Conference Coverage

SINGAPORE – A few months after releasing its phase 1 and 2 data, OSE Immunotherapeutics, which is based in Nantes, France, has announced positive results for its therapeutic vaccine to treat cancer. Following its promising findings concerning early-stage melanoma, pancreatic cancer, ENT cancers, and HPV-associated anogenital cancer, the company-funded phase 3 Atalante-1 trial has shown the benefits of the Tedopi (OSE2101) vaccine in treating patients with advanced non–small cell lung cancer who are on their second or third line of treatment.

The results suggest that Tedopi is the most developmentally advanced therapeutic vaccine for cancer.

The data from Atalante-1 were presented at the World Conference on Lung Cancer and were simultaneously published in Annals of Oncology.

Tedopi is composed of synthetic tumoral neo-epitopes (peptide fragments) that target five tumoral antigens, permitting the activation of tumor-specific T-lymphocytes for patients who are HLA-A2 positive. In 95% of cases, tumors express at least one of these five antigens. The aim of integrating these five antigens is to prevent immune escape. The technology uses the human leukocyte antigen (HLA) system, one of the keys for presenting antigens to T-lymphocytes. The vaccine is effective for patients who express the HLA-A2 gene, which is present in around half of the population. The HLA-A2 biomarker, detected via a blood test, can identify appropriate patients.
 

Study protocol

In the Atalante-1 trial, participants had locally advanced (unresectable and not eligible for radiotherapy) or metastatic (without alteration of the EGFR and ALK genes) non–small cell lung cancer that was resistant to previous immunotherapy. They had an HLA-A2 phenotype, as determined by a blood draw to determine whether their immune system could respond to the vaccine.

In this trial, 219 patients were randomly assigned in a 2:1 ratio to receive the vaccine or standard-of-care chemotherapy (80% received docetaxel). The vaccine was administered subcutaneously on day 1 every 3 weeks for six cycles. After that point, the vaccine was administered every 8 weeks until 1 year of treatment and every 12 weeks thereafter. The primary endpoint was overall survival.
 

Secondary resistance

The plan was to enroll 363 patients in the protocol, but the study did not complete its recruitment phase because of the COVID-19 pandemic. As a result, the study was stopped after the enrollment of 219 patients.

“It didn’t have the power we would have liked, but it helped us understand that the people who benefited the most from the vaccine were patients who had responded to immunotherapy in the past. These patients have what is called ‘secondary resistance,’ ” explained Benjamin Besse, MD, PhD, during a press conference organized by OSE Immunotherapeutics. Dr. Besse, the study’s principal investigator, is the director of clinical research at Gustave Roussy, Villejuif, France.

Overall, the results weren’t significant. But the results were positive for patients who had previously responded well to immunotherapy for at least 3 months. Of the 219 patients, 118 (54%) had a positive response.

Among these patients with secondary resistance to immunotherapy, median OS was 11.1 months with Tedopi versus 7.5 months with docetaxel.

For these patients, the risk of death was reduced by 41% with the vaccine, compared with chemotherapy. Overall, 44% of patients lived for another year after receiving Tedopi, versus 27.5% with docetaxel.

“This study is a positive signal for overall survival in the selected population. In this study of 219 patients, we realized that just half of patients really benefited from the vaccine: those who had previously responded to immunotherapy,” said Dr. Besse. “The study needs confirmation from a further, larger phase 3 study in more than 300 patients with secondary resistance to immunotherapy to give us the statistical power we need to convince the regulatory authorities.”
 

Tolerability profile

Fewer serious adverse effects were reported with the vaccine than with chemotherapy (11.4% with Tedopi and 35.1% with docetaxel).

The vaccine also allowed patients to maintain a better quality of life. Scores from the Quality of Life Questionnaire Core 30, which explores several areas of daily life, were better with the vaccine. Change in patients’ overall well-being was delayed in the vaccine group: 3.3 months in the chemotherapy arm versus 9 months in the vaccine arm.

“The vaccine was well tolerated. It has benefits in terms of controlling disease symptoms and causes few side effects. Chemotherapy with docetaxel, meanwhile, is more toxic and may affect a patient’s overall well-being. It causes hair loss in practically 100% of patients, induces neuropathy, makes hands and feet swell, damages the nails, is associated with nausea and vomiting ...” noted Dr. Besse. He went on to say that after the trial, of the patients who stopped receiving the vaccine or chemotherapy (either for toxicity reasons or for disease progression), those who had been given the vaccine responded better to the subsequent chemotherapy “because their overall health was better.”
 

Clinical development

The clinical development of Tedopi is ongoing. Three trials are currently taking place. One study is comparing the Tedopi vaccine plus docetaxel with Tedopi plus nivolumab (immunotherapy not used as a first-line treatment) to determine whether the effects of these treatment combinations might might be enhanced for patients with previously treated lung cancer.

Another study relating to ovarian cancer is in the recruitment phase. The researchers seek to evaluate the vaccine alone or in combination with pembrolizumab for patients with platinum-sensitive ovarian cancer. Results from both trials are expected in 2025.

The third trial seeks to assess FOLFIRI as maintenance therapy or FOLFIRI as maintenance plus Tedopi for patients with pancreatic cancer to improve disease management. Efficacy data are expected next year.

OSE Immunotherapeutics is simultaneously working on a companion biomarker, the HLA-A2 test.

The study was funded by OSE Immunotherapeutics. Dr. Besse disclosed the following conflicts of interest (research funding, institution): AbbVie, Amgen, AstraZeneca, Chugai Pharmaceutical, Daiichi-Sankyo, Ellipse Pharma, EISAI, Genmab, Genzyme Corporation, Hedera Dx, Inivata, IPSEN, Janssen, MSD, Pharmamar, Roche-Genentech, Sanofi, Socar Research, Taiho Oncology, and Turning Point Therapeutics.

This article was translated from the Medscape French Edition and a version appeared on Medscape.com.

SINGAPORE – A few months after releasing its phase 1 and 2 data, OSE Immunotherapeutics, which is based in Nantes, France, has announced positive results for its therapeutic vaccine to treat cancer. Following its promising findings concerning early-stage melanoma, pancreatic cancer, ENT cancers, and HPV-associated anogenital cancer, the company-funded phase 3 Atalante-1 trial has shown the benefits of the Tedopi (OSE2101) vaccine in treating patients with advanced non–small cell lung cancer who are on their second or third line of treatment.

The results suggest that Tedopi is the most developmentally advanced therapeutic vaccine for cancer.

The data from Atalante-1 were presented at the World Conference on Lung Cancer and were simultaneously published in Annals of Oncology.

Tedopi is composed of synthetic tumoral neo-epitopes (peptide fragments) that target five tumoral antigens, permitting the activation of tumor-specific T-lymphocytes for patients who are HLA-A2 positive. In 95% of cases, tumors express at least one of these five antigens. The aim of integrating these five antigens is to prevent immune escape. The technology uses the human leukocyte antigen (HLA) system, one of the keys for presenting antigens to T-lymphocytes. The vaccine is effective for patients who express the HLA-A2 gene, which is present in around half of the population. The HLA-A2 biomarker, detected via a blood test, can identify appropriate patients.
 

Study protocol

In the Atalante-1 trial, participants had locally advanced (unresectable and not eligible for radiotherapy) or metastatic (without alteration of the EGFR and ALK genes) non–small cell lung cancer that was resistant to previous immunotherapy. They had an HLA-A2 phenotype, as determined by a blood draw to determine whether their immune system could respond to the vaccine.

In this trial, 219 patients were randomly assigned in a 2:1 ratio to receive the vaccine or standard-of-care chemotherapy (80% received docetaxel). The vaccine was administered subcutaneously on day 1 every 3 weeks for six cycles. After that point, the vaccine was administered every 8 weeks until 1 year of treatment and every 12 weeks thereafter. The primary endpoint was overall survival.
 

Secondary resistance

The plan was to enroll 363 patients in the protocol, but the study did not complete its recruitment phase because of the COVID-19 pandemic. As a result, the study was stopped after the enrollment of 219 patients.

