Pharmacology

Preliminary data suggest that a certain pattern of gut microbes may be useful in predicting which patients with advanced gastric cancer are likely to benefit from treatment with the immunotherapy nivolumab.

Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.

“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.

Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.

The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.

Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.

“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”

In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.

The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.

Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.

Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.

The phylogenetic composition of common bacterial taxa was similar for both cohorts.

In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.

The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.

An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.

Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.
 

Still some gaps

In a discussion of the study, Jonathan Yeung, MD, PhD, of Princess Margaret Cancer Center, Toronto, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to obtain these data.”

However, Dr. Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.

“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”

Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs. 417 patients). This could have affected the statistical power of the study.

But overall, Dr. Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.

The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Dr. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, and Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo, Lilly Japan, Sanofi, Taiho Pharmaceutical, and Takeda. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

Preliminary data suggest that a certain pattern of gut microbes may be useful in predicting which patients with advanced gastric cancer are likely to benefit from treatment with the immunotherapy nivolumab.

Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.

“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.

Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.

The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.

Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.

“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”

In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.

The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.

Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.

Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.

The phylogenetic composition of common bacterial taxa was similar for both cohorts.

In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.

The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.

An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.

Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.
 

Still some gaps

In a discussion of the study, Jonathan Yeung, MD, PhD, of Princess Margaret Cancer Center, Toronto, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to obtain these data.”

However, Dr. Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.

“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”

Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs. 417 patients). This could have affected the statistical power of the study.

But overall, Dr. Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.

The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Dr. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, and Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo, Lilly Japan, Sanofi, Taiho Pharmaceutical, and Takeda. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

Preliminary data suggest that a certain pattern of gut microbes may be useful in predicting which patients with advanced gastric cancer are likely to benefit from treatment with the immunotherapy nivolumab.

Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.

“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.

Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.

The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.

Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.

“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”

In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.

The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.

Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.

Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.

The phylogenetic composition of common bacterial taxa was similar for both cohorts.

In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.

The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.

An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.

Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.
 

Still some gaps

In a discussion of the study, Jonathan Yeung, MD, PhD, of Princess Margaret Cancer Center, Toronto, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to obtain these data.”

However, Dr. Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.

“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”

Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs. 417 patients). This could have affected the statistical power of the study.

But overall, Dr. Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.

The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Dr. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, and Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo, Lilly Japan, Sanofi, Taiho Pharmaceutical, and Takeda. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

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

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

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

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

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

New findings suggest that monoclonal antibodies used to treat RA could improve severe COVID-19 outcomes, including risk for death.

Given within 24 hours of critical illness, tocilizumab (Actemra) was associated with a median of 10 days free of respiratory and cardiovascular support up to day 21, the primary outcome. Similarly, sarilumab (Kevzara) was linked to a median of 11 days. In contrast, the usual care control group experienced zero such days in the hospital.

However, the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial comes with a caveat. The preprint findings have not yet been peer reviewed and “should not be used to guide clinical practice,” the authors stated.

The results were published online Jan. 7 in MedRxiv.

Nevertheless, the trial also revealed a mortality benefit associated with the two interleukin-6 antagonists. The hospital mortality rate was 22% with sarilumab, 28% with tocilizumab, and almost 36% with usual care.

“That’s a big change in survival. They are both lifesaving drugs,” lead coinvestigator Anthony Gordon, an Imperial College London professor of anesthesia and critical care, commented in a recent  story by Reuters.
 

Consider the big picture

“What I think is important is ... this is one of many trials,” Paul Auwaerter, MD, MBA, said in an interview. Many other studies looking at monoclonal antibody therapy for people with COVID-19 were halted because they did not show improvement.

One exception is the EMPACTA trial, which suggested that tocilizumab was effective if given before a person becomes ill enough to be placed on a ventilator, said Dr. Auwaerter, clinical director of the division of infectious diseases at Johns Hopkins Medicine and a contributor to this news organization. “It appeared to reduce the need for mechanical ventilation or death.”

“These two trials are the first randomized, prospective trials that show a benefit on a background of others which have not,” Dr. Auwaerter added.
 

Interim findings

The REMAP-CAP investigators randomly assigned adults within 24 hours of critical care for COVID-19 to 8 mg/kg tocilizumab, 400 mg sarilumab, or usual care at 113 sites in six countries. There were 353 participants in the tocilizumab arm, 48 in the sarilumab group, and 402 in the control group.

Compared with the control group, the 10 days free of organ support in the tocilizumab cohort was associated with an adjusted odds ratio of 1.64 (95% confidence interval, 1.25-2.14). The 11 days free of organ support in the sarilumab cohort was likewise superior to control (adjusted odds ratio, 1.76; 95% CI, 1.17-2.91).

“All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists,” the authors note. These endpoints included 90-day survival, time to intensive care unit discharge, and hospital discharge.
 

Cautious optimism?

“The results were quite impressive – having 10 or 11 fewer days in the ICU, compared to standard of care,” Deepa Gotur, MD, said in an interview. “Choosing the right patient population and providing the anti-IL-6 treatment at the right time would be the key here.”

In addition to not yet receiving peer review, an open-label design, a relatively short follow-up of 21 days, and steroids becoming standard of care about halfway through the trial are potential limitations, said Dr. Gotur, an intensivist at Houston Methodist Hospital and associate professor of clinical medicine at Weill Cornell Medicine, New York.

“This is an interesting study,” Carl J. Fichtenbaum, MD, professor of clinical medicine at the University of Cincinnati, said in a comment.

Additional detail on how many participants in each group received steroids is warranted, Dr. Fichtenbaum said. “The analysis did not carefully adjust for the use of steroids that might have influenced outcomes.”

Dr. Fichtenbaum said it’s important to look at what is distinctive about REMAP-CAP because “there are several other studies showing opposite results.”

Dr. Gotur was an investigator on a previous study evaluating tocilizumab for patients already on mechanical ventilation. “One of the key differences between this and other studies is that they included more of the ICU population,” she said. “They also included patients within 24 hours of requiring organ support, cardiac, as well as respiratory support.” Some other research included less-acute patients, including all comers into the ED who required oxygen and received tocilizumab.

The prior studies also evaluated cytokine or inflammatory markers. In contrast, REMAP-CAP researchers “looked at organ failure itself ... which I think makes sense,” Dr. Gotur said.

Cytokine release syndrome can cause organ damage or organ failure, she added, “but these markers are all over the place. I’ve seen patients who are very, very sick despite having a low [C-reactive protein] or IL-6 level.”
 

Backing from the British

Citing the combined 24% decrease in the risk for death associated with these agents in the REMAP-CAP trial, the U.K. government announced Jan. 7 it will work to make tocilizumab and sarilumab available to citizens with severe COVID-19.

Experts in the United Kingdom shared their perspectives on the REMAP-CAP interim findings through the U.K. Science Media Centre.

“There are few treatments for severe COVID-19,” said Robin Ferner, MD, honorary professor of clinical pharmacology at the University of Birmingham (England) and honorary consultant physician at City Hospital Birmingham. “If the published data from REMAP-CAP are supported by further studies, this suggests that two IL-6 receptor antagonists can reduce the death rate in the most severely ill patients.”

Dr. Ferner added that the findings are not a “magic cure,” however. He pointed out that of 401 patients given the drugs, 109 died, and with standard treatment, 144 out of 402 died.

Peter Horby, MD, PhD, was more optimistic. “It is great to see a positive result at a time that we really need good news and more tools to fight COVID. This is great achievement for REMAP-CAP,” he said.

“We hope to soon have results from RECOVERY on the effect of tocilizumab in less severely ill patients in the hospital,” said Dr. Horby, cochief investigator of the RECOVERY trial and professor of emerging infectious diseases at the Centre for Tropical Medicine and Global Health at the University of Oxford (England).

Stephen Evans, BA, MSc, FRCP, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, said, “This is a high-quality trial, and although published as a preprint, is of much higher quality than many non–peer-reviewed papers.”

Dr. Evans also noted the addition of steroid therapy for many participants. “Partway through the trial, the RECOVERY trial findings showed that the corticosteroid drug dexamethasone had notable mortality benefits. Consequently, quite a number of the patients in this trial had also received a corticosteroid.”

“It does look as though these drugs give some additional benefit beyond that given by dexamethasone,” he added.

Awaiting peer review

“We need to wait for the final results and ensure it was adequately powered with enough observations to make us confident in the results,” Dr. Fichtenbaum said.

“We in the United States have to step back and look at the entire set of studies and also, for this particular one, REMAP-CAP, to be in a peer-reviewed publication,” Dr. Auwaerter said. Preprints are often released “in the setting of the pandemic, where there may be important findings, especially if they impact mortality or severity of illness.”

“We need to make sure these findings, as outlined, hold up,” he said.

In the meantime, Dr. Auwaerter added, “Exactly how this will fit in is unclear. But it’s important to me as another potential drug that can help our critically ill patients.”

The REMAP-CAP study is ongoing and updated results will be provided online.

Dr. Auwaerter disclosed that he is a consultant for EMD Serono and a member of the data monitoring safety board for Humanigen. Dr. Gotur, Dr. Fichtenbaum, Dr. Ferner, and Dr. Evans disclosed no relevant financial relationships. Dr. Horby reported that Oxford University receives funding for the RECOVERY trial from U.K. Research and Innovation and the National Institute for Health Research. Roche Products and Sanofi supported REMAP-CAP through provision of tocilizumab and sarilumab in the United Kingdom.

