 0.1%), and acute kidney injury (0.8% vs. 1.2%), were either lower or the same on active treatment versus no treatment.
According to Dr. Tita, who called CHAP one of the largest and most diverse studies to address the value of treating mild hypertension in pregnancy, the American College of Obstetricians and Gynecologists (ACOG) is evaluating these data for changing their current guidelines for managing hypertension during pregnancy.
“The rate of chronic hypertension during pregnancy has been rising in the United States due to the increase in the average age of pregnant women and the rising rates of obesity,” Dr. Tita commented.
“We definitely needed these data,” said Mary Norine Walsh, MD, medical director, Ascension Saint Vincent Cardiovascular Research Institute, Indianapolis. Not only has the value of treating mild hypertension been unresolved, but Dr. Walsh pointed out that the rates of maternal mortality in the United States are rising and now generally exceed those of many other developed countries.
There are several features in the design of this trial that make the results even more salient to clinical practice, according to Dr. Walsh. This includes the fact that about half of patients enrolled were on Medicaid. As a result, the study confirmed benefit in what Dr. Walsh characterized as a “vulnerable” population.
“We will be busy now to make sure that our [pregnant] patients are achieving these target blood pressures,” Dr. Walsh said. She indicated that CHAP validates the treatment target of 140/90 mm Hg as a standard of care.
The results were published in the New England Journal of Medicine simultaneously with its ACC presentation.
The trial was funded by the National Heart, Lung, and Blood Institute. Dr. Tita reports research grants from Pfizer. Dr. Walsh reports a financial relationship with EBR Systems. Dr. Poppas reports no potential conflicts of interest.
Pregnant women with even mild hypertension should receive blood pressure–lowering medications to reduce the likelihood of adverse outcomes for the mother and the child, according to a large, open-label, randomized trial.
“Treating to the blood pressure goal in this study reduced the risk of adverse events associated with pregnancy but did not impair fetal growth,” Alan T. Tita, MD, PhD, associate dean for Global and Women’s Health, University of Alabama, Birmingham, reported at the annual scientific sessions of the American College of Cardiology.
The question of whether to treat chronic hypertension during pregnancy has been “an international controversy for decades,” said Dr. Tita, who led the investigator-initiated Chronic Hypertension and Pregnancy (CHAP) trial.
For the composite primary outcome of severe preeclampsia, medically indicated preterm birth at less than 35 weeks of gestation, placental abruption, or fetal/neonatal death, the treatment of hypertension versus no treatment showed a relative risk reduction of 18% (30.2% vs. 37%, (hazard ratio, 0.82; P < .001).
Small for gestational age is primary safety endpoint
An increase in preeclampsia risk in women whose fetus was small for gestational age (SGA), a theoretical consequence of reductions in arterial pressure, was not seen. The rate of SGA, defined as below the 10th percentile, was slightly higher in the treatment group (11.2% vs. 10.4%), but the difference did not approach significance (P = 0.76).
By answering this long-pending question, the CHAP data are “practice changing,” declared an ACC-invited commentator, Athena Poppas, MD, chief of cardiology and director of the Lifespan Cardiovascular Institute, Providence, R.I. She agreed that the need for treatment of mild chronic hypertension has been a dilemma for clinicians that is now acceptably resolved.
In this trial, 2,408 pregnant women with chronic mild hypertension defined as a blood pressure of 160/90 mm Hg were randomized to treatment with a goal blood pressure of less than 140/90 mm Hg or no treatment unless the blood pressure rose to at least 160/105. All women had singleton pregnancies. Enrollment before 23 weeks of gestation was required. Severe hypertension (at least 160/105 mm Hg) was an exclusion criterion, as were several comorbidities, such as kidney disease.
Combination therapy accepted for <140/90 mm Hg goal
The beta-blocker labetalol or the calcium channel blocker nifedipine as single agents were the preferred antihypertensive medications in the protocol, but other medications were permitted. To reach the blood pressure goal, the single-agent therapy was titrated to the maximum dose before starting a second agent.