“It didn’t have the power we would have liked, but it helped us understand that the people who benefited the most from the vaccine were patients who had responded to immunotherapy in the past. These patients have what is called ‘secondary resistance,’ ” explained Benjamin Besse, MD, PhD, during a press conference organized by OSE Immunotherapeutics. Dr. Besse, the study’s principal investigator, is the director of clinical research at Gustave Roussy, Villejuif, France.

Overall, the results weren’t significant. But the results were positive for patients who had previously responded well to immunotherapy for at least 3 months. Of the 219 patients, 118 (54%) had a positive response.

Among these patients with secondary resistance to immunotherapy, median OS was 11.1 months with Tedopi versus 7.5 months with docetaxel.

For these patients, the risk of death was reduced by 41% with the vaccine, compared with chemotherapy. Overall, 44% of patients lived for another year after receiving Tedopi, versus 27.5% with docetaxel.

“This study is a positive signal for overall survival in the selected population. In this study of 219 patients, we realized that just half of patients really benefited from the vaccine: those who had previously responded to immunotherapy,” said Dr. Besse. “The study needs confirmation from a further, larger phase 3 study in more than 300 patients with secondary resistance to immunotherapy to give us the statistical power we need to convince the regulatory authorities.”
 

Tolerability profile

Fewer serious adverse effects were reported with the vaccine than with chemotherapy (11.4% with Tedopi and 35.1% with docetaxel).

The vaccine also allowed patients to maintain a better quality of life. Scores from the Quality of Life Questionnaire Core 30, which explores several areas of daily life, were better with the vaccine. Change in patients’ overall well-being was delayed in the vaccine group: 3.3 months in the chemotherapy arm versus 9 months in the vaccine arm.

“The vaccine was well tolerated. It has benefits in terms of controlling disease symptoms and causes few side effects. Chemotherapy with docetaxel, meanwhile, is more toxic and may affect a patient’s overall well-being. It causes hair loss in practically 100% of patients, induces neuropathy, makes hands and feet swell, damages the nails, is associated with nausea and vomiting ...” noted Dr. Besse. He went on to say that after the trial, of the patients who stopped receiving the vaccine or chemotherapy (either for toxicity reasons or for disease progression), those who had been given the vaccine responded better to the subsequent chemotherapy “because their overall health was better.”
 

Clinical development

The clinical development of Tedopi is ongoing. Three trials are currently taking place. One study is comparing the Tedopi vaccine plus docetaxel with Tedopi plus nivolumab (immunotherapy not used as a first-line treatment) to determine whether the effects of these treatment combinations might might be enhanced for patients with previously treated lung cancer.

Another study relating to ovarian cancer is in the recruitment phase. The researchers seek to evaluate the vaccine alone or in combination with pembrolizumab for patients with platinum-sensitive ovarian cancer. Results from both trials are expected in 2025.

The third trial seeks to assess FOLFIRI as maintenance therapy or FOLFIRI as maintenance plus Tedopi for patients with pancreatic cancer to improve disease management. Efficacy data are expected next year.

OSE Immunotherapeutics is simultaneously working on a companion biomarker, the HLA-A2 test.

The study was funded by OSE Immunotherapeutics. Dr. Besse disclosed the following conflicts of interest (research funding, institution): AbbVie, Amgen, AstraZeneca, Chugai Pharmaceutical, Daiichi-Sankyo, Ellipse Pharma, EISAI, Genmab, Genzyme Corporation, Hedera Dx, Inivata, IPSEN, Janssen, MSD, Pharmamar, Roche-Genentech, Sanofi, Socar Research, Taiho Oncology, and Turning Point Therapeutics.

This article was translated from the Medscape French Edition and a version appeared on Medscape.com.

SINGAPORE – A few months after releasing its phase 1 and 2 data, OSE Immunotherapeutics, which is based in Nantes, France, has announced positive results for its therapeutic vaccine to treat cancer. Following its promising findings concerning early-stage melanoma, pancreatic cancer, ENT cancers, and HPV-associated anogenital cancer, the company-funded phase 3 Atalante-1 trial has shown the benefits of the Tedopi (OSE2101) vaccine in treating patients with advanced non–small cell lung cancer who are on their second or third line of treatment.

The results suggest that Tedopi is the most developmentally advanced therapeutic vaccine for cancer.

The data from Atalante-1 were presented at the World Conference on Lung Cancer and were simultaneously published in Annals of Oncology.

Tedopi is composed of synthetic tumoral neo-epitopes (peptide fragments) that target five tumoral antigens, permitting the activation of tumor-specific T-lymphocytes for patients who are HLA-A2 positive. In 95% of cases, tumors express at least one of these five antigens. The aim of integrating these five antigens is to prevent immune escape. The technology uses the human leukocyte antigen (HLA) system, one of the keys for presenting antigens to T-lymphocytes. The vaccine is effective for patients who express the HLA-A2 gene, which is present in around half of the population. The HLA-A2 biomarker, detected via a blood test, can identify appropriate patients.
 

Study protocol

In the Atalante-1 trial, participants had locally advanced (unresectable and not eligible for radiotherapy) or metastatic (without alteration of the EGFR and ALK genes) non–small cell lung cancer that was resistant to previous immunotherapy. They had an HLA-A2 phenotype, as determined by a blood draw to determine whether their immune system could respond to the vaccine.

In this trial, 219 patients were randomly assigned in a 2:1 ratio to receive the vaccine or standard-of-care chemotherapy (80% received docetaxel). The vaccine was administered subcutaneously on day 1 every 3 weeks for six cycles. After that point, the vaccine was administered every 8 weeks until 1 year of treatment and every 12 weeks thereafter. The primary endpoint was overall survival.
 

Secondary resistance

The plan was to enroll 363 patients in the protocol, but the study did not complete its recruitment phase because of the COVID-19 pandemic. As a result, the study was stopped after the enrollment of 219 patients.

“It didn’t have the power we would have liked, but it helped us understand that the people who benefited the most from the vaccine were patients who had responded to immunotherapy in the past. These patients have what is called ‘secondary resistance,’ ” explained Benjamin Besse, MD, PhD, during a press conference organized by OSE Immunotherapeutics. Dr. Besse, the study’s principal investigator, is the director of clinical research at Gustave Roussy, Villejuif, France.

Overall, the results weren’t significant. But the results were positive for patients who had previously responded well to immunotherapy for at least 3 months. Of the 219 patients, 118 (54%) had a positive response.

Among these patients with secondary resistance to immunotherapy, median OS was 11.1 months with Tedopi versus 7.5 months with docetaxel.

For these patients, the risk of death was reduced by 41% with the vaccine, compared with chemotherapy. Overall, 44% of patients lived for another year after receiving Tedopi, versus 27.5% with docetaxel.

“This study is a positive signal for overall survival in the selected population. In this study of 219 patients, we realized that just half of patients really benefited from the vaccine: those who had previously responded to immunotherapy,” said Dr. Besse. “The study needs confirmation from a further, larger phase 3 study in more than 300 patients with secondary resistance to immunotherapy to give us the statistical power we need to convince the regulatory authorities.”
 

Tolerability profile

Fewer serious adverse effects were reported with the vaccine than with chemotherapy (11.4% with Tedopi and 35.1% with docetaxel).

The vaccine also allowed patients to maintain a better quality of life. Scores from the Quality of Life Questionnaire Core 30, which explores several areas of daily life, were better with the vaccine. Change in patients’ overall well-being was delayed in the vaccine group: 3.3 months in the chemotherapy arm versus 9 months in the vaccine arm.

“The vaccine was well tolerated. It has benefits in terms of controlling disease symptoms and causes few side effects. Chemotherapy with docetaxel, meanwhile, is more toxic and may affect a patient’s overall well-being. It causes hair loss in practically 100% of patients, induces neuropathy, makes hands and feet swell, damages the nails, is associated with nausea and vomiting ...” noted Dr. Besse. He went on to say that after the trial, of the patients who stopped receiving the vaccine or chemotherapy (either for toxicity reasons or for disease progression), those who had been given the vaccine responded better to the subsequent chemotherapy “because their overall health was better.”
 