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

New findings suggest that monoclonal antibodies used to treat RA could improve severe COVID-19 outcomes, including risk for death.

Given within 24 hours of critical illness, tocilizumab (Actemra) was associated with a median of 10 days free of respiratory and cardiovascular support up to day 21, the primary outcome. Similarly, sarilumab (Kevzara) was linked to a median of 11 days. In contrast, the usual care control group experienced zero such days in the hospital.

However, the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial comes with a caveat. The preprint findings have not yet been peer reviewed and “should not be used to guide clinical practice,” the authors stated.

The results were published online Jan. 7 in MedRxiv.

Nevertheless, the trial also revealed a mortality benefit associated with the two interleukin-6 antagonists. The hospital mortality rate was 22% with sarilumab, 28% with tocilizumab, and almost 36% with usual care.

“That’s a big change in survival. They are both lifesaving drugs,” lead coinvestigator Anthony Gordon, an Imperial College London professor of anesthesia and critical care, commented in a recent  story by Reuters.
 

Consider the big picture

“What I think is important is ... this is one of many trials,” Paul Auwaerter, MD, MBA, said in an interview. Many other studies looking at monoclonal antibody therapy for people with COVID-19 were halted because they did not show improvement.

One exception is the EMPACTA trial, which suggested that tocilizumab was effective if given before a person becomes ill enough to be placed on a ventilator, said Dr. Auwaerter, clinical director of the division of infectious diseases at Johns Hopkins Medicine and a contributor to this news organization. “It appeared to reduce the need for mechanical ventilation or death.”

“These two trials are the first randomized, prospective trials that show a benefit on a background of others which have not,” Dr. Auwaerter added.
 

Interim findings

The REMAP-CAP investigators randomly assigned adults within 24 hours of critical care for COVID-19 to 8 mg/kg tocilizumab, 400 mg sarilumab, or usual care at 113 sites in six countries. There were 353 participants in the tocilizumab arm, 48 in the sarilumab group, and 402 in the control group.

Compared with the control group, the 10 days free of organ support in the tocilizumab cohort was associated with an adjusted odds ratio of 1.64 (95% confidence interval, 1.25-2.14). The 11 days free of organ support in the sarilumab cohort was likewise superior to control (adjusted odds ratio, 1.76; 95% CI, 1.17-2.91).

“All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists,” the authors note. These endpoints included 90-day survival, time to intensive care unit discharge, and hospital discharge.
 

Cautious optimism?

“The results were quite impressive – having 10 or 11 fewer days in the ICU, compared to standard of care,” Deepa Gotur, MD, said in an interview. “Choosing the right patient population and providing the anti-IL-6 treatment at the right time would be the key here.”

In addition to not yet receiving peer review, an open-label design, a relatively short follow-up of 21 days, and steroids becoming standard of care about halfway through the trial are potential limitations, said Dr. Gotur, an intensivist at Houston Methodist Hospital and associate professor of clinical medicine at Weill Cornell Medicine, New York.

“This is an interesting study,” Carl J. Fichtenbaum, MD, professor of clinical medicine at the University of Cincinnati, said in a comment.

Additional detail on how many participants in each group received steroids is warranted, Dr. Fichtenbaum said. “The analysis did not carefully adjust for the use of steroids that might have influenced outcomes.”

Dr. Fichtenbaum said it’s important to look at what is distinctive about REMAP-CAP because “there are several other studies showing opposite results.”

Dr. Gotur was an investigator on a previous study evaluating tocilizumab for patients already on mechanical ventilation. “One of the key differences between this and other studies is that they included more of the ICU population,” she said. “They also included patients within 24 hours of requiring organ support, cardiac, as well as respiratory support.” Some other research included less-acute patients, including all comers into the ED who required oxygen and received tocilizumab.

The prior studies also evaluated cytokine or inflammatory markers. In contrast, REMAP-CAP researchers “looked at organ failure itself ... which I think makes sense,” Dr. Gotur said.

Cytokine release syndrome can cause organ damage or organ failure, she added, “but these markers are all over the place. I’ve seen patients who are very, very sick despite having a low [C-reactive protein] or IL-6 level.”
 

Backing from the British

Citing the combined 24% decrease in the risk for death associated with these agents in the REMAP-CAP trial, the U.K. government announced Jan. 7 it will work to make tocilizumab and sarilumab available to citizens with severe COVID-19.

Experts in the United Kingdom shared their perspectives on the REMAP-CAP interim findings through the U.K. Science Media Centre.

“There are few treatments for severe COVID-19,” said Robin Ferner, MD, honorary professor of clinical pharmacology at the University of Birmingham (England) and honorary consultant physician at City Hospital Birmingham. “If the published data from REMAP-CAP are supported by further studies, this suggests that two IL-6 receptor antagonists can reduce the death rate in the most severely ill patients.”

Dr. Ferner added that the findings are not a “magic cure,” however. He pointed out that of 401 patients given the drugs, 109 died, and with standard treatment, 144 out of 402 died.

Peter Horby, MD, PhD, was more optimistic. “It is great to see a positive result at a time that we really need good news and more tools to fight COVID. This is great achievement for REMAP-CAP,” he said.

“We hope to soon have results from RECOVERY on the effect of tocilizumab in less severely ill patients in the hospital,” said Dr. Horby, cochief investigator of the RECOVERY trial and professor of emerging infectious diseases at the Centre for Tropical Medicine and Global Health at the University of Oxford (England).

Stephen Evans, BA, MSc, FRCP, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, said, “This is a high-quality trial, and although published as a preprint, is of much higher quality than many non–peer-reviewed papers.”

Dr. Evans also noted the addition of steroid therapy for many participants. “Partway through the trial, the RECOVERY trial findings showed that the corticosteroid drug dexamethasone had notable mortality benefits. Consequently, quite a number of the patients in this trial had also received a corticosteroid.”

“It does look as though these drugs give some additional benefit beyond that given by dexamethasone,” he added.

Awaiting peer review

“We need to wait for the final results and ensure it was adequately powered with enough observations to make us confident in the results,” Dr. Fichtenbaum said.

“We in the United States have to step back and look at the entire set of studies and also, for this particular one, REMAP-CAP, to be in a peer-reviewed publication,” Dr. Auwaerter said. Preprints are often released “in the setting of the pandemic, where there may be important findings, especially if they impact mortality or severity of illness.”

“We need to make sure these findings, as outlined, hold up,” he said.

In the meantime, Dr. Auwaerter added, “Exactly how this will fit in is unclear. But it’s important to me as another potential drug that can help our critically ill patients.”

The REMAP-CAP study is ongoing and updated results will be provided online.

Dr. Auwaerter disclosed that he is a consultant for EMD Serono and a member of the data monitoring safety board for Humanigen. Dr. Gotur, Dr. Fichtenbaum, Dr. Ferner, and Dr. Evans disclosed no relevant financial relationships. Dr. Horby reported that Oxford University receives funding for the RECOVERY trial from U.K. Research and Innovation and the National Institute for Health Research. Roche Products and Sanofi supported REMAP-CAP through provision of tocilizumab and sarilumab in the United Kingdom.

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

New findings suggest that monoclonal antibodies used to treat RA could improve severe COVID-19 outcomes, including risk for death.

Given within 24 hours of critical illness, tocilizumab (Actemra) was associated with a median of 10 days free of respiratory and cardiovascular support up to day 21, the primary outcome. Similarly, sarilumab (Kevzara) was linked to a median of 11 days. In contrast, the usual care control group experienced zero such days in the hospital.

However, the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial comes with a caveat. The preprint findings have not yet been peer reviewed and “should not be used to guide clinical practice,” the authors stated.

The results were published online Jan. 7 in MedRxiv.

Nevertheless, the trial also revealed a mortality benefit associated with the two interleukin-6 antagonists. The hospital mortality rate was 22% with sarilumab, 28% with tocilizumab, and almost 36% with usual care.

“That’s a big change in survival. They are both lifesaving drugs,” lead coinvestigator Anthony Gordon, an Imperial College London professor of anesthesia and critical care, commented in a recent  story by Reuters.
 

Consider the big picture

“What I think is important is ... this is one of many trials,” Paul Auwaerter, MD, MBA, said in an interview. Many other studies looking at monoclonal antibody therapy for people with COVID-19 were halted because they did not show improvement.

One exception is the EMPACTA trial, which suggested that tocilizumab was effective if given before a person becomes ill enough to be placed on a ventilator, said Dr. Auwaerter, clinical director of the division of infectious diseases at Johns Hopkins Medicine and a contributor to this news organization. “It appeared to reduce the need for mechanical ventilation or death.”

“These two trials are the first randomized, prospective trials that show a benefit on a background of others which have not,” Dr. Auwaerter added.
 

Interim findings

The REMAP-CAP investigators randomly assigned adults within 24 hours of critical care for COVID-19 to 8 mg/kg tocilizumab, 400 mg sarilumab, or usual care at 113 sites in six countries. There were 353 participants in the tocilizumab arm, 48 in the sarilumab group, and 402 in the control group.