After randomization the systolic and diastolic blood pressures fell in both groups, but they fell more and remained consistently lower in the active treatment group, particularly during the first 20 weeks after randomization, according to graphs displayed by Dr. Tita. Over the course of the study, the mean diastolic blood pressures were 129.5 and 132.6 mm Hg in the active treatment and control groups, respectively, while the systolic pressures were 79.1 vs. 81.5 mm Hg.
When the components of the primary outcome were evaluated separately, the greatest advantage of treatment was the reduction in the rate of severe eclampsia (23.3% vs. 29.1%; HR, 0.80: 95% confidence interval, 0.70-0.92) and preterm birth (12.2% vs. 16.7%; HR, 0.73: 95% CI, 0.60-0.89).
Across a large array of subgroups, including those with or without diabetes and those treated before or after 14 weeks of gestation, there was a consistent advantage for treatment, even if not statistically different. It is notable that 48% of patients were Black and 35% had a body mass index of at least 40. The active treatment was favored across all groups stratified by these characteristics.
Although the incidences of placental abruption (1.7% on treatment vs. 1.9% without) and fetal or neonatal death (3.5% vs. 4.3%) were lower in the active treatment group, they were uncommon events in both arms of the study. The differences did not reach statistical significance.
Maternal morbidity rates lower on treatment
Severe SGA, which was defined as below the 5th percentile, was also numerically but not significantly higher in the control arm than in the group receiving treatment (5.1% vs. 5.5%), but the incidence of composite adverse maternal events was numerically lower (2.1% vs. 2.8%). The incidences of all components of maternal morbidity, such as maternal death (0.1% vs. 0.2%) pulmonary edema (0.4% vs. 0.9%), heart failure (0.1% vs. 0.1%), and acute kidney injury (0.8% vs. 1.2%), were either lower or the same on active treatment versus no treatment.
According to Dr. Tita, who called CHAP one of the largest and most diverse studies to address the value of treating mild hypertension in pregnancy, the American College of Obstetricians and Gynecologists (ACOG) is evaluating these data for changing their current guidelines for managing hypertension during pregnancy.
“The rate of chronic hypertension during pregnancy has been rising in the United States due to the increase in the average age of pregnant women and the rising rates of obesity,” Dr. Tita commented.
“We definitely needed these data,” said Mary Norine Walsh, MD, medical director, Ascension Saint Vincent Cardiovascular Research Institute, Indianapolis. Not only has the value of treating mild hypertension been unresolved, but Dr. Walsh pointed out that the rates of maternal mortality in the United States are rising and now generally exceed those of many other developed countries.
There are several features in the design of this trial that make the results even more salient to clinical practice, according to Dr. Walsh. This includes the fact that about half of patients enrolled were on Medicaid. As a result, the study confirmed benefit in what Dr. Walsh characterized as a “vulnerable” population.
“We will be busy now to make sure that our [pregnant] patients are achieving these target blood pressures,” Dr. Walsh said. She indicated that CHAP validates the treatment target of 140/90 mm Hg as a standard of care.
The results were published in the New England Journal of Medicine simultaneously with its ACC presentation.
The trial was funded by the National Heart, Lung, and Blood Institute. Dr. Tita reports research grants from Pfizer. Dr. Walsh reports a financial relationship with EBR Systems. Dr. Poppas reports no potential conflicts of interest.
Pregnant women with even mild hypertension should receive blood pressure–lowering medications to reduce the likelihood of adverse outcomes for the mother and the child, according to a large, open-label, randomized trial.
“Treating to the blood pressure goal in this study reduced the risk of adverse events associated with pregnancy but did not impair fetal growth,” Alan T. Tita, MD, PhD, associate dean for Global and Women’s Health, University of Alabama, Birmingham, reported at the annual scientific sessions of the American College of Cardiology.
The question of whether to treat chronic hypertension during pregnancy has been “an international controversy for decades,” said Dr. Tita, who led the investigator-initiated Chronic Hypertension and Pregnancy (CHAP) trial.
For the composite primary outcome of severe preeclampsia, medically indicated preterm birth at less than 35 weeks of gestation, placental abruption, or fetal/neonatal death, the treatment of hypertension versus no treatment showed a relative risk reduction of 18% (30.2% vs. 37%, (hazard ratio, 0.82; P < .001).