Clinical development

The clinical development of Tedopi is ongoing. Three trials are currently taking place. One study is comparing the Tedopi vaccine plus docetaxel with Tedopi plus nivolumab (immunotherapy not used as a first-line treatment) to determine whether the effects of these treatment combinations might might be enhanced for patients with previously treated lung cancer.

Another study relating to ovarian cancer is in the recruitment phase. The researchers seek to evaluate the vaccine alone or in combination with pembrolizumab for patients with platinum-sensitive ovarian cancer. Results from both trials are expected in 2025.

The third trial seeks to assess FOLFIRI as maintenance therapy or FOLFIRI as maintenance plus Tedopi for patients with pancreatic cancer to improve disease management. Efficacy data are expected next year.

OSE Immunotherapeutics is simultaneously working on a companion biomarker, the HLA-A2 test.

The study was funded by OSE Immunotherapeutics. Dr. Besse disclosed the following conflicts of interest (research funding, institution): AbbVie, Amgen, AstraZeneca, Chugai Pharmaceutical, Daiichi-Sankyo, Ellipse Pharma, EISAI, Genmab, Genzyme Corporation, Hedera Dx, Inivata, IPSEN, Janssen, MSD, Pharmamar, Roche-Genentech, Sanofi, Socar Research, Taiho Oncology, and Turning Point Therapeutics.

This article was translated from the Medscape French Edition and a version appeared on Medscape.com.

Multiple emerging risk factors for cardiovascular disease in women must be recognized and assessed to provide timely diagnosis and treatment, according to Dipti N. Itchhaporia, MD, an interventional cardiologist in southern California. These risk factors include pregnancy complications, autoimmune diseases, depression, breast cancer, and breast arterial calcification.

During the session titled “Cardiac Care in Women: Emerging Risk Factors” at CardioAcademic 2023, the former president of the American College of Cardiology emphasized that gender equity in care for cardiovascular disease will be achieved only when risk factors are evaluated from a gender-dependent perspective and when assessments are broadened to include novel and unrecognized risk factors, not just traditional risk factors.

Dr. Itchhaporia also remarked that women and primary care clinicians must be educated on the symptoms of heart disease so that they can be on the alert and provide patients with comprehensive treatments when necessary.

“Cardiovascular disease remains the leading cause of death in women, at least in the United States, and globally the outlook is similar,” she explained. “That’s why we need to provide our patients with guidance and carefully investigate when they experience chest pain. We need to remember that smoking and obesity pose a higher risk for cardiovascular disease in women than in men. Taking these risk factors into account will really make a difference by allowing us to provide more timely and targeted care.”

In her presentation, Dr. Itchhaporia noted that cardiovascular disease accounts for 35% of deaths in women worldwide. She reminded her audience that, according to The Lancet Women and Cardiovascular Disease Commission, heart diseases in this population remain “understudied, underrecognized, underdiagnosed, and undertreated. Furthermore, women are underrepresented in cardiovascular [clinical practice].”

She mentioned this because, despite U.S. legislation enacted between 1980 and 1990 that mandated the inclusion of women in clinical trials, women accounted for less than 39% of participants in cardiovascular clinical trials between 2010 and 2017. According to Dr. Itchhaporia, this situation limits the potential for developing tailored strategies and recommendations to treat the cardiovascular diseases affecting women.
 

Emerging risk factors

Dr. Itchhaporia pointed out that traditional risk factors have been known for many years. For example, 80% of women aged 75 years or younger have arterial hypertension. Only 29% receive adequate blood pressure control, those living with diabetes have a 45% greater risk of suffering ischemic heart disease, and obesity confers a 64% higher risk of developing ischemic heart disease in women versus 46% in men.

In addition to these factors, she noted that emerging factors must be assessed carefully. For example, women who experience pregnancy complications like gestational diabetes have a higher risk for ischemic heart disease and type 2 diabetes. Women with hypertension and preeclampsia are at a threefold higher risk of developing ischemic heart disease.

“Pregnancy can really be a major stress test for the heart, and I believe that, as health care professionals, we should all be asking women if they have had pregnancy-related complications. I don’t think that’s something we’ve been doing on a regular basis. Statistically, we know that 10%-20% of pregnant women report complications during pregnancy, and strong associations have been shown between gestational hypertension [and] preeclampsia.”

Dr. Itchhaporia explained that depression, a condition that globally affects women twice as much as men, is another emerging factor (though it has received some increased recognition). She explained that, in women, depression is a significant risk factor for developing a major adverse cardiovascular event or a combined event of cardiac death and myocardial infarction related to the target lesion and revascularization of the target lesion because of ischemia. Furthermore, women who have experienced a cardiac-related event are more likely to have depression than men.

“If we look into it in more detail, depression leads to changes in behavioral habits and physiological mechanisms,” she said. “Women living with depression are at higher risk of smoking, not exercising as much, are perhaps less careful with their hygiene, are not likely to adhere to their medications, and don’t sleep as well. All this moves them in the direction of heart disease.”

Added to these factors are autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, where the female-to-male ratio for rheumatoid arthritis is 2½:1 and for lupus it’s 9:1. Dr. Itchhaporia explained that patients with rheumatoid arthritis are at two- to threefold greater risk for myocardial infarction and have a 50% higher risk for stroke. In the case of systemic lupus, the risk of myocardial infarction is 7-50 times greater than in the general population. She noted that cardiovascular risk calculators underestimate the burden of risk in patients with these diseases.

Lastly, she brought up breast cancer and breast arterial calcification as additional emerging risk factors. She explained that women with breast cancer are more likely to develop hypertension and diabetes, compared with women without this diagnosis. Women with hypertension or diabetes before developing breast cancer have twice the risk for heart problems after cancer.

She added that 12.7% of women screened for breast cancer have some degree of breast calcification. She explained that this occurs when calcium accumulates in the middle layer of artery walls in the breast, which is linked to aging, type 2 diabetes, or arterial hypertension and may be a marker of arterial stiffening, which is a cardiovascular disease.

“It’s extremely important to take into consideration data suggesting a strong association between breast calcifications and cardiovascular disease, independent of other known risk factors of cardiovascular disease. We need to improve our tests for detecting cardiovascular disease in women and we need to ask specific questions and not overlook these emerging factors,” she noted.
 

Improving health outcomes

Panelist María Guadalupe Parra Machuca, MD, a cardiologist in Guadalajara, Mexico, specializing in women’s heart disease, agreed that it is high time that clinical practice reflect public health policies, so that efforts to diagnose and treat cardiovascular diseases in women more effectively can transition from theory to reality.

“As physicians, we cannot allow public policy to remain outside of the reality we face,” she stressed. “We need to let it impact the decisions we make. Everything we see day to day, the things we learn at these conferences – let’s put it into practice. Otherwise, all our discussions and all the steps taken to improve care, from primary to highly specialized care and to detect and treat cardiovascular disease in women, will be nothing but rhetoric.”

Clinical cardiology specialist Victor Leal, MD, noted that, according to preliminary results from the national survey of cardiovascular risk factors in Mexican women, Mexico is no exception to these emerging risk factors for cardiovascular disease in women. More than 50% of women in Mexico have traditional risk factors, most notably hypertension, obesity, and diabetes, while hypertensive disorders of pregnancy top the list of other sex-specific risk factors.

“Not only are these factors increasing, but also having them increases the risk of a worse prognosis, leaving us with a very challenging scenario,” said Dr. Leal. “Not only do we need to educate patients about the traditional risk factors, but also about factors that might not be on our radar. We need to get women to link these factors to cardiovascular disease and to the possibility of developing much more adverse outcomes. This will reinforce our diagnosis and treatment.”

In an interview, Dr. Itchhaporia emphasized the changing face of cardiovascular disease for women, who have worse short- and long-term outcomes than men because they are not asked sex-specific questions during initial encounters and they experience greater prehospital delays.