Compared with the control group, the 10 days free of organ support in the tocilizumab cohort was associated with an adjusted odds ratio of 1.64 (95% confidence interval, 1.25-2.14). The 11 days free of organ support in the sarilumab cohort was likewise superior to control (adjusted odds ratio, 1.76; 95% CI, 1.17-2.91).

“All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists,” the authors note. These endpoints included 90-day survival, time to intensive care unit discharge, and hospital discharge.
 

Cautious optimism?

“The results were quite impressive – having 10 or 11 fewer days in the ICU, compared to standard of care,” Deepa Gotur, MD, said in an interview. “Choosing the right patient population and providing the anti-IL-6 treatment at the right time would be the key here.”

In addition to not yet receiving peer review, an open-label design, a relatively short follow-up of 21 days, and steroids becoming standard of care about halfway through the trial are potential limitations, said Dr. Gotur, an intensivist at Houston Methodist Hospital and associate professor of clinical medicine at Weill Cornell Medicine, New York.

“This is an interesting study,” Carl J. Fichtenbaum, MD, professor of clinical medicine at the University of Cincinnati, said in a comment.

Additional detail on how many participants in each group received steroids is warranted, Dr. Fichtenbaum said. “The analysis did not carefully adjust for the use of steroids that might have influenced outcomes.”

Dr. Fichtenbaum said it’s important to look at what is distinctive about REMAP-CAP because “there are several other studies showing opposite results.”

Dr. Gotur was an investigator on a previous study evaluating tocilizumab for patients already on mechanical ventilation. “One of the key differences between this and other studies is that they included more of the ICU population,” she said. “They also included patients within 24 hours of requiring organ support, cardiac, as well as respiratory support.” Some other research included less-acute patients, including all comers into the ED who required oxygen and received tocilizumab.

The prior studies also evaluated cytokine or inflammatory markers. In contrast, REMAP-CAP researchers “looked at organ failure itself ... which I think makes sense,” Dr. Gotur said.

Cytokine release syndrome can cause organ damage or organ failure, she added, “but these markers are all over the place. I’ve seen patients who are very, very sick despite having a low [C-reactive protein] or IL-6 level.”
 

Backing from the British

Citing the combined 24% decrease in the risk for death associated with these agents in the REMAP-CAP trial, the U.K. government announced Jan. 7 it will work to make tocilizumab and sarilumab available to citizens with severe COVID-19.

Experts in the United Kingdom shared their perspectives on the REMAP-CAP interim findings through the U.K. Science Media Centre.

“There are few treatments for severe COVID-19,” said Robin Ferner, MD, honorary professor of clinical pharmacology at the University of Birmingham (England) and honorary consultant physician at City Hospital Birmingham. “If the published data from REMAP-CAP are supported by further studies, this suggests that two IL-6 receptor antagonists can reduce the death rate in the most severely ill patients.”

Dr. Ferner added that the findings are not a “magic cure,” however. He pointed out that of 401 patients given the drugs, 109 died, and with standard treatment, 144 out of 402 died.

Peter Horby, MD, PhD, was more optimistic. “It is great to see a positive result at a time that we really need good news and more tools to fight COVID. This is great achievement for REMAP-CAP,” he said.

“We hope to soon have results from RECOVERY on the effect of tocilizumab in less severely ill patients in the hospital,” said Dr. Horby, cochief investigator of the RECOVERY trial and professor of emerging infectious diseases at the Centre for Tropical Medicine and Global Health at the University of Oxford (England).

Stephen Evans, BA, MSc, FRCP, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, said, “This is a high-quality trial, and although published as a preprint, is of much higher quality than many non–peer-reviewed papers.”

Dr. Evans also noted the addition of steroid therapy for many participants. “Partway through the trial, the RECOVERY trial findings showed that the corticosteroid drug dexamethasone had notable mortality benefits. Consequently, quite a number of the patients in this trial had also received a corticosteroid.”

“It does look as though these drugs give some additional benefit beyond that given by dexamethasone,” he added.

Awaiting peer review

“We need to wait for the final results and ensure it was adequately powered with enough observations to make us confident in the results,” Dr. Fichtenbaum said.

“We in the United States have to step back and look at the entire set of studies and also, for this particular one, REMAP-CAP, to be in a peer-reviewed publication,” Dr. Auwaerter said. Preprints are often released “in the setting of the pandemic, where there may be important findings, especially if they impact mortality or severity of illness.”

“We need to make sure these findings, as outlined, hold up,” he said.

In the meantime, Dr. Auwaerter added, “Exactly how this will fit in is unclear. But it’s important to me as another potential drug that can help our critically ill patients.”

The REMAP-CAP study is ongoing and updated results will be provided online.

Dr. Auwaerter disclosed that he is a consultant for EMD Serono and a member of the data monitoring safety board for Humanigen. Dr. Gotur, Dr. Fichtenbaum, Dr. Ferner, and Dr. Evans disclosed no relevant financial relationships. Dr. Horby reported that Oxford University receives funding for the RECOVERY trial from U.K. Research and Innovation and the National Institute for Health Research. Roche Products and Sanofi supported REMAP-CAP through provision of tocilizumab and sarilumab in the United Kingdom.

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

A single injection of denosumab (Prolia, Amgen), frequently used to treat osteoporosis, may reduce the need for revision surgery in patients with symptomatic osteolysis following total hip arthroplasty, a new proof-of-concept study suggests.

Aseptic loosening is the result of wear-induced osteolysis caused by the prosthetic hip and is a major contributor to the need for revision surgery in many parts of the world.

“The only established treatment for prosthesis-related osteolysis after joint replacement is revision surgery, which carries substantially greater morbidity and mortality than primary joint replacement,” Mohit M. Mahatma, MRes, of the University of Sheffield, England, and colleagues wrote in their article, published online Jan. 11 in The Lancet Rheumatology.

As well as an increased risk of infection and other complications, revision surgery is much more costly than a first-time operation, they added.

“The results of this proof-of-concept clinical trial indicate that denosumab is effective at reducing bone resorption activity within osteolytic lesion tissue and is well tolerated within the limitations of the single dose used here,” they concluded.

Commenting on the findings, Antonia Chen, MD, associate professor of orthopedic surgery, Harvard Medical School, Boston, emphasized that further studies are needed to assess the effectiveness of this strategy to reduce the need for hip revision surgery.

Nevertheless, “osteolysis is still unfortunately a problem we do have to deal with and we do not have any other way to prevent it,” she said in an interview. “So it’s a good start ... although further studies are definitely needed,” Dr. Chen added.

In an accompanying editorial, Hannu Aro, MD, Turku University Hospital in Finland, agreed: “Without a doubt, the trial is a breakthrough, but it represents only the first step in the development of pharmacological therapy aiming to slow, prevent, or even reverse the process of wear-induced periprosthetic osteolysis.”
 

Small single-center study

The phase 2, single-center, randomized, controlled trial involved 22 patients who had previously undergone hip replacement surgery at Sheffield Teaching Hospitals and were scheduled for revision surgery due to symptomatic osteolysis. They were randomized to a single subcutaneous injection of denosumab at a dose of 60 mg, or placebo, on their second hospital visit.

“The primary outcome was the between-group difference in the number of osteoclasts per mm of osteolytic membrane at the osteolytic membrane-bone interface at week 8,” the authors noted.

At this time point, there were 83% fewer osteoclasts at the interface in the denosumab group compared with placebo, at a median of 0.05 per mm in the treatment group compared with 0.30 per mm in the placebo group (P = .011). 

Secondary histological outcomes were also significantly improved in favor of the denosumab group compared with placebo.
 

Potential to prevent half of all hip revision surgeries?

Patients who received denosumab also demonstrated an acute fall in serum and urinary markers of bone resorption following administration of the drug, reaching a nadir at week 4, which was maintained until revision surgery at week 8.

In contrast, “no change in these markers was observed in the placebo group [P < .0003 for all biomarkers],” the investigators noted. Rates of adverse events were comparable in both treatment groups.

As the authors explained, osteolysis occurs following joint replacement surgery when particles of plastic wear off from the prosthesis, triggering an immune reaction that attacks the bone around the implant, causing the joint to loosen.

“It is very clear from our bone biopsies and bone imaging that the [denosumab] injection stops the bone absorbing the microplastic particles from the replacement joint and therefore could prevent the bone from being eaten away and the need for revision surgery,” senior author Mark Wilkinson, MBChB, PhD, honorary consultant orthopedic surgeon, Sheffield Teaching Hospitals, said in a press release from his institution.

“This study is a significant breakthrough as we’ve demonstrated that there is a drug, already available and successful in the treatment of osteoporosis, that has the potential to prevent up to half of all revised replacement surgeries which are caused by osteolysis,” he added.

Dr. Wilkinson and coauthors said their results justify the need for future trials targeting earlier-stage disease to further test the use of denosumab to prevent or reduce the need for revision surgery.

In 2018, aseptic loosening accounted for over half of all revision procedures, as reported to the National Joint Registry in England and Wales.
 