Small for gestational age is primary safety endpoint
An increase in preeclampsia risk in women whose fetus was small for gestational age (SGA), a theoretical consequence of reductions in arterial pressure, was not seen. The rate of SGA, defined as below the 10th percentile, was slightly higher in the treatment group (11.2% vs. 10.4%), but the difference did not approach significance (P = 0.76).
By answering this long-pending question, the CHAP data are “practice changing,” declared an ACC-invited commentator, Athena Poppas, MD, chief of cardiology and director of the Lifespan Cardiovascular Institute, Providence, R.I. She agreed that the need for treatment of mild chronic hypertension has been a dilemma for clinicians that is now acceptably resolved.
In this trial, 2,408 pregnant women with chronic mild hypertension defined as a blood pressure of 160/90 mm Hg were randomized to treatment with a goal blood pressure of less than 140/90 mm Hg or no treatment unless the blood pressure rose to at least 160/105. All women had singleton pregnancies. Enrollment before 23 weeks of gestation was required. Severe hypertension (at least 160/105 mm Hg) was an exclusion criterion, as were several comorbidities, such as kidney disease.
Combination therapy accepted for <140/90 mm Hg goal
The beta-blocker labetalol or the calcium channel blocker nifedipine as single agents were the preferred antihypertensive medications in the protocol, but other medications were permitted. To reach the blood pressure goal, the single-agent therapy was titrated to the maximum dose before starting a second agent.
After randomization the systolic and diastolic blood pressures fell in both groups, but they fell more and remained consistently lower in the active treatment group, particularly during the first 20 weeks after randomization, according to graphs displayed by Dr. Tita. Over the course of the study, the mean diastolic blood pressures were 129.5 and 132.6 mm Hg in the active treatment and control groups, respectively, while the systolic pressures were 79.1 vs. 81.5 mm Hg.
When the components of the primary outcome were evaluated separately, the greatest advantage of treatment was the reduction in the rate of severe eclampsia (23.3% vs. 29.1%; HR, 0.80: 95% confidence interval, 0.70-0.92) and preterm birth (12.2% vs. 16.7%; HR, 0.73: 95% CI, 0.60-0.89).
Across a large array of subgroups, including those with or without diabetes and those treated before or after 14 weeks of gestation, there was a consistent advantage for treatment, even if not statistically different. It is notable that 48% of patients were Black and 35% had a body mass index of at least 40. The active treatment was favored across all groups stratified by these characteristics.
Although the incidences of placental abruption (1.7% on treatment vs. 1.9% without) and fetal or neonatal death (3.5% vs. 4.3%) were lower in the active treatment group, they were uncommon events in both arms of the study. The differences did not reach statistical significance.
Maternal morbidity rates lower on treatment
Severe SGA, which was defined as below the 5th percentile, was also numerically but not significantly higher in the control arm than in the group receiving treatment (5.1% vs. 5.5%), but the incidence of composite adverse maternal events was numerically lower (2.1% vs. 2.8%). The incidences of all components of maternal morbidity, such as maternal death (0.1% vs. 0.2%) pulmonary edema (0.4% vs. 0.9%), heart failure (0.1% vs. 0.1%), and acute kidney injury (0.8% vs. 1.2%), were either lower or the same on active treatment versus no treatment.
According to Dr. Tita, who called CHAP one of the largest and most diverse studies to address the value of treating mild hypertension in pregnancy, the American College of Obstetricians and Gynecologists (ACOG) is evaluating these data for changing their current guidelines for managing hypertension during pregnancy.
“The rate of chronic hypertension during pregnancy has been rising in the United States due to the increase in the average age of pregnant women and the rising rates of obesity,” Dr. Tita commented.
“We definitely needed these data,” said Mary Norine Walsh, MD, medical director, Ascension Saint Vincent Cardiovascular Research Institute, Indianapolis. Not only has the value of treating mild hypertension been unresolved, but Dr. Walsh pointed out that the rates of maternal mortality in the United States are rising and now generally exceed those of many other developed countries.
There are several features in the design of this trial that make the results even more salient to clinical practice, according to Dr. Walsh. This includes the fact that about half of patients enrolled were on Medicaid. As a result, the study confirmed benefit in what Dr. Walsh characterized as a “vulnerable” population.