She noted that, while experts need to raise awareness of the emerging risk factors among health care professionals, they also need to use information campaigns to make women aware of what the risks are. Then, if they experience any of the emerging risk factors, they can discuss it with their treating physicians.

“We need to assess both the traditional risk factors and the novel ones, those that are underrecognized. We need to include the history of pregnancy and complications during this period and we need to educate women about symptoms of heart disease like chest pain, difficulty breathing, and increasing fatigue,” she emphasized. “We must also provide guidance as to lifestyle, diet, and levels of physical activity and be aware of stress and symptoms of depression. Only then will we bring greater awareness to the fact that cardiovascular disease is the leading cause of death among women, and then we can reverse these trends.”

Dr. Itchhaporia, Dr. Parra, and Dr. Leal reported no relevant financial relationships.

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

Multiple emerging risk factors for cardiovascular disease in women must be recognized and assessed to provide timely diagnosis and treatment, according to Dipti N. Itchhaporia, MD, an interventional cardiologist in southern California. These risk factors include pregnancy complications, autoimmune diseases, depression, breast cancer, and breast arterial calcification.

During the session titled “Cardiac Care in Women: Emerging Risk Factors” at CardioAcademic 2023, the former president of the American College of Cardiology emphasized that gender equity in care for cardiovascular disease will be achieved only when risk factors are evaluated from a gender-dependent perspective and when assessments are broadened to include novel and unrecognized risk factors, not just traditional risk factors.

Dr. Itchhaporia also remarked that women and primary care clinicians must be educated on the symptoms of heart disease so that they can be on the alert and provide patients with comprehensive treatments when necessary.

“Cardiovascular disease remains the leading cause of death in women, at least in the United States, and globally the outlook is similar,” she explained. “That’s why we need to provide our patients with guidance and carefully investigate when they experience chest pain. We need to remember that smoking and obesity pose a higher risk for cardiovascular disease in women than in men. Taking these risk factors into account will really make a difference by allowing us to provide more timely and targeted care.”

In her presentation, Dr. Itchhaporia noted that cardiovascular disease accounts for 35% of deaths in women worldwide. She reminded her audience that, according to The Lancet Women and Cardiovascular Disease Commission, heart diseases in this population remain “understudied, underrecognized, underdiagnosed, and undertreated. Furthermore, women are underrepresented in cardiovascular [clinical practice].”

She mentioned this because, despite U.S. legislation enacted between 1980 and 1990 that mandated the inclusion of women in clinical trials, women accounted for less than 39% of participants in cardiovascular clinical trials between 2010 and 2017. According to Dr. Itchhaporia, this situation limits the potential for developing tailored strategies and recommendations to treat the cardiovascular diseases affecting women.
 

Emerging risk factors

Dr. Itchhaporia pointed out that traditional risk factors have been known for many years. For example, 80% of women aged 75 years or younger have arterial hypertension. Only 29% receive adequate blood pressure control, those living with diabetes have a 45% greater risk of suffering ischemic heart disease, and obesity confers a 64% higher risk of developing ischemic heart disease in women versus 46% in men.

In addition to these factors, she noted that emerging factors must be assessed carefully. For example, women who experience pregnancy complications like gestational diabetes have a higher risk for ischemic heart disease and type 2 diabetes. Women with hypertension and preeclampsia are at a threefold higher risk of developing ischemic heart disease.

“Pregnancy can really be a major stress test for the heart, and I believe that, as health care professionals, we should all be asking women if they have had pregnancy-related complications. I don’t think that’s something we’ve been doing on a regular basis. Statistically, we know that 10%-20% of pregnant women report complications during pregnancy, and strong associations have been shown between gestational hypertension [and] preeclampsia.”

Dr. Itchhaporia explained that depression, a condition that globally affects women twice as much as men, is another emerging factor (though it has received some increased recognition). She explained that, in women, depression is a significant risk factor for developing a major adverse cardiovascular event or a combined event of cardiac death and myocardial infarction related to the target lesion and revascularization of the target lesion because of ischemia. Furthermore, women who have experienced a cardiac-related event are more likely to have depression than men.

“If we look into it in more detail, depression leads to changes in behavioral habits and physiological mechanisms,” she said. “Women living with depression are at higher risk of smoking, not exercising as much, are perhaps less careful with their hygiene, are not likely to adhere to their medications, and don’t sleep as well. All this moves them in the direction of heart disease.”

Added to these factors are autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, where the female-to-male ratio for rheumatoid arthritis is 2½:1 and for lupus it’s 9:1. Dr. Itchhaporia explained that patients with rheumatoid arthritis are at two- to threefold greater risk for myocardial infarction and have a 50% higher risk for stroke. In the case of systemic lupus, the risk of myocardial infarction is 7-50 times greater than in the general population. She noted that cardiovascular risk calculators underestimate the burden of risk in patients with these diseases.

Lastly, she brought up breast cancer and breast arterial calcification as additional emerging risk factors. She explained that women with breast cancer are more likely to develop hypertension and diabetes, compared with women without this diagnosis. Women with hypertension or diabetes before developing breast cancer have twice the risk for heart problems after cancer.

She added that 12.7% of women screened for breast cancer have some degree of breast calcification. She explained that this occurs when calcium accumulates in the middle layer of artery walls in the breast, which is linked to aging, type 2 diabetes, or arterial hypertension and may be a marker of arterial stiffening, which is a cardiovascular disease.

“It’s extremely important to take into consideration data suggesting a strong association between breast calcifications and cardiovascular disease, independent of other known risk factors of cardiovascular disease. We need to improve our tests for detecting cardiovascular disease in women and we need to ask specific questions and not overlook these emerging factors,” she noted.
 

Improving health outcomes

Panelist María Guadalupe Parra Machuca, MD, a cardiologist in Guadalajara, Mexico, specializing in women’s heart disease, agreed that it is high time that clinical practice reflect public health policies, so that efforts to diagnose and treat cardiovascular diseases in women more effectively can transition from theory to reality.

“As physicians, we cannot allow public policy to remain outside of the reality we face,” she stressed. “We need to let it impact the decisions we make. Everything we see day to day, the things we learn at these conferences – let’s put it into practice. Otherwise, all our discussions and all the steps taken to improve care, from primary to highly specialized care and to detect and treat cardiovascular disease in women, will be nothing but rhetoric.”

Clinical cardiology specialist Victor Leal, MD, noted that, according to preliminary results from the national survey of cardiovascular risk factors in Mexican women, Mexico is no exception to these emerging risk factors for cardiovascular disease in women. More than 50% of women in Mexico have traditional risk factors, most notably hypertension, obesity, and diabetes, while hypertensive disorders of pregnancy top the list of other sex-specific risk factors.

“Not only are these factors increasing, but also having them increases the risk of a worse prognosis, leaving us with a very challenging scenario,” said Dr. Leal. “Not only do we need to educate patients about the traditional risk factors, but also about factors that might not be on our radar. We need to get women to link these factors to cardiovascular disease and to the possibility of developing much more adverse outcomes. This will reinforce our diagnosis and treatment.”

In an interview, Dr. Itchhaporia emphasized the changing face of cardiovascular disease for women, who have worse short- and long-term outcomes than men because they are not asked sex-specific questions during initial encounters and they experience greater prehospital delays.

She noted that, while experts need to raise awareness of the emerging risk factors among health care professionals, they also need to use information campaigns to make women aware of what the risks are. Then, if they experience any of the emerging risk factors, they can discuss it with their treating physicians.

“We need to assess both the traditional risk factors and the novel ones, those that are underrecognized. We need to include the history of pregnancy and complications during this period and we need to educate women about symptoms of heart disease like chest pain, difficulty breathing, and increasing fatigue,” she emphasized. “We must also provide guidance as to lifestyle, diet, and levels of physical activity and be aware of stress and symptoms of depression. Only then will we bring greater awareness to the fact that cardiovascular disease is the leading cause of death among women, and then we can reverse these trends.”

Dr. Itchhaporia, Dr. Parra, and Dr. Leal reported no relevant financial relationships.