Older polyethylene prostheses are the main culprit

Commenting further on the study, Dr. Chen noted that osteolysis still plagues orthopedic surgeons because the original polyethylene prostheses were not very good. A better prosthesis developed at Massachusetts General Hospital is made up of highly crossed-link polyethylene and still wears over time but to a much lesser extent than the older polyethylene prostheses.

Metal and ceramic prostheses also can induce osteolysis, but again to a much lesser extent than the older polyethylene implants.

“Any particle can technically cause osteolysis but plastic produces the most particles,” Dr. Chen explained. Although hip revision rates in the United States are low to begin with, aseptic loosening is still one of the main reasons that patients need to undergo revision surgery, she observed.

“A lot of patients are still living with the old plastic [implants] so there is still a need for something like this,” she stressed.

However, many questions about this potential new strategy remain to be answered, including when best to initiate treatment and how to manage patients at risk for osteolysis 20-30 years after they have received their original implant.

In his editorial, Dr. Aro said that serious adverse consequences often become evident 10-20 years after patients have undergone the original hip replacement procedures, when they are potentially less physically fit than they were at the time of the operation and thus less able to withstand the rigors of a difficult revision surgery.

“In this context, the concept of nonsurgical pharmacological treatment of periprosthetic osteolysis ... brings a new hope for the ever-increasing population of patients with total hip arthroplasty to avoid revision surgery,” Dr. Aro suggested.

However, Dr. Aro cautioned that reduction of bone turnover by antiresorptive agents such as denosumab has been associated with the development of atypical femoral fractures.

The study was funded by Amgen. Dr. Wilkinson has reported receiving a grant from Amgen. Dr. Chen has reported serving as a consultant for Striker and b-One Ortho. Dr. Aro has reported receiving a grant to his institution from Amgen Finland and the Academy of Finland. He has also served as a member of an advisory scientific board for Amgen Finland.

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

A single injection of denosumab (Prolia, Amgen), frequently used to treat osteoporosis, may reduce the need for revision surgery in patients with symptomatic osteolysis following total hip arthroplasty, a new proof-of-concept study suggests.

Aseptic loosening is the result of wear-induced osteolysis caused by the prosthetic hip and is a major contributor to the need for revision surgery in many parts of the world.

“The only established treatment for prosthesis-related osteolysis after joint replacement is revision surgery, which carries substantially greater morbidity and mortality than primary joint replacement,” Mohit M. Mahatma, MRes, of the University of Sheffield, England, and colleagues wrote in their article, published online Jan. 11 in The Lancet Rheumatology.

As well as an increased risk of infection and other complications, revision surgery is much more costly than a first-time operation, they added.

“The results of this proof-of-concept clinical trial indicate that denosumab is effective at reducing bone resorption activity within osteolytic lesion tissue and is well tolerated within the limitations of the single dose used here,” they concluded.

Commenting on the findings, Antonia Chen, MD, associate professor of orthopedic surgery, Harvard Medical School, Boston, emphasized that further studies are needed to assess the effectiveness of this strategy to reduce the need for hip revision surgery.

Nevertheless, “osteolysis is still unfortunately a problem we do have to deal with and we do not have any other way to prevent it,” she said in an interview. “So it’s a good start ... although further studies are definitely needed,” Dr. Chen added.

In an accompanying editorial, Hannu Aro, MD, Turku University Hospital in Finland, agreed: “Without a doubt, the trial is a breakthrough, but it represents only the first step in the development of pharmacological therapy aiming to slow, prevent, or even reverse the process of wear-induced periprosthetic osteolysis.”
 

Small single-center study

The phase 2, single-center, randomized, controlled trial involved 22 patients who had previously undergone hip replacement surgery at Sheffield Teaching Hospitals and were scheduled for revision surgery due to symptomatic osteolysis. They were randomized to a single subcutaneous injection of denosumab at a dose of 60 mg, or placebo, on their second hospital visit.

“The primary outcome was the between-group difference in the number of osteoclasts per mm of osteolytic membrane at the osteolytic membrane-bone interface at week 8,” the authors noted.

At this time point, there were 83% fewer osteoclasts at the interface in the denosumab group compared with placebo, at a median of 0.05 per mm in the treatment group compared with 0.30 per mm in the placebo group (P = .011). 

Secondary histological outcomes were also significantly improved in favor of the denosumab group compared with placebo.
 

Potential to prevent half of all hip revision surgeries?

Patients who received denosumab also demonstrated an acute fall in serum and urinary markers of bone resorption following administration of the drug, reaching a nadir at week 4, which was maintained until revision surgery at week 8.

In contrast, “no change in these markers was observed in the placebo group [P < .0003 for all biomarkers],” the investigators noted. Rates of adverse events were comparable in both treatment groups.

As the authors explained, osteolysis occurs following joint replacement surgery when particles of plastic wear off from the prosthesis, triggering an immune reaction that attacks the bone around the implant, causing the joint to loosen.

“It is very clear from our bone biopsies and bone imaging that the [denosumab] injection stops the bone absorbing the microplastic particles from the replacement joint and therefore could prevent the bone from being eaten away and the need for revision surgery,” senior author Mark Wilkinson, MBChB, PhD, honorary consultant orthopedic surgeon, Sheffield Teaching Hospitals, said in a press release from his institution.

“This study is a significant breakthrough as we’ve demonstrated that there is a drug, already available and successful in the treatment of osteoporosis, that has the potential to prevent up to half of all revised replacement surgeries which are caused by osteolysis,” he added.

Dr. Wilkinson and coauthors said their results justify the need for future trials targeting earlier-stage disease to further test the use of denosumab to prevent or reduce the need for revision surgery.

In 2018, aseptic loosening accounted for over half of all revision procedures, as reported to the National Joint Registry in England and Wales.
 

Older polyethylene prostheses are the main culprit

Commenting further on the study, Dr. Chen noted that osteolysis still plagues orthopedic surgeons because the original polyethylene prostheses were not very good. A better prosthesis developed at Massachusetts General Hospital is made up of highly crossed-link polyethylene and still wears over time but to a much lesser extent than the older polyethylene prostheses.

Metal and ceramic prostheses also can induce osteolysis, but again to a much lesser extent than the older polyethylene implants.

“Any particle can technically cause osteolysis but plastic produces the most particles,” Dr. Chen explained. Although hip revision rates in the United States are low to begin with, aseptic loosening is still one of the main reasons that patients need to undergo revision surgery, she observed.

“A lot of patients are still living with the old plastic [implants] so there is still a need for something like this,” she stressed.

However, many questions about this potential new strategy remain to be answered, including when best to initiate treatment and how to manage patients at risk for osteolysis 20-30 years after they have received their original implant.

In his editorial, Dr. Aro said that serious adverse consequences often become evident 10-20 years after patients have undergone the original hip replacement procedures, when they are potentially less physically fit than they were at the time of the operation and thus less able to withstand the rigors of a difficult revision surgery.

“In this context, the concept of nonsurgical pharmacological treatment of periprosthetic osteolysis ... brings a new hope for the ever-increasing population of patients with total hip arthroplasty to avoid revision surgery,” Dr. Aro suggested.

However, Dr. Aro cautioned that reduction of bone turnover by antiresorptive agents such as denosumab has been associated with the development of atypical femoral fractures.

The study was funded by Amgen. Dr. Wilkinson has reported receiving a grant from Amgen. Dr. Chen has reported serving as a consultant for Striker and b-One Ortho. Dr. Aro has reported receiving a grant to his institution from Amgen Finland and the Academy of Finland. He has also served as a member of an advisory scientific board for Amgen Finland.

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

A single injection of denosumab (Prolia, Amgen), frequently used to treat osteoporosis, may reduce the need for revision surgery in patients with symptomatic osteolysis following total hip arthroplasty, a new proof-of-concept study suggests.

Aseptic loosening is the result of wear-induced osteolysis caused by the prosthetic hip and is a major contributor to the need for revision surgery in many parts of the world.

“The only established treatment for prosthesis-related osteolysis after joint replacement is revision surgery, which carries substantially greater morbidity and mortality than primary joint replacement,” Mohit M. Mahatma, MRes, of the University of Sheffield, England, and colleagues wrote in their article, published online Jan. 11 in The Lancet Rheumatology.

As well as an increased risk of infection and other complications, revision surgery is much more costly than a first-time operation, they added.

“The results of this proof-of-concept clinical trial indicate that denosumab is effective at reducing bone resorption activity within osteolytic lesion tissue and is well tolerated within the limitations of the single dose used here,” they concluded.

Commenting on the findings, Antonia Chen, MD, associate professor of orthopedic surgery, Harvard Medical School, Boston, emphasized that further studies are needed to assess the effectiveness of this strategy to reduce the need for hip revision surgery.

Nevertheless, “osteolysis is still unfortunately a problem we do have to deal with and we do not have any other way to prevent it,” she said in an interview. “So it’s a good start ... although further studies are definitely needed,” Dr. Chen added.

In an accompanying editorial, Hannu Aro, MD, Turku University Hospital in Finland, agreed: “Without a doubt, the trial is a breakthrough, but it represents only the first step in the development of pharmacological therapy aiming to slow, prevent, or even reverse the process of wear-induced periprosthetic osteolysis.”
 