“We will be busy now to make sure that our [pregnant] patients are achieving these target blood pressures,” Dr. Walsh said. She indicated that CHAP validates the treatment target of 140/90 mm Hg as a standard of care.
The results were published in the New England Journal of Medicine simultaneously with its ACC presentation.
The trial was funded by the National Heart, Lung, and Blood Institute. Dr. Tita reports research grants from Pfizer. Dr. Walsh reports a financial relationship with EBR Systems. Dr. Poppas reports no potential conflicts of interest.
FROM ACC 2022
Dupilumab treats itch and clears lesions in prurigo nodularis patients
BOSTON – of treatment, in a phase 3 trial presented at the American Academy of Dermatology 2022 Annual Meeting.
There are currently no Food and Drug Administration–approved systemic therapies for PN. Although several treatments for the disease are used off label for the condition, such as ultraviolet light therapy and immunosuppressive agents, moderate to severe PN is usually difficult to control, noted Gil Yosipovitch, MD, director of the Miami Itch Center at the University of Miami Miller School of Medicine, Florida. He led the research and presented the findings at the conference.
“Many dermatologists feel very uncomfortable dealing with these patients because they suffer from chronicity, they are miserable, and previously, the drugs didn’t work well,” Dr. Yosipovitch told this news organization. The results from this trial “are very promising,” he said. “It opens a new field of treatment for itchy conditions.”
The trial, named LIBERTY-PN PRIME2, enrolled patients aged 18-80 who had been living with PN for at least 3 months. Patients had at least 20 lesions at baseline as well as severe itch, defined as a score of 7 or greater on the Worst Itch Numerical Rating Scale (WI-NRS). The scale ranges from 0 (no itch) to 10 (worst itch imaginable). Participants also had a history of treatment failure with medium to super-potent topical corticosteroids (TCSs), or treatment with TCSs was not medically advisable for them.
The randomized, double-blinded study enrolled 160 adults with PN. Of those, 78 were assigned to the treatment arm and received a 600-mg loading dose of dupilumab, administered subcutaneously, followed by 300-mg doses every 2 weeks for 24 weeks; 82 patients were allocated to receive placebo.
During the study, 25 patients in the placebo arm discontinued treatment. In the treatment arm, one patient was not treated and two discontinued treatment due to lack of efficacy.
The primary endpoint of the study was a reduction of at least 4 points on the WI-NRS at 12 weeks. Secondary endpoints included at least a 4-point WI-NRS reduction at 24 weeks and clear to nearly clear skin, defined as having a score of 0 or 1 on the Investigator’s Global Assessment PN-Stage (IGN PN-S). The scale ranges from 0 (clear) to 4 (severe).
At 12 weeks, 37.2% of patients given dupilumab reported a reduction of at least 4 points in WI-NRS, compared with 22.0% of patients given placebo (P = .0216). By 24 weeks, 57.7% of adults who received dupilumab achieved a greater than or equal to 4-point reduction in WI-NRS, compared with 19.5% of those who received placebo (P < .0001). Additionally, 44.9% of participants in the treatment arm achieved a score of 0 or 1 on the IGA PN-S, compared with 15.9% of those in the placebo arm (P < .0001).
Forty-four participants who received dupilumab (57.1%) and 42 participants who received placebo (51.2%) reported at least one treatment-emergent adverse event (TEAE) during the study, though none of these events were serious. The most common TEAE in the study was headache, occurring in five patients taking placebo and four patients receiving dupilumab. In the dupilumab group, there were five cases of herpes virus infection, four non-herpes skin infections, and three cases of conjunctivitis. In the placebo group, seven non-herpes skin infections were reported.
Sanofi and Regeneron, who jointly developed dupilumab, plan to file for regulatory approval for dupilumab for PN “around the world” in the first half of this year, according to a press release.
“It’s great news and a step in the right direction,” Sarina Elmariah, MD, PhD, a dermatologist at Massachusetts General Hospital and instructor of dermatology at Harvard Medical School, both in Boston, told this news organization. She was not involved with the research.
“We’re finally starting to shed light on this condition and its pathogenesis,” she said. She noted that other potential therapeutics for PN are also in development. “It’s reflective of the fact that we are making strides in this area.”