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

Multiple emerging risk factors for cardiovascular disease in women must be recognized and assessed to provide timely diagnosis and treatment, according to Dipti N. Itchhaporia, MD, an interventional cardiologist in southern California. These risk factors include pregnancy complications, autoimmune diseases, depression, breast cancer, and breast arterial calcification.

During the session titled “Cardiac Care in Women: Emerging Risk Factors” at CardioAcademic 2023, the former president of the American College of Cardiology emphasized that gender equity in care for cardiovascular disease will be achieved only when risk factors are evaluated from a gender-dependent perspective and when assessments are broadened to include novel and unrecognized risk factors, not just traditional risk factors.

Dr. Itchhaporia also remarked that women and primary care clinicians must be educated on the symptoms of heart disease so that they can be on the alert and provide patients with comprehensive treatments when necessary.

“Cardiovascular disease remains the leading cause of death in women, at least in the United States, and globally the outlook is similar,” she explained. “That’s why we need to provide our patients with guidance and carefully investigate when they experience chest pain. We need to remember that smoking and obesity pose a higher risk for cardiovascular disease in women than in men. Taking these risk factors into account will really make a difference by allowing us to provide more timely and targeted care.”

In her presentation, Dr. Itchhaporia noted that cardiovascular disease accounts for 35% of deaths in women worldwide. She reminded her audience that, according to The Lancet Women and Cardiovascular Disease Commission, heart diseases in this population remain “understudied, underrecognized, underdiagnosed, and undertreated. Furthermore, women are underrepresented in cardiovascular [clinical practice].”

She mentioned this because, despite U.S. legislation enacted between 1980 and 1990 that mandated the inclusion of women in clinical trials, women accounted for less than 39% of participants in cardiovascular clinical trials between 2010 and 2017. According to Dr. Itchhaporia, this situation limits the potential for developing tailored strategies and recommendations to treat the cardiovascular diseases affecting women.
 

Emerging risk factors

Dr. Itchhaporia pointed out that traditional risk factors have been known for many years. For example, 80% of women aged 75 years or younger have arterial hypertension. Only 29% receive adequate blood pressure control, those living with diabetes have a 45% greater risk of suffering ischemic heart disease, and obesity confers a 64% higher risk of developing ischemic heart disease in women versus 46% in men.

In addition to these factors, she noted that emerging factors must be assessed carefully. For example, women who experience pregnancy complications like gestational diabetes have a higher risk for ischemic heart disease and type 2 diabetes. Women with hypertension and preeclampsia are at a threefold higher risk of developing ischemic heart disease.

“Pregnancy can really be a major stress test for the heart, and I believe that, as health care professionals, we should all be asking women if they have had pregnancy-related complications. I don’t think that’s something we’ve been doing on a regular basis. Statistically, we know that 10%-20% of pregnant women report complications during pregnancy, and strong associations have been shown between gestational hypertension [and] preeclampsia.”

Dr. Itchhaporia explained that depression, a condition that globally affects women twice as much as men, is another emerging factor (though it has received some increased recognition). She explained that, in women, depression is a significant risk factor for developing a major adverse cardiovascular event or a combined event of cardiac death and myocardial infarction related to the target lesion and revascularization of the target lesion because of ischemia. Furthermore, women who have experienced a cardiac-related event are more likely to have depression than men.

“If we look into it in more detail, depression leads to changes in behavioral habits and physiological mechanisms,” she said. “Women living with depression are at higher risk of smoking, not exercising as much, are perhaps less careful with their hygiene, are not likely to adhere to their medications, and don’t sleep as well. All this moves them in the direction of heart disease.”

Added to these factors are autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, where the female-to-male ratio for rheumatoid arthritis is 2½:1 and for lupus it’s 9:1. Dr. Itchhaporia explained that patients with rheumatoid arthritis are at two- to threefold greater risk for myocardial infarction and have a 50% higher risk for stroke. In the case of systemic lupus, the risk of myocardial infarction is 7-50 times greater than in the general population. She noted that cardiovascular risk calculators underestimate the burden of risk in patients with these diseases.

Lastly, she brought up breast cancer and breast arterial calcification as additional emerging risk factors. She explained that women with breast cancer are more likely to develop hypertension and diabetes, compared with women without this diagnosis. Women with hypertension or diabetes before developing breast cancer have twice the risk for heart problems after cancer.

She added that 12.7% of women screened for breast cancer have some degree of breast calcification. She explained that this occurs when calcium accumulates in the middle layer of artery walls in the breast, which is linked to aging, type 2 diabetes, or arterial hypertension and may be a marker of arterial stiffening, which is a cardiovascular disease.

“It’s extremely important to take into consideration data suggesting a strong association between breast calcifications and cardiovascular disease, independent of other known risk factors of cardiovascular disease. We need to improve our tests for detecting cardiovascular disease in women and we need to ask specific questions and not overlook these emerging factors,” she noted.
 

Improving health outcomes

Panelist María Guadalupe Parra Machuca, MD, a cardiologist in Guadalajara, Mexico, specializing in women’s heart disease, agreed that it is high time that clinical practice reflect public health policies, so that efforts to diagnose and treat cardiovascular diseases in women more effectively can transition from theory to reality.

“As physicians, we cannot allow public policy to remain outside of the reality we face,” she stressed. “We need to let it impact the decisions we make. Everything we see day to day, the things we learn at these conferences – let’s put it into practice. Otherwise, all our discussions and all the steps taken to improve care, from primary to highly specialized care and to detect and treat cardiovascular disease in women, will be nothing but rhetoric.”

Clinical cardiology specialist Victor Leal, MD, noted that, according to preliminary results from the national survey of cardiovascular risk factors in Mexican women, Mexico is no exception to these emerging risk factors for cardiovascular disease in women. More than 50% of women in Mexico have traditional risk factors, most notably hypertension, obesity, and diabetes, while hypertensive disorders of pregnancy top the list of other sex-specific risk factors.

“Not only are these factors increasing, but also having them increases the risk of a worse prognosis, leaving us with a very challenging scenario,” said Dr. Leal. “Not only do we need to educate patients about the traditional risk factors, but also about factors that might not be on our radar. We need to get women to link these factors to cardiovascular disease and to the possibility of developing much more adverse outcomes. This will reinforce our diagnosis and treatment.”

In an interview, Dr. Itchhaporia emphasized the changing face of cardiovascular disease for women, who have worse short- and long-term outcomes than men because they are not asked sex-specific questions during initial encounters and they experience greater prehospital delays.

She noted that, while experts need to raise awareness of the emerging risk factors among health care professionals, they also need to use information campaigns to make women aware of what the risks are. Then, if they experience any of the emerging risk factors, they can discuss it with their treating physicians.

“We need to assess both the traditional risk factors and the novel ones, those that are underrecognized. We need to include the history of pregnancy and complications during this period and we need to educate women about symptoms of heart disease like chest pain, difficulty breathing, and increasing fatigue,” she emphasized. “We must also provide guidance as to lifestyle, diet, and levels of physical activity and be aware of stress and symptoms of depression. Only then will we bring greater awareness to the fact that cardiovascular disease is the leading cause of death among women, and then we can reverse these trends.”

Dr. Itchhaporia, Dr. Parra, and Dr. Leal reported no relevant financial relationships.

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

TOPLINE:

Patients with type 1 diabetes who received transplanted islets along with a kidney transplant had significantly reduced mortality and transplant failure risks, compared with those who received kidney alone and continued to use insulin.

METHODOLOGY:

• Study population was all patients with type 1 diabetes in France who received a kidney transplant between 2000 and 2017.
• Among 2,393 patients, 327 were eligible for islet transplantation, including 47 who were actually transplanted with islets.
• The subjects were matched for factors including year of transplantation, recipient age, kidney function, and hemoglobin A1c.

TAKEAWAY:

• Those receiving islets along with the kidney transplant had a 53% lower risk of graft failure, compared with the kidney-alone group.
• Those receiving islet transplantation had a significantly higher estimated life expectancy during 10-year follow-up (9.61 vs. 8.85 years).
• At 1 year post islet transplant, there was an estimated 89.4% probability of graft survival and a 70.2% probability of achieving independence from insulin.