Small single-center study

The phase 2, single-center, randomized, controlled trial involved 22 patients who had previously undergone hip replacement surgery at Sheffield Teaching Hospitals and were scheduled for revision surgery due to symptomatic osteolysis. They were randomized to a single subcutaneous injection of denosumab at a dose of 60 mg, or placebo, on their second hospital visit.

“The primary outcome was the between-group difference in the number of osteoclasts per mm of osteolytic membrane at the osteolytic membrane-bone interface at week 8,” the authors noted.

At this time point, there were 83% fewer osteoclasts at the interface in the denosumab group compared with placebo, at a median of 0.05 per mm in the treatment group compared with 0.30 per mm in the placebo group (P = .011). 

Secondary histological outcomes were also significantly improved in favor of the denosumab group compared with placebo.
 

Potential to prevent half of all hip revision surgeries?

Patients who received denosumab also demonstrated an acute fall in serum and urinary markers of bone resorption following administration of the drug, reaching a nadir at week 4, which was maintained until revision surgery at week 8.

In contrast, “no change in these markers was observed in the placebo group [P < .0003 for all biomarkers],” the investigators noted. Rates of adverse events were comparable in both treatment groups.

As the authors explained, osteolysis occurs following joint replacement surgery when particles of plastic wear off from the prosthesis, triggering an immune reaction that attacks the bone around the implant, causing the joint to loosen.

“It is very clear from our bone biopsies and bone imaging that the [denosumab] injection stops the bone absorbing the microplastic particles from the replacement joint and therefore could prevent the bone from being eaten away and the need for revision surgery,” senior author Mark Wilkinson, MBChB, PhD, honorary consultant orthopedic surgeon, Sheffield Teaching Hospitals, said in a press release from his institution.

“This study is a significant breakthrough as we’ve demonstrated that there is a drug, already available and successful in the treatment of osteoporosis, that has the potential to prevent up to half of all revised replacement surgeries which are caused by osteolysis,” he added.

Dr. Wilkinson and coauthors said their results justify the need for future trials targeting earlier-stage disease to further test the use of denosumab to prevent or reduce the need for revision surgery.

In 2018, aseptic loosening accounted for over half of all revision procedures, as reported to the National Joint Registry in England and Wales.
 

Older polyethylene prostheses are the main culprit

Commenting further on the study, Dr. Chen noted that osteolysis still plagues orthopedic surgeons because the original polyethylene prostheses were not very good. A better prosthesis developed at Massachusetts General Hospital is made up of highly crossed-link polyethylene and still wears over time but to a much lesser extent than the older polyethylene prostheses.

Metal and ceramic prostheses also can induce osteolysis, but again to a much lesser extent than the older polyethylene implants.

“Any particle can technically cause osteolysis but plastic produces the most particles,” Dr. Chen explained. Although hip revision rates in the United States are low to begin with, aseptic loosening is still one of the main reasons that patients need to undergo revision surgery, she observed.

“A lot of patients are still living with the old plastic [implants] so there is still a need for something like this,” she stressed.

However, many questions about this potential new strategy remain to be answered, including when best to initiate treatment and how to manage patients at risk for osteolysis 20-30 years after they have received their original implant.

In his editorial, Dr. Aro said that serious adverse consequences often become evident 10-20 years after patients have undergone the original hip replacement procedures, when they are potentially less physically fit than they were at the time of the operation and thus less able to withstand the rigors of a difficult revision surgery.

“In this context, the concept of nonsurgical pharmacological treatment of periprosthetic osteolysis ... brings a new hope for the ever-increasing population of patients with total hip arthroplasty to avoid revision surgery,” Dr. Aro suggested.

However, Dr. Aro cautioned that reduction of bone turnover by antiresorptive agents such as denosumab has been associated with the development of atypical femoral fractures.

The study was funded by Amgen. Dr. Wilkinson has reported receiving a grant from Amgen. Dr. Chen has reported serving as a consultant for Striker and b-One Ortho. Dr. Aro has reported receiving a grant to his institution from Amgen Finland and the Academy of Finland. He has also served as a member of an advisory scientific board for Amgen Finland.

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

Inhaled treprostinil improved the exercise capacity of patients with pulmonary hypertension attributable to interstitial lung disease and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.

To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female

At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).

In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.

“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.

Next steps: Assess clinical outcomes after inhaled treprostinil

Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”

While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.

He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”

Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.

“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”

The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.

As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”

The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.

Inhaled treprostinil improved the exercise capacity of patients with pulmonary hypertension attributable to interstitial lung disease and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.

To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female

At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).

In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.

“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.

Next steps: Assess clinical outcomes after inhaled treprostinil

Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”

While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.

He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”

Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.

“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”

The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.

As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”

The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.

Inhaled treprostinil improved the exercise capacity of patients with pulmonary hypertension attributable to interstitial lung disease and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.

To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female

At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).

In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.

“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.

Next steps: Assess clinical outcomes after inhaled treprostinil

Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”

While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.

He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”

Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.

“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”

The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.

As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”

The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.

The United States has allocated more than 641,000 monoclonal antibody treatments for outpatients to ease pressure on strained hospitals, but officials from Operation Warp Speed report that more than half of that reserve sits unused as clinicians grapple with best practices.

There are space and personnel limitations in hospitals right now, Janet Woodcock, MD, therapeutics lead on Operation Warp Speed, acknowledges in an interview with this news organization. “Special areas and procedures must be set up.” And the operation is in the process of broadening availability beyond hospitals, she points out.

But for frontline clinicians, questions about treatment efficacy and the logistics of administering intravenous drugs to infectious outpatients loom large.

More than 50 monoclonal antibody products that target SARS-CoV-2 are now in development. The U.S. Food and Drug Administration has already issued Emergency Use Authorization (EUA) for two such drugs on the basis of phase 2 trial data – bamlanivimab, made by Eli Lilly, and a cocktail of casirivimab plus imdevimab, made by Regeneron – and another two-antibody cocktail from AstraZeneca, AZD7442, has started phase 3 clinical trials. The Regeneron combination was used to treat President Donald Trump when he contracted COVID-19 in October.

Monoclonal antibody drugs are based on the natural antibodies that the body uses to fight infections. They work by binding to a specific target and then blocking its action or flagging it for destruction by other parts of the immune system. Both bamlanivimab and the casirivimab plus imdevimab combination target the spike protein of the virus and stop it from attaching to and entering human cells.
 

Targeting the spike protein out of the hospital

The antibody drugs covered by EUAs do not cure COVID-19, but they have been shown to reduce hospitalizations and visits to the emergency department for patients at high risk for disease progression. They are approved to treat patients older than 12 years with mild to moderate COVID-19 who are at high risk of progressing to severe disease or hospitalization. They are not authorized for use in patients who have been hospitalized or who are on ventilators. The hope is that antibody drugs will reduce the number of severe cases of COVID-19 and ease pressure on overstretched hospitals.

Most COVID-19 patients are outpatients, so we need something to keep them from getting worse.

This is important because it targets the greatest need in COVID-19 therapeutics, says Rajesh Gandhi, MD, an infectious disease physician at Harvard Medical School in Boston, who is a member of two panels evaluating COVID-19 treatments: one for the Infectious Disease Society of America and the other for the National Institutes of Health. “Up to now, most of the focus has been on hospitalized patients,” he says, but “most COVID-19 patients are outpatients, so we need something to keep them from getting worse.”

Both panels have said that, despite the EUAs, more evidence is needed to be sure of the efficacy of the drugs and to determine which patients will benefit the most from them.

These aren’t the mature data from drug development that guideline groups are accustomed to working with, Dr. Woodcock points out. “But this is an emergency and the data taken as a whole are pretty convincing,” she says. “As I look at the totality of the evidence, monoclonal antibodies will have a big effect in keeping people out of the hospital and helping them recover faster.”

High-risk patients are eligible for treatment, especially those older than 65 years and those with comorbidities who are younger. Access to the drugs is increasing for clinicians who are able to infuse safely or work with a site that will.

In the Boston area, several hospitals, including Massachusetts General where Dr. Gandhi works, have set up infusion centers where newly diagnosed patients can get the antibody treatment if their doctor thinks it will benefit them. And Coram, a provider of at-home infusion therapy owned by the CVS pharmacy chain, is running a pilot program offering the Eli Lilly drug to people in seven cities – including Boston, Chicago, Los Angeles, and Tampa – and their surrounding communities with a physician referral.

Getting that referral could be tricky, however, for patients without a primary care physician or for those whose doctor isn’t already connected to one of the institutions providing the infusions. The hospitals are sending out communications on how patients and physicians can get the therapy, but Dr. Gandhi says that making information about access available should be a priority. The window for the effective treatment is small – the drugs appear to work best before patients begin to make their own antibodies, says Dr. Gandhi – so it’s vital that doctors act quickly if they have a patient who is eligible.

And rolling out the new therapies to patients around the world will be a major logistical undertaking.

The first hurdle will be making enough of them to go around. Case numbers are skyrocketing around the globe, and producing the drugs is a complex time- and labor-intensive process that requires specialized facilities. Antibodies are produced by cell lines in bioreactors, so a plant that churns out generic aspirin tablets can’t simply be converted into an antibody factory.

“These types of drugs are manufactured in a sterile injectables plant, which is different from a plant where oral solids are made,” says Kim Crabtree, senior director of pharma portfolio management for Henry Schein Medical, a medical supplies distributor. “Those are not as plentiful as a standard pill factory.”

The doses required are also relatively high – 1.2 g of each antibody in Regeneron’s cocktail – which will further strain production capacity. Leah Lipsich, PhD, vice president of strategic program direction at Regeneron, says the company is prepared for high demand and has been able to respond, thanks to its rapid development and manufacturing technology, known as VelociSuite, which allows it to rapidly scale-up from discovery to productions in weeks instead of months.

“We knew supply would be a huge problem for COVID-19, but because we had such confidence in our technology, we went immediately from research-scale to our largest-scale manufacturing,” she says. “We’ve been manufacturing our cocktail for months now.”

The company has also partnered with Roche, the biggest manufacturer and vendor of monoclonal antibodies in the world, to manufacture and supply the drugs. Once full manufacturing capacity is reached in 2021, the companies expect to produce at least 2 million doses a year.

Then there is the issue of getting the drugs from the factories to the places they will be used.

Antibodies are temperature sensitive and need to be refrigerated during transport and storage, so a cold-chain-compliant supply chain is required. Fortunately, they can be kept at standard refrigerator temperatures, ranging from 2° C to 8° C, rather than the ultra-low temperatures required by some COVID-19 vaccines.
 

Two million doses a year

Medical logistics companies have a lot of experience dealing with products like these and are well prepared to handle the new antibody drugs. “There are quite a few products like these on the market, and the supply chain is used to shipping them,” Ms. Crabtree says.

They will be shipped to distribution centers in refrigerated trucks, repacked into smaller lots that can sustain the correct temperature for 24 hours, and then sent to their final destination, often in something as simple as a Styrofoam cooler filled with dry ice.

The expected rise in demand shouldn’t be too much of an issue for distributors either, says Ms. Crabtree; they have built systems that can deal with short-term surges in volume. The annual flu vaccine, for example, involves shipping a lot of product in a very short time, usually from August to November. “The distribution system is used to seasonal variations and peaks in demand,” she says.

The next question is how the treatments will be administered. Although most patients who will receive monoclonal antibodies will be ambulatory and not hospitalized, the administration requires intravenous infusion. Hospitals, of course, have a lot of experience with intravenous drugs, but typically give them only to inpatients. Most other monoclonal antibody drugs – such as those for cancer and autoimmune disorders – are given in specialized suites in doctor’s offices or in stand-alone infusion clinics.

That means that the places best suited to treat COVID-19 patients with antibodies are those that regularly deal with people who are immunocompromised, and such patients should not be interacting with people who have an infectious disease. “How do we protect the staff and other patients?” Dr. Gandhi asks.
 

Protecting staff and other patients

This is not an insurmountable obstacle, he points out, but it is one that requires careful thought and planning to accommodate COVID-19 patients without unduly disrupting life-saving treatments for other patients. It might involve, for example, treating COVID-19 patients in sequestered parts of the clinic or at different times of day, with even greater attention paid to cleaning, he explains. “We now have many months of experience with infection control, so we know how to do this; it’s just a question of logistics.”

But even once all the details around manufacturing, transporting, and administering the drugs are sorted out, there is still the issue of how they will be distributed fairly and equitably.

Despite multiple companies working to produce an array of different antibody drugs, demand is still expected to exceed supply for many months. “With more than 200,000 new cases a day in the United States, there won’t be enough antibodies to treat all of the high-risk patients,” says Dr. Gandhi. “Most of us are worried that demand will far outstrip supply. People are talking about lotteries to determine who gets them.”

The Department of Health and Human Services will continue to distribute the drugs to states on the basis of their COVID-19 burdens, and the states will then decide how much to provide to each health care facility.

Although the HHS goal is to ensure that the drugs reach as many patients as possible, no matter where they live and regardless of their income, there are still concerns that larger facilities serving more affluent areas will end up being favored, if only because they are the ones best equipped to deal with the drugs right now.

“We are all aware that this has affected certain communities more, so we need to make sure that the drugs are used equitably and made available to the communities that were hardest hit,” says Dr. Gandhi. The ability to monitor drug distribution should be built into the rollout, so that institutions and governments will have some sense of whether they are being doled out evenly, he adds.

Equity in distribution will be an issue for the rest of the world as well. Currently, 80% of monoclonal antibodies are sold in Canada, Europe, and the United States; few, if any, are available in low- and middle-income countries. The treatments are expensive: the cost of producing one g of marketed monoclonal antibodies is between $95 and $200, which does not include the cost of R&D, packaging, shipping, or administration. The median price for antibody treatment not related to COVID-19 runs from $15,000 to $200,000 per year in the United States.

Regeneron’s Dr. Lipsich says that the company has not yet set a price for its antibody cocktail. The government paid $450 million for its 300,000 doses, but that price includes the costs of research, manufacturing, and distribution, so is not a useful indicator of the eventual per-dose price. “We’re not in a position to talk about how it will be priced yet, but we will do our best to make it affordable and accessible to all,” she says.

There are some projects underway to ensure that the drugs are made available in poorer countries. In April, the COVID-19 Therapeutics Accelerator – an initiative launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard to speed-up the response to the global pandemic – reserved manufacturing capacity with Fujifilm Diosynth Biotechnologies in Denmark for future monoclonal antibody therapies that will supply low- and middle-income countries. In October, the initiative announced that Eli Lilly would use that reserved capacity to produce its antibody drug starting in April 2021.

In the meantime, Lilly will make some of its product manufactured in other facilities available to lower-income countries. To help keep costs down, the company’s collaborators have agreed to waive their royalties on antibodies distributed in low- and middle-income countries.

“Everyone is looking carefully at how the drugs are distributed to ensure all will get access,” said Dr. Lipsich.

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

The United States has allocated more than 641,000 monoclonal antibody treatments for outpatients to ease pressure on strained hospitals, but officials from Operation Warp Speed report that more than half of that reserve sits unused as clinicians grapple with best practices.

There are space and personnel limitations in hospitals right now, Janet Woodcock, MD, therapeutics lead on Operation Warp Speed, acknowledges in an interview with this news organization. “Special areas and procedures must be set up.” And the operation is in the process of broadening availability beyond hospitals, she points out.

But for frontline clinicians, questions about treatment efficacy and the logistics of administering intravenous drugs to infectious outpatients loom large.

More than 50 monoclonal antibody products that target SARS-CoV-2 are now in development. The U.S. Food and Drug Administration has already issued Emergency Use Authorization (EUA) for two such drugs on the basis of phase 2 trial data – bamlanivimab, made by Eli Lilly, and a cocktail of casirivimab plus imdevimab, made by Regeneron – and another two-antibody cocktail from AstraZeneca, AZD7442, has started phase 3 clinical trials. The Regeneron combination was used to treat President Donald Trump when he contracted COVID-19 in October.

Monoclonal antibody drugs are based on the natural antibodies that the body uses to fight infections. They work by binding to a specific target and then blocking its action or flagging it for destruction by other parts of the immune system. Both bamlanivimab and the casirivimab plus imdevimab combination target the spike protein of the virus and stop it from attaching to and entering human cells.
 

Targeting the spike protein out of the hospital

The antibody drugs covered by EUAs do not cure COVID-19, but they have been shown to reduce hospitalizations and visits to the emergency department for patients at high risk for disease progression. They are approved to treat patients older than 12 years with mild to moderate COVID-19 who are at high risk of progressing to severe disease or hospitalization. They are not authorized for use in patients who have been hospitalized or who are on ventilators. The hope is that antibody drugs will reduce the number of severe cases of COVID-19 and ease pressure on overstretched hospitals.

Most COVID-19 patients are outpatients, so we need something to keep them from getting worse.

This is important because it targets the greatest need in COVID-19 therapeutics, says Rajesh Gandhi, MD, an infectious disease physician at Harvard Medical School in Boston, who is a member of two panels evaluating COVID-19 treatments: one for the Infectious Disease Society of America and the other for the National Institutes of Health. “Up to now, most of the focus has been on hospitalized patients,” he says, but “most COVID-19 patients are outpatients, so we need something to keep them from getting worse.”

Both panels have said that, despite the EUAs, more evidence is needed to be sure of the efficacy of the drugs and to determine which patients will benefit the most from them.

These aren’t the mature data from drug development that guideline groups are accustomed to working with, Dr. Woodcock points out. “But this is an emergency and the data taken as a whole are pretty convincing,” she says. “As I look at the totality of the evidence, monoclonal antibodies will have a big effect in keeping people out of the hospital and helping them recover faster.”

High-risk patients are eligible for treatment, especially those older than 65 years and those with comorbidities who are younger. Access to the drugs is increasing for clinicians who are able to infuse safely or work with a site that will.

In the Boston area, several hospitals, including Massachusetts General where Dr. Gandhi works, have set up infusion centers where newly diagnosed patients can get the antibody treatment if their doctor thinks it will benefit them. And Coram, a provider of at-home infusion therapy owned by the CVS pharmacy chain, is running a pilot program offering the Eli Lilly drug to people in seven cities – including Boston, Chicago, Los Angeles, and Tampa – and their surrounding communities with a physician referral.

Getting that referral could be tricky, however, for patients without a primary care physician or for those whose doctor isn’t already connected to one of the institutions providing the infusions. The hospitals are sending out communications on how patients and physicians can get the therapy, but Dr. Gandhi says that making information about access available should be a priority. The window for the effective treatment is small – the drugs appear to work best before patients begin to make their own antibodies, says Dr. Gandhi – so it’s vital that doctors act quickly if they have a patient who is eligible.

And rolling out the new therapies to patients around the world will be a major logistical undertaking.

The first hurdle will be making enough of them to go around. Case numbers are skyrocketing around the globe, and producing the drugs is a complex time- and labor-intensive process that requires specialized facilities. Antibodies are produced by cell lines in bioreactors, so a plant that churns out generic aspirin tablets can’t simply be converted into an antibody factory.

“These types of drugs are manufactured in a sterile injectables plant, which is different from a plant where oral solids are made,” says Kim Crabtree, senior director of pharma portfolio management for Henry Schein Medical, a medical supplies distributor. “Those are not as plentiful as a standard pill factory.”

The doses required are also relatively high – 1.2 g of each antibody in Regeneron’s cocktail – which will further strain production capacity. Leah Lipsich, PhD, vice president of strategic program direction at Regeneron, says the company is prepared for high demand and has been able to respond, thanks to its rapid development and manufacturing technology, known as VelociSuite, which allows it to rapidly scale-up from discovery to productions in weeks instead of months.

“We knew supply would be a huge problem for COVID-19, but because we had such confidence in our technology, we went immediately from research-scale to our largest-scale manufacturing,” she says. “We’ve been manufacturing our cocktail for months now.”

The company has also partnered with Roche, the biggest manufacturer and vendor of monoclonal antibodies in the world, to manufacture and supply the drugs. Once full manufacturing capacity is reached in 2021, the companies expect to produce at least 2 million doses a year.

Then there is the issue of getting the drugs from the factories to the places they will be used.

Antibodies are temperature sensitive and need to be refrigerated during transport and storage, so a cold-chain-compliant supply chain is required. Fortunately, they can be kept at standard refrigerator temperatures, ranging from 2° C to 8° C, rather than the ultra-low temperatures required by some COVID-19 vaccines.
 

Two million doses a year

Medical logistics companies have a lot of experience dealing with products like these and are well prepared to handle the new antibody drugs. “There are quite a few products like these on the market, and the supply chain is used to shipping them,” Ms. Crabtree says.

They will be shipped to distribution centers in refrigerated trucks, repacked into smaller lots that can sustain the correct temperature for 24 hours, and then sent to their final destination, often in something as simple as a Styrofoam cooler filled with dry ice.

The expected rise in demand shouldn’t be too much of an issue for distributors either, says Ms. Crabtree; they have built systems that can deal with short-term surges in volume. The annual flu vaccine, for example, involves shipping a lot of product in a very short time, usually from August to November. “The distribution system is used to seasonal variations and peaks in demand,” she says.

The next question is how the treatments will be administered. Although most patients who will receive monoclonal antibodies will be ambulatory and not hospitalized, the administration requires intravenous infusion. Hospitals, of course, have a lot of experience with intravenous drugs, but typically give them only to inpatients. Most other monoclonal antibody drugs – such as those for cancer and autoimmune disorders – are given in specialized suites in doctor’s offices or in stand-alone infusion clinics.

That means that the places best suited to treat COVID-19 patients with antibodies are those that regularly deal with people who are immunocompromised, and such patients should not be interacting with people who have an infectious disease. “How do we protect the staff and other patients?” Dr. Gandhi asks.
 

Protecting staff and other patients

This is not an insurmountable obstacle, he points out, but it is one that requires careful thought and planning to accommodate COVID-19 patients without unduly disrupting life-saving treatments for other patients. It might involve, for example, treating COVID-19 patients in sequestered parts of the clinic or at different times of day, with even greater attention paid to cleaning, he explains. “We now have many months of experience with infection control, so we know how to do this; it’s just a question of logistics.”

But even once all the details around manufacturing, transporting, and administering the drugs are sorted out, there is still the issue of how they will be distributed fairly and equitably.

Despite multiple companies working to produce an array of different antibody drugs, demand is still expected to exceed supply for many months. “With more than 200,000 new cases a day in the United States, there won’t be enough antibodies to treat all of the high-risk patients,” says Dr. Gandhi. “Most of us are worried that demand will far outstrip supply. People are talking about lotteries to determine who gets them.”

The Department of Health and Human Services will continue to distribute the drugs to states on the basis of their COVID-19 burdens, and the states will then decide how much to provide to each health care facility.

Although the HHS goal is to ensure that the drugs reach as many patients as possible, no matter where they live and regardless of their income, there are still concerns that larger facilities serving more affluent areas will end up being favored, if only because they are the ones best equipped to deal with the drugs right now.

“We are all aware that this has affected certain communities more, so we need to make sure that the drugs are used equitably and made available to the communities that were hardest hit,” says Dr. Gandhi. The ability to monitor drug distribution should be built into the rollout, so that institutions and governments will have some sense of whether they are being doled out evenly, he adds.

Equity in distribution will be an issue for the rest of the world as well. Currently, 80% of monoclonal antibodies are sold in Canada, Europe, and the United States; few, if any, are available in low- and middle-income countries. The treatments are expensive: the cost of producing one g of marketed monoclonal antibodies is between $95 and $200, which does not include the cost of R&D, packaging, shipping, or administration. The median price for antibody treatment not related to COVID-19 runs from $15,000 to $200,000 per year in the United States.

Regeneron’s Dr. Lipsich says that the company has not yet set a price for its antibody cocktail. The government paid $450 million for its 300,000 doses, but that price includes the costs of research, manufacturing, and distribution, so is not a useful indicator of the eventual per-dose price. “We’re not in a position to talk about how it will be priced yet, but we will do our best to make it affordable and accessible to all,” she says.

There are some projects underway to ensure that the drugs are made available in poorer countries. In April, the COVID-19 Therapeutics Accelerator – an initiative launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard to speed-up the response to the global pandemic – reserved manufacturing capacity with Fujifilm Diosynth Biotechnologies in Denmark for future monoclonal antibody therapies that will supply low- and middle-income countries. In October, the initiative announced that Eli Lilly would use that reserved capacity to produce its antibody drug starting in April 2021.

In the meantime, Lilly will make some of its product manufactured in other facilities available to lower-income countries. To help keep costs down, the company’s collaborators have agreed to waive their royalties on antibodies distributed in low- and middle-income countries.

“Everyone is looking carefully at how the drugs are distributed to ensure all will get access,” said Dr. Lipsich.

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

The United States has allocated more than 641,000 monoclonal antibody treatments for outpatients to ease pressure on strained hospitals, but officials from Operation Warp Speed report that more than half of that reserve sits unused as clinicians grapple with best practices.

There are space and personnel limitations in hospitals right now, Janet Woodcock, MD, therapeutics lead on Operation Warp Speed, acknowledges in an interview with this news organization. “Special areas and procedures must be set up.” And the operation is in the process of broadening availability beyond hospitals, she points out.

But for frontline clinicians, questions about treatment efficacy and the logistics of administering intravenous drugs to infectious outpatients loom large.

More than 50 monoclonal antibody products that target SARS-CoV-2 are now in development. The U.S. Food and Drug Administration has already issued Emergency Use Authorization (EUA) for two such drugs on the basis of phase 2 trial data – bamlanivimab, made by Eli Lilly, and a cocktail of casirivimab plus imdevimab, made by Regeneron – and another two-antibody cocktail from AstraZeneca, AZD7442, has started phase 3 clinical trials. The Regeneron combination was used to treat President Donald Trump when he contracted COVID-19 in October.

Monoclonal antibody drugs are based on the natural antibodies that the body uses to fight infections. They work by binding to a specific target and then blocking its action or flagging it for destruction by other parts of the immune system. Both bamlanivimab and the casirivimab plus imdevimab combination target the spike protein of the virus and stop it from attaching to and entering human cells.
 

Targeting the spike protein out of the hospital

The antibody drugs covered by EUAs do not cure COVID-19, but they have been shown to reduce hospitalizations and visits to the emergency department for patients at high risk for disease progression. They are approved to treat patients older than 12 years with mild to moderate COVID-19 who are at high risk of progressing to severe disease or hospitalization. They are not authorized for use in patients who have been hospitalized or who are on ventilators. The hope is that antibody drugs will reduce the number of severe cases of COVID-19 and ease pressure on overstretched hospitals.

Most COVID-19 patients are outpatients, so we need something to keep them from getting worse.

This is important because it targets the greatest need in COVID-19 therapeutics, says Rajesh Gandhi, MD, an infectious disease physician at Harvard Medical School in Boston, who is a member of two panels evaluating COVID-19 treatments: one for the Infectious Disease Society of America and the other for the National Institutes of Health. “Up to now, most of the focus has been on hospitalized patients,” he says, but “most COVID-19 patients are outpatients, so we need something to keep them from getting worse.”

Both panels have said that, despite the EUAs, more evidence is needed to be sure of the efficacy of the drugs and to determine which patients will benefit the most from them.

These aren’t the mature data from drug development that guideline groups are accustomed to working with, Dr. Woodcock points out. “But this is an emergency and the data taken as a whole are pretty convincing,” she says. “As I look at the totality of the evidence, monoclonal antibodies will have a big effect in keeping people out of the hospital and helping them recover faster.”

High-risk patients are eligible for treatment, especially those older than 65 years and those with comorbidities who are younger. Access to the drugs is increasing for clinicians who are able to infuse safely or work with a site that will.

In the Boston area, several hospitals, including Massachusetts General where Dr. Gandhi works, have set up infusion centers where newly diagnosed patients can get the antibody treatment if their doctor thinks it will benefit them. And Coram, a provider of at-home infusion therapy owned by the CVS pharmacy chain, is running a pilot program offering the Eli Lilly drug to people in seven cities – including Boston, Chicago, Los Angeles, and Tampa – and their surrounding communities with a physician referral.

Getting that referral could be tricky, however, for patients without a primary care physician or for those whose doctor isn’t already connected to one of the institutions providing the infusions. The hospitals are sending out communications on how patients and physicians can get the therapy, but Dr. Gandhi says that making information about access available should be a priority. The window for the effective treatment is small – the drugs appear to work best before patients begin to make their own antibodies, says Dr. Gandhi – so it’s vital that doctors act quickly if they have a patient who is eligible.

And rolling out the new therapies to patients around the world will be a major logistical undertaking.

The first hurdle will be making enough of them to go around. Case numbers are skyrocketing around the globe, and producing the drugs is a complex time- and labor-intensive process that requires specialized facilities. Antibodies are produced by cell lines in bioreactors, so a plant that churns out generic aspirin tablets can’t simply be converted into an antibody factory.

“These types of drugs are manufactured in a sterile injectables plant, which is different from a plant where oral solids are made,” says Kim Crabtree, senior director of pharma portfolio management for Henry Schein Medical, a medical supplies distributor. “Those are not as plentiful as a standard pill factory.”

The doses required are also relatively high – 1.2 g of each antibody in Regeneron’s cocktail – which will further strain production capacity. Leah Lipsich, PhD, vice president of strategic program direction at Regeneron, says the company is prepared for high demand and has been able to respond, thanks to its rapid development and manufacturing technology, known as VelociSuite, which allows it to rapidly scale-up from discovery to productions in weeks instead of months.

“We knew supply would be a huge problem for COVID-19, but because we had such confidence in our technology, we went immediately from research-scale to our largest-scale manufacturing,” she says. “We’ve been manufacturing our cocktail for months now.”

The company has also partnered with Roche, the biggest manufacturer and vendor of monoclonal antibodies in the world, to manufacture and supply the drugs. Once full manufacturing capacity is reached in 2021, the companies expect to produce at least 2 million doses a year.

Then there is the issue of getting the drugs from the factories to the places they will be used.

Antibodies are temperature sensitive and need to be refrigerated during transport and storage, so a cold-chain-compliant supply chain is required. Fortunately, they can be kept at standard refrigerator temperatures, ranging from 2° C to 8° C, rather than the ultra-low temperatures required by some COVID-19 vaccines.
 

Two million doses a year

Medical logistics companies have a lot of experience dealing with products like these and are well prepared to handle the new antibody drugs. “There are quite a few products like these on the market, and the supply chain is used to shipping them,” Ms. Crabtree says.

They will be shipped to distribution centers in refrigerated trucks, repacked into smaller lots that can sustain the correct temperature for 24 hours, and then sent to their final destination, often in something as simple as a Styrofoam cooler filled with dry ice.

The expected rise in demand shouldn’t be too much of an issue for distributors either, says Ms. Crabtree; they have built systems that can deal with short-term surges in volume. The annual flu vaccine, for example, involves shipping a lot of product in a very short time, usually from August to November. “The distribution system is used to seasonal variations and peaks in demand,” she says.

The next question is how the treatments will be administered. Although most patients who will receive monoclonal antibodies will be ambulatory and not hospitalized, the administration requires intravenous infusion. Hospitals, of course, have a lot of experience with intravenous drugs, but typically give them only to inpatients. Most other monoclonal antibody drugs – such as those for cancer and autoimmune disorders – are given in specialized suites in doctor’s offices or in stand-alone infusion clinics.

That means that the places best suited to treat COVID-19 patients with antibodies are those that regularly deal with people who are immunocompromised, and such patients should not be interacting with people who have an infectious disease. “How do we protect the staff and other patients?” Dr. Gandhi asks.
 

Protecting staff and other patients

This is not an insurmountable obstacle, he points out, but it is one that requires careful thought and planning to accommodate COVID-19 patients without unduly disrupting life-saving treatments for other patients. It might involve, for example, treating COVID-19 patients in sequestered parts of the clinic or at different times of day, with even greater attention paid to cleaning, he explains. “We now have many months of experience with infection control, so we know how to do this; it’s just a question of logistics.”

But even once all the details around manufacturing, transporting, and administering the drugs are sorted out, there is still the issue of how they will be distributed fairly and equitably.

Despite multiple companies working to produce an array of different antibody drugs, demand is still expected to exceed supply for many months. “With more than 200,000 new cases a day in the United States, there won’t be enough antibodies to treat all of the high-risk patients,” says Dr. Gandhi. “Most of us are worried that demand will far outstrip supply. People are talking about lotteries to determine who gets them.”

The Department of Health and Human Services will continue to distribute the drugs to states on the basis of their COVID-19 burdens, and the states will then decide how much to provide to each health care facility.

Although the HHS goal is to ensure that the drugs reach as many patients as possible, no matter where they live and regardless of their income, there are still concerns that larger facilities serving more affluent areas will end up being favored, if only because they are the ones best equipped to deal with the drugs right now.

“We are all aware that this has affected certain communities more, so we need to make sure that the drugs are used equitably and made available to the communities that were hardest hit,” says Dr. Gandhi. The ability to monitor drug distribution should be built into the rollout, so that institutions and governments will have some sense of whether they are being doled out evenly, he adds.

Equity in distribution will be an issue for the rest of the world as well. Currently, 80% of monoclonal antibodies are sold in Canada, Europe, and the United States; few, if any, are available in low- and middle-income countries. The treatments are expensive: the cost of producing one g of marketed monoclonal antibodies is between $95 and $200, which does not include the cost of R&D, packaging, shipping, or administration. The median price for antibody treatment not related to COVID-19 runs from $15,000 to $200,000 per year in the United States.

Regeneron’s Dr. Lipsich says that the company has not yet set a price for its antibody cocktail. The government paid $450 million for its 300,000 doses, but that price includes the costs of research, manufacturing, and distribution, so is not a useful indicator of the eventual per-dose price. “We’re not in a position to talk about how it will be priced yet, but we will do our best to make it affordable and accessible to all,” she says.

There are some projects underway to ensure that the drugs are made available in poorer countries. In April, the COVID-19 Therapeutics Accelerator – an initiative launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard to speed-up the response to the global pandemic – reserved manufacturing capacity with Fujifilm Diosynth Biotechnologies in Denmark for future monoclonal antibody therapies that will supply low- and middle-income countries. In October, the initiative announced that Eli Lilly would use that reserved capacity to produce its antibody drug starting in April 2021.

In the meantime, Lilly will make some of its product manufactured in other facilities available to lower-income countries. To help keep costs down, the company’s collaborators have agreed to waive their royalties on antibodies distributed in low- and middle-income countries.

“Everyone is looking carefully at how the drugs are distributed to ensure all will get access,” said Dr. Lipsich.

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

Among patients taking direct oral anticoagulants (DOACs), elective endoscopy procedures carry a risk of bleeding and thromboembolic events similar to that seen in those receiving vitamin K antagonists (VKAs), according to a multicenter, prospective observational study conducted at 12 Spanish academic and community centers.

DOACs have several advantages over VKAs, including more predictable pharmacokinetic profiles and fewer food and drug interactions, but they have not been well studied in the elective endoscopy setting. Some previous studies suggested a lower risk with DOACs than with VKAs, but they were retrospective or based on administrative databases.

It also remains unclear when anticoagulant therapy should be resumed following high-risk procedures. The new study, which was led by Enrique Rodríguez de Santiago of Universidad de Alcalá (Spain) and published in Clinical Gastroenterology and Hepatology, suggested that early resumption may be safe. “It certainly showed there was an acceptable rate of clinically significant rate of bleeding for patients on anticoagulants, and the thing I appreciated the most was that there was no statistically significant difference in terms of bleeding depending on when you resumed the anticoagulant,” said Robert Jay Sealock, MD, assistant professor of medicine at Baylor College of Medicine in Houston. Dr. Sealock was not involved in the study.

The researchers examined data from 1,623 patients who underwent 1,874 endoscopic procedures. Among these patients, 62.7% were taking VKAs, and 37.3% were taking DOACs; 58.9% were men, and the mean age was 74.2 years. Overall, 75.5% were on anticoagulant therapy for atrial fibrillation.

The most common procedures were colonoscopy (68.3%) and esophagogastroduodenoscopy (27.3%).

Within 30 days, The risk of bleeding was similar between patients taking VKAs (6.2%; 95% confidence interval, 4.8-7.8%) and DOACs (6.7%; 95