Sanofi and Regeneron Pharmaceuticals sponsored the LIBERTY-PN PRIME2 trial. Dr. Yosipovitch has reported financial relationships with Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, and Trevi Therapeutics. Dr. Elmariah is on the advisory boards of Sanofi, Galderma, and Trevi Therapeutics.
A version of this article first appeared on Medscape.com.
BOSTON – of treatment, in a phase 3 trial presented at the American Academy of Dermatology 2022 Annual Meeting.
There are currently no Food and Drug Administration–approved systemic therapies for PN. Although several treatments for the disease are used off label for the condition, such as ultraviolet light therapy and immunosuppressive agents, moderate to severe PN is usually difficult to control, noted Gil Yosipovitch, MD, director of the Miami Itch Center at the University of Miami Miller School of Medicine, Florida. He led the research and presented the findings at the conference.
“Many dermatologists feel very uncomfortable dealing with these patients because they suffer from chronicity, they are miserable, and previously, the drugs didn’t work well,” Dr. Yosipovitch told this news organization. The results from this trial “are very promising,” he said. “It opens a new field of treatment for itchy conditions.”
The trial, named LIBERTY-PN PRIME2, enrolled patients aged 18-80 who had been living with PN for at least 3 months. Patients had at least 20 lesions at baseline as well as severe itch, defined as a score of 7 or greater on the Worst Itch Numerical Rating Scale (WI-NRS). The scale ranges from 0 (no itch) to 10 (worst itch imaginable). Participants also had a history of treatment failure with medium to super-potent topical corticosteroids (TCSs), or treatment with TCSs was not medically advisable for them.
The randomized, double-blinded study enrolled 160 adults with PN. Of those, 78 were assigned to the treatment arm and received a 600-mg loading dose of dupilumab, administered subcutaneously, followed by 300-mg doses every 2 weeks for 24 weeks; 82 patients were allocated to receive placebo.
During the study, 25 patients in the placebo arm discontinued treatment. In the treatment arm, one patient was not treated and two discontinued treatment due to lack of efficacy.
The primary endpoint of the study was a reduction of at least 4 points on the WI-NRS at 12 weeks. Secondary endpoints included at least a 4-point WI-NRS reduction at 24 weeks and clear to nearly clear skin, defined as having a score of 0 or 1 on the Investigator’s Global Assessment PN-Stage (IGN PN-S). The scale ranges from 0 (clear) to 4 (severe).
At 12 weeks, 37.2% of patients given dupilumab reported a reduction of at least 4 points in WI-NRS, compared with 22.0% of patients given placebo (P = .0216). By 24 weeks, 57.7% of adults who received dupilumab achieved a greater than or equal to 4-point reduction in WI-NRS, compared with 19.5% of those who received placebo (P < .0001). Additionally, 44.9% of participants in the treatment arm achieved a score of 0 or 1 on the IGA PN-S, compared with 15.9% of those in the placebo arm (P < .0001).
Forty-four participants who received dupilumab (57.1%) and 42 participants who received placebo (51.2%) reported at least one treatment-emergent adverse event (TEAE) during the study, though none of these events were serious. The most common TEAE in the study was headache, occurring in five patients taking placebo and four patients receiving dupilumab. In the dupilumab group, there were five cases of herpes virus infection, four non-herpes skin infections, and three cases of conjunctivitis. In the placebo group, seven non-herpes skin infections were reported.
Sanofi and Regeneron, who jointly developed dupilumab, plan to file for regulatory approval for dupilumab for PN “around the world” in the first half of this year, according to a press release.
“It’s great news and a step in the right direction,” Sarina Elmariah, MD, PhD, a dermatologist at Massachusetts General Hospital and instructor of dermatology at Harvard Medical School, both in Boston, told this news organization. She was not involved with the research.
“We’re finally starting to shed light on this condition and its pathogenesis,” she said. She noted that other potential therapeutics for PN are also in development. “It’s reflective of the fact that we are making strides in this area.”