IN PRACTICE:

“Although islet transplantation has previously been shown to improve glycemic control, compared with conventional insulin therapy in recent clinical trials, little was known about its long-term impact on patient prognosis until now. ... These results are exciting and provide hope for people living with type 1 diabetes and kidney transplants.”

SOURCE:

Presented Sept. 17, 2023, at the European Society for Organ Transplantation (ESOT) Congress 2023 by Mehdi Maanaoui, MD, a nephrologist at the University of Lille (France).

LIMITATIONS:

Observational, potential for residual confounding.

DISCLOSURES:

Dr. Maanaoui reports no relevant financial relationships.

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

TOPLINE:

Patients with type 1 diabetes who received transplanted islets along with a kidney transplant had significantly reduced mortality and transplant failure risks, compared with those who received kidney alone and continued to use insulin.

METHODOLOGY:

• Study population was all patients with type 1 diabetes in France who received a kidney transplant between 2000 and 2017.
• Among 2,393 patients, 327 were eligible for islet transplantation, including 47 who were actually transplanted with islets.
• The subjects were matched for factors including year of transplantation, recipient age, kidney function, and hemoglobin A1c.

TAKEAWAY:

• Those receiving islets along with the kidney transplant had a 53% lower risk of graft failure, compared with the kidney-alone group.
• Those receiving islet transplantation had a significantly higher estimated life expectancy during 10-year follow-up (9.61 vs. 8.85 years).
• At 1 year post islet transplant, there was an estimated 89.4% probability of graft survival and a 70.2% probability of achieving independence from insulin.

IN PRACTICE:

“Although islet transplantation has previously been shown to improve glycemic control, compared with conventional insulin therapy in recent clinical trials, little was known about its long-term impact on patient prognosis until now. ... These results are exciting and provide hope for people living with type 1 diabetes and kidney transplants.”

SOURCE:

Presented Sept. 17, 2023, at the European Society for Organ Transplantation (ESOT) Congress 2023 by Mehdi Maanaoui, MD, a nephrologist at the University of Lille (France).

LIMITATIONS:

Observational, potential for residual confounding.

DISCLOSURES:

Dr. Maanaoui reports no relevant financial relationships.

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

TOPLINE:

Patients with type 1 diabetes who received transplanted islets along with a kidney transplant had significantly reduced mortality and transplant failure risks, compared with those who received kidney alone and continued to use insulin.

METHODOLOGY:

• Study population was all patients with type 1 diabetes in France who received a kidney transplant between 2000 and 2017.
• Among 2,393 patients, 327 were eligible for islet transplantation, including 47 who were actually transplanted with islets.
• The subjects were matched for factors including year of transplantation, recipient age, kidney function, and hemoglobin A1c.

TAKEAWAY:

• Those receiving islets along with the kidney transplant had a 53% lower risk of graft failure, compared with the kidney-alone group.
• Those receiving islet transplantation had a significantly higher estimated life expectancy during 10-year follow-up (9.61 vs. 8.85 years).
• At 1 year post islet transplant, there was an estimated 89.4% probability of graft survival and a 70.2% probability of achieving independence from insulin.

IN PRACTICE:

“Although islet transplantation has previously been shown to improve glycemic control, compared with conventional insulin therapy in recent clinical trials, little was known about its long-term impact on patient prognosis until now. ... These results are exciting and provide hope for people living with type 1 diabetes and kidney transplants.”

SOURCE:

Presented Sept. 17, 2023, at the European Society for Organ Transplantation (ESOT) Congress 2023 by Mehdi Maanaoui, MD, a nephrologist at the University of Lille (France).

LIMITATIONS:

Observational, potential for residual confounding.

DISCLOSURES:

Dr. Maanaoui reports no relevant financial relationships.

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

Investigational muvalaplin (Eli Lilly), the first oral therapy being developed to lower lipoprotein (a) levels, was shown to reduce levels in a phase 1 trial, with no safety concerns, researchers report.

In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.

Researchers presented these findings in two late breaking science sessions at the recent annual congress of the European Society of Cardiology. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.
 

Phase 1 trial of muvalaplin

Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues wrote.

In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) – both injectable therapies.

Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Dr. Nicholls, from Monash University and Victoria Heart Institute, both in Melbourne.

In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100-800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he said in an interview.

Approximately 20% of the population have high LP(a) levels, Dr. Nicholls noted.

“We saw in the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials.

The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m² or less, into two groups.

The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were White. Their median Lp(a) level was 10.3 mg/dL.

The 59 participants in the multiple ascending dose group, who were required to have Lp(a) of at least 30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were White. Their median Lp(a) level was 58.4 mg/dL.

The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of at least 100 mg.

The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300- to 800-mg doses. 

There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.  

Muvalaplin had no significant effects on LDL cholesterol, HDL cholesterol, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.

The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥ 175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.
 

OCEAN (a)-DOSE extended study of olpasiran

In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).

courtesy Brigham and Women's Hospital

Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).

Dr. O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the 2022 annual scientific sessions of the American Heart Association, and the trial was simultaneously published online in the New England Journal of Medicine.

The trial included 281 patients with established atherosclerotic CVD and Lp(a) greater than 150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.

At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).

The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 (OxPL-apoB) and on levels of Lp(a), as well as safety, after the last administered dose.

The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).

The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, Dr. O’Donoghue reported.

Patients on doses of at least 75 mg every 12 weeks “sustained around a 40%-50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”

The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.

These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session cochairperson Louise Bowman, MD, University of Oxford (England).

In reply to questions from the audience, Dr. O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection-site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.

The muvalaplin study was funded by Eli Lilly. Dr. Nicholls reported numerous conflicts of interest with various pharmaceutical companies. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Merck, and Novartis; consulting with Amgen and Novartis; and serving as a data and safety monitor for AstraZeneca and Janssen.

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

Investigational muvalaplin (Eli Lilly), the first oral therapy being developed to lower lipoprotein (a) levels, was shown to reduce levels in a phase 1 trial, with no safety concerns, researchers report.

In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.

Researchers presented these findings in two late breaking science sessions at the recent annual congress of the European Society of Cardiology. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.
 

Phase 1 trial of muvalaplin

Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues wrote.

In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) – both injectable therapies.

Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Dr. Nicholls, from Monash University and Victoria Heart Institute, both in Melbourne.

In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100-800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he said in an interview.

Approximately 20% of the population have high LP(a) levels, Dr. Nicholls noted.

“We saw in the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials.

The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m² or less, into two groups.

The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were White. Their median Lp(a) level was 10.3 mg/dL.

The 59 participants in the multiple ascending dose group, who were required to have Lp(a) of at least 30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were White. Their median Lp(a) level was 58.4 mg/dL.

The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of at least 100 mg.

The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300- to 800-mg doses. 

There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.  

Muvalaplin had no significant effects on LDL cholesterol, HDL cholesterol, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.

The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥ 175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.
 

OCEAN (a)-DOSE extended study of olpasiran

In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).

courtesy Brigham and Women's Hospital

Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).

Dr. O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the 2022 annual scientific sessions of the American Heart Association, and the trial was simultaneously published online in the New England Journal of Medicine.

The trial included 281 patients with established atherosclerotic CVD and Lp(a) greater than 150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.

At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).

The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 (OxPL-apoB) and on levels of Lp(a), as well as safety, after the last administered dose.

The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).

The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, Dr. O’Donoghue reported.

Patients on doses of at least 75 mg every 12 weeks “sustained around a 40%-50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”

The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.

These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session cochairperson Louise Bowman, MD, University of Oxford (England).

In reply to questions from the audience, Dr. O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection-site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.

The muvalaplin study was funded by Eli Lilly. Dr. Nicholls reported numerous conflicts of interest with various pharmaceutical companies. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Merck, and Novartis; consulting with Amgen and Novartis; and serving as a data and safety monitor for AstraZeneca and Janssen.

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

Investigational muvalaplin (Eli Lilly), the first oral therapy being developed to lower lipoprotein (a) levels, was shown to reduce levels in a phase 1 trial, with no safety concerns, researchers report.

In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.

Researchers presented these findings in two late breaking science sessions at the recent annual congress of the European Society of Cardiology. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.
 

Phase 1 trial of muvalaplin

Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues wrote.

In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) – both injectable therapies.

Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Dr. Nicholls, from Monash University and Victoria Heart Institute, both in Melbourne.

In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100-800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he said in an interview.

Approximately 20% of the population have high LP(a) levels, Dr. Nicholls noted.

“We saw in the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials.

The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m² or less, into two groups.

The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were White. Their median Lp(a) level was 10.3 mg/dL.

The 59 participants in the multiple ascending dose group, who were required to have Lp(a) of at least 30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were White. Their median Lp(a) level was 58.4 mg/dL.

The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of at least 100 mg.

The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300- to 800-mg doses. 

There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.  

Muvalaplin had no significant effects on LDL cholesterol, HDL cholesterol, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.

The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥ 175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.
 

OCEAN (a)-DOSE extended study of olpasiran

In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).

courtesy Brigham and Women's Hospital

Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).

Dr. O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the 2022 annual scientific sessions of the American Heart Association, and the trial was simultaneously published online in the New England Journal of Medicine.

The trial included 281 patients with established atherosclerotic CVD and Lp(a) greater than 150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.

At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).

The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 (OxPL-apoB) and on levels of Lp(a), as well as safety, after the last administered dose.

The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).

The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, Dr. O’Donoghue reported.

Patients on doses of at least 75 mg every 12 weeks “sustained around a 40%-50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”

The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.

These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session cochairperson Louise Bowman, MD, University of Oxford (England).

In reply to questions from the audience, Dr. O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection-site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.

The muvalaplin study was funded by Eli Lilly. Dr. Nicholls reported numerous conflicts of interest with various pharmaceutical companies. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Merck, and Novartis; consulting with Amgen and Novartis; and serving as a data and safety monitor for AstraZeneca and Janssen.

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

SAN DIEGO – In the clinical experience of Mathew M. Avram, MD, JD, fractional lasers work best in combination with other devices and wavelengths when treating signs of photoaging, such as dyspigmentation, wrinkles, and actinic damage.

“Using a fractional laser as a solo treatment is missing an opportunity to achieve more dramatic improvement for your patients,” Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital, Boston, said at the annual Masters of Aesthetics Symposium. Among the laser treatments he performs, “combination fractional treatments, typically using the 1927-nm laser” are associated with the highest patient satisfaction, he said.

The order of device use matters, he noted. First, he recommended, use a pulsed dye laser, KTP, or intense pulsed light (IPL) for erythema and telangiectasias, and/or a Q-switched or picosecond laser for pigment. Second, use an ablative or nonablative fractional laser for resurfacing. “A lot of seborrheic keratoses don’t respond to selective photothermolysis well, so I’ll use liquid nitrogen at the time of treatment and before or after treat with a picosecond laser,” added Dr. Avram. “This combined treatment approach is less painful than ablative fractional treatment. You’re going to have downtime anyway, so why not maximize the results at that one treatment session?”

The fractional 1927 laser delivers hundreds of thousands of microscopic pulses and fosters high water absorption, so it targets superficial skin conditions such as actinic keratoses, lentigines, and ephelides at depths of 200-250 microns. It thermally coagulates 30%-40% of skin, which heals without affecting surrounding skin and leaves no perceptible scar, he said.

Clinicians can also combine devices to treat scars. “For red scars, it’s often best to treat both erythema and scar texture with two lasers at the same session,” Dr. Avram said. Again, the order matters. First, he recommended using the pulse dye laser, IPL, or KTP at low fluence and short pulse duration. Second, treat with an ablative or nonablative fractional laser at a low density. “In my experience the ablative fractional lasers are far more efficacious,” he said. “Then we typically add a little Kenalog and 5-FU via laser-assisted drug delivery.”

Dr. Avram disclosed that he has received consulting fees from Allergan. He also reported holding shareholder interest and intellectual property rights with Cytrellis Biosystems.

SAN DIEGO – In the clinical experience of Mathew M. Avram, MD, JD, fractional lasers work best in combination with other devices and wavelengths when treating signs of photoaging, such as dyspigmentation, wrinkles, and actinic damage.

“Using a fractional laser as a solo treatment is missing an opportunity to achieve more dramatic improvement for your patients,” Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital, Boston, said at the annual Masters of Aesthetics Symposium. Among the laser treatments he performs, “combination fractional treatments, typically using the 1927-nm laser” are associated with the highest patient satisfaction, he said.

The order of device use matters, he noted. First, he recommended, use a pulsed dye laser, KTP, or intense pulsed light (IPL) for erythema and telangiectasias, and/or a Q-switched or picosecond laser for pigment. Second, use an ablative or nonablative fractional laser for resurfacing. “A lot of seborrheic keratoses don’t respond to selective photothermolysis well, so I’ll use liquid nitrogen at the time of treatment and before or after treat with a picosecond laser,” added Dr. Avram. “This combined treatment approach is less painful than ablative fractional treatment. You’re going to have downtime anyway, so why not maximize the results at that one treatment session?”

The fractional 1927 laser delivers hundreds of thousands of microscopic pulses and fosters high water absorption, so it targets superficial skin conditions such as actinic keratoses, lentigines, and ephelides at depths of 200-250 microns. It thermally coagulates 30%-40% of skin, which heals without affecting surrounding skin and leaves no perceptible scar, he said.

Clinicians can also combine devices to treat scars. “For red scars, it’s often best to treat both erythema and scar texture with two lasers at the same session,” Dr. Avram said. Again, the order matters. First, he recommended using the pulse dye laser, IPL, or KTP at low fluence and short pulse duration. Second, treat with an ablative or nonablative fractional laser at a low density. “In my experience the ablative fractional lasers are far more efficacious,” he said. “Then we typically add a little Kenalog and 5-FU via laser-assisted drug delivery.”

Dr. Avram disclosed that he has received consulting fees from Allergan. He also reported holding shareholder interest and intellectual property rights with Cytrellis Biosystems.

SAN DIEGO – In the clinical experience of Mathew M. Avram, MD, JD, fractional lasers work best in combination with other devices and wavelengths when treating signs of photoaging, such as dyspigmentation, wrinkles, and actinic damage.

“Using a fractional laser as a solo treatment is missing an opportunity to achieve more dramatic improvement for your patients,” Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital, Boston, said at the annual Masters of Aesthetics Symposium. Among the laser treatments he performs, “combination fractional treatments, typically using the 1927-nm laser” are associated with the highest patient satisfaction, he said.

The order of device use matters, he noted. First, he recommended, use a pulsed dye laser, KTP, or intense pulsed light (IPL) for erythema and telangiectasias, and/or a Q-switched or picosecond laser for pigment. Second, use an ablative or nonablative fractional laser for resurfacing. “A lot of seborrheic keratoses don’t respond to selective photothermolysis well, so I’ll use liquid nitrogen at the time of treatment and before or after treat with a picosecond laser,” added Dr. Avram. “This combined treatment approach is less painful than ablative fractional treatment. You’re going to have downtime anyway, so why not maximize the results at that one treatment session?”

The fractional 1927 laser delivers hundreds of thousands of microscopic pulses and fosters high water absorption, so it targets superficial skin conditions such as actinic keratoses, lentigines, and ephelides at depths of 200-250 microns. It thermally coagulates 30%-40% of skin, which heals without affecting surrounding skin and leaves no perceptible scar, he said.

Clinicians can also combine devices to treat scars. “For red scars, it’s often best to treat both erythema and scar texture with two lasers at the same session,” Dr. Avram said. Again, the order matters. First, he recommended using the pulse dye laser, IPL, or KTP at low fluence and short pulse duration. Second, treat with an ablative or nonablative fractional laser at a low density. “In my experience the ablative fractional lasers are far more efficacious,” he said. “Then we typically add a little Kenalog and 5-FU via laser-assisted drug delivery.”

Dr. Avram disclosed that he has received consulting fees from Allergan. He also reported holding shareholder interest and intellectual property rights with Cytrellis Biosystems.

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

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

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

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

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

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

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

SAN DIEGO – Injecting a scar with intralesional steroids is a popular way to reduce its size and soften the surrounding tissue, but proper technique matters, according to Victor Ross, MD.

“A lot of lip service is paid to how to inject the steroid,” Dr. Ross, director of laser and cosmetic dermatology at the Scripps Clinic in San Diego, said at the annual Masters of Aesthetics Symposium. “The most important part is the amount and the fastidiousness that you have injecting. You should see the tip of the needle and be very slow. Use a 1 cc syringe.” He used to inject scars with triamcinolone acetate 40 mg/mL, but now he almost always injects 10-20 mg/mL to avoid inducing white streak-like atrophy or hypopigmentation around the treated area.

“When you treat a scar, you treat the features of the scar that make it stand out,” Dr. Ross continued. “If it’s red, you address the hyperemia. If it’s brown, you address the pigment. You want to have a reasonable pathophysiological basis for what you’re doing. Understand how the scar got there and have a reasonable algorithm.” When he counsels patients about clinical outcomes to expect, he emphasizes rehabilitation instead of blemish-free perfection. “It’s not making the scar go away,” he said. “It’s not restoring completely normal skin form and function; it’s a restorative effort to get toward normality. That’s what it’s all about.”

Besides injecting scars with triamcinolone acetate, other scar treatment options include intralesional 5-fluorouracil, oral antihistamines, COX-2 inhibitors, hydrogel sheeting, compression, acoustic wave therapy, photodynamic therapy, radiofrequency, and lasers. “I’m not a big fan of low-level light; it probably does something [to scars], but I’m skeptical,” Dr. Ross said.

In his clinical opinion, most scars respond best to treatments with ablative and nonablative fractional lasers tuned to gentle settings such as an energy level of 20 millijoules at a density of 5%-10%. “Every scar deserves a chance for laser remediation and rehabilitation,” he said. “With radiation scars you want to be particularly gentle. If you have a Mohs scar that has been subsequently treated with radiation, I would lower my settings by half, because I’ve had some scars worsen with settings for red scars after radiation therapy.”

He often uses fractional lasers for stubborn acne scarring. “The hyperemic component you can treat with a vascular laser, then come back [and treat the scarring] with a nonablative fractional laser, or you could use radiofrequency microneedling as well,” Dr. Ross said.

New or innovative scar treatments coming down the pike, he said, include the following: mitomycin C (applied topically, he said that this has worked well for postoperative keloids), tamoxifen, oral methotrexate, imiquimod (which has mixed results to date), platelet-rich plasma, and retinoids.

Dr. Ross disclosed having research and financial ties to numerous pharmaceutical and device companies.

SAN DIEGO – Injecting a scar with intralesional steroids is a popular way to reduce its size and soften the surrounding tissue, but proper technique matters, according to Victor Ross, MD.

“A lot of lip service is paid to how to inject the steroid,” Dr. Ross, director of laser and cosmetic dermatology at the Scripps Clinic in San Diego, said at the annual Masters of Aesthetics Symposium. “The most important part is the amount and the fastidiousness that you have injecting. You should see the tip of the needle and be very slow. Use a 1 cc syringe.” He used to inject scars with triamcinolone acetate 40 mg/mL, but now he almost always injects 10-20 mg/mL to avoid inducing white streak-like atrophy or hypopigmentation around the treated area.

“When you treat a scar, you treat the features of the scar that make it stand out,” Dr. Ross continued. “If it’s red, you address the hyperemia. If it’s brown, you address the pigment. You want to have a reasonable pathophysiological basis for what you’re doing. Understand how the scar got there and have a reasonable algorithm.” When he counsels patients about clinical outcomes to expect, he emphasizes rehabilitation instead of blemish-free perfection. “It’s not making the scar go away,” he said. “It’s not restoring completely normal skin form and function; it’s a restorative effort to get toward normality. That’s what it’s all about.”

Besides injecting scars with triamcinolone acetate, other scar treatment options include intralesional 5-fluorouracil, oral antihistamines, COX-2 inhibitors, hydrogel sheeting, compression, acoustic wave therapy, photodynamic therapy, radiofrequency, and lasers. “I’m not a big fan of low-level light; it probably does something [to scars], but I’m skeptical,” Dr. Ross said.

In his clinical opinion, most scars respond best to treatments with ablative and nonablative fractional lasers tuned to gentle settings such as an energy level of 20 millijoules at a density of 5%-10%. “Every scar deserves a chance for laser remediation and rehabilitation,” he said. “With radiation scars you want to be particularly gentle. If you have a Mohs scar that has been subsequently treated with radiation, I would lower my settings by half, because I’ve had some scars worsen with settings for red scars after radiation therapy.”

He often uses fractional lasers for stubborn acne scarring. “The hyperemic component you can treat with a vascular laser, then come back [and treat the scarring] with a nonablative fractional laser, or you could use radiofrequency microneedling as well,” Dr. Ross said.

New or innovative scar treatments coming down the pike, he said, include the following: mitomycin C (applied topically, he said that this has worked well for postoperative keloids), tamoxifen, oral methotrexate, imiquimod (which has mixed results to date), platelet-rich plasma, and retinoids.

Dr. Ross disclosed having research and financial ties to numerous pharmaceutical and device companies.

SAN DIEGO – Injecting a scar with intralesional steroids is a popular way to reduce its size and soften the surrounding tissue, but proper technique matters, according to Victor Ross, MD.

“A lot of lip service is paid to how to inject the steroid,” Dr. Ross, director of laser and cosmetic dermatology at the Scripps Clinic in San Diego, said at the annual Masters of Aesthetics Symposium. “The most important part is the amount and the fastidiousness that you have injecting. You should see the tip of the needle and be very slow. Use a 1 cc syringe.” He used to inject scars with triamcinolone acetate 40 mg/mL, but now he almost always injects 10-20 mg/mL to avoid inducing white streak-like atrophy or hypopigmentation around the treated area.

“When you treat a scar, you treat the features of the scar that make it stand out,” Dr. Ross continued. “If it’s red, you address the hyperemia. If it’s brown, you address the pigment. You want to have a reasonable pathophysiological basis for what you’re doing. Understand how the scar got there and have a reasonable algorithm.” When he counsels patients about clinical outcomes to expect, he emphasizes rehabilitation instead of blemish-free perfection. “It’s not making the scar go away,” he said. “It’s not restoring completely normal skin form and function; it’s a restorative effort to get toward normality. That’s what it’s all about.”

Besides injecting scars with triamcinolone acetate, other scar treatment options include intralesional 5-fluorouracil, oral antihistamines, COX-2 inhibitors, hydrogel sheeting, compression, acoustic wave therapy, photodynamic therapy, radiofrequency, and lasers. “I’m not a big fan of low-level light; it probably does something [to scars], but I’m skeptical,” Dr. Ross said.

In his clinical opinion, most scars respond best to treatments with ablative and nonablative fractional lasers tuned to gentle settings such as an energy level of 20 millijoules at a density of 5%-10%. “Every scar deserves a chance for laser remediation and rehabilitation,” he said. “With radiation scars you want to be particularly gentle. If you have a Mohs scar that has been subsequently treated with radiation, I would lower my settings by half, because I’ve had some scars worsen with settings for red scars after radiation therapy.”

He often uses fractional lasers for stubborn acne scarring. “The hyperemic component you can treat with a vascular laser, then come back [and treat the scarring] with a nonablative fractional laser, or you could use radiofrequency microneedling as well,” Dr. Ross said.

New or innovative scar treatments coming down the pike, he said, include the following: mitomycin C (applied topically, he said that this has worked well for postoperative keloids), tamoxifen, oral methotrexate, imiquimod (which has mixed results to date), platelet-rich plasma, and retinoids.

Dr. Ross disclosed having research and financial ties to numerous pharmaceutical and device companies.