Sanofi and Regeneron Pharmaceuticals sponsored the LIBERTY-PN PRIME2 trial. Dr. Yosipovitch has reported financial relationships with Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, and Trevi Therapeutics. Dr. Elmariah is on the advisory boards of Sanofi, Galderma, and Trevi Therapeutics.
A version of this article first appeared on Medscape.com.
BOSTON – of treatment, in a phase 3 trial presented at the American Academy of Dermatology 2022 Annual Meeting.
There are currently no Food and Drug Administration–approved systemic therapies for PN. Although several treatments for the disease are used off label for the condition, such as ultraviolet light therapy and immunosuppressive agents, moderate to severe PN is usually difficult to control, noted Gil Yosipovitch, MD, director of the Miami Itch Center at the University of Miami Miller School of Medicine, Florida. He led the research and presented the findings at the conference.
“Many dermatologists feel very uncomfortable dealing with these patients because they suffer from chronicity, they are miserable, and previously, the drugs didn’t work well,” Dr. Yosipovitch told this news organization. The results from this trial “are very promising,” he said. “It opens a new field of treatment for itchy conditions.”
The trial, named LIBERTY-PN PRIME2, enrolled patients aged 18-80 who had been living with PN for at least 3 months. Patients had at least 20 lesions at baseline as well as severe itch, defined as a score of 7 or greater on the Worst Itch Numerical Rating Scale (WI-NRS). The scale ranges from 0 (no itch) to 10 (worst itch imaginable). Participants also had a history of treatment failure with medium to super-potent topical corticosteroids (TCSs), or treatment with TCSs was not medically advisable for them.
The randomized, double-blinded study enrolled 160 adults with PN. Of those, 78 were assigned to the treatment arm and received a 600-mg loading dose of dupilumab, administered subcutaneously, followed by 300-mg doses every 2 weeks for 24 weeks; 82 patients were allocated to receive placebo.
During the study, 25 patients in the placebo arm discontinued treatment. In the treatment arm, one patient was not treated and two discontinued treatment due to lack of efficacy.
The primary endpoint of the study was a reduction of at least 4 points on the WI-NRS at 12 weeks. Secondary endpoints included at least a 4-point WI-NRS reduction at 24 weeks and clear to nearly clear skin, defined as having a score of 0 or 1 on the Investigator’s Global Assessment PN-Stage (IGN PN-S). The scale ranges from 0 (clear) to 4 (severe).
At 12 weeks, 37.2% of patients given dupilumab reported a reduction of at least 4 points in WI-NRS, compared with 22.0% of patients given placebo (P = .0216). By 24 weeks, 57.7% of adults who received dupilumab achieved a greater than or equal to 4-point reduction in WI-NRS, compared with 19.5% of those who received placebo (P < .0001). Additionally, 44.9% of participants in the treatment arm achieved a score of 0 or 1 on the IGA PN-S, compared with 15.9% of those in the placebo arm (P < .0001).
Forty-four participants who received dupilumab (57.1%) and 42 participants who received placebo (51.2%) reported at least one treatment-emergent adverse event (TEAE) during the study, though none of these events were serious. The most common TEAE in the study was headache, occurring in five patients taking placebo and four patients receiving dupilumab. In the dupilumab group, there were five cases of herpes virus infection, four non-herpes skin infections, and three cases of conjunctivitis. In the placebo group, seven non-herpes skin infections were reported.
Sanofi and Regeneron, who jointly developed dupilumab, plan to file for regulatory approval for dupilumab for PN “around the world” in the first half of this year, according to a press release.
“It’s great news and a step in the right direction,” Sarina Elmariah, MD, PhD, a dermatologist at Massachusetts General Hospital and instructor of dermatology at Harvard Medical School, both in Boston, told this news organization. She was not involved with the research.
“We’re finally starting to shed light on this condition and its pathogenesis,” she said. She noted that other potential therapeutics for PN are also in development. “It’s reflective of the fact that we are making strides in this area.”
Sanofi and Regeneron Pharmaceuticals sponsored the LIBERTY-PN PRIME2 trial. Dr. Yosipovitch has reported financial relationships with Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, and Trevi Therapeutics. Dr. Elmariah is on the advisory boards of Sanofi, Galderma, and Trevi Therapeutics.
A version of this article first appeared on Medscape.com.
AT AAD 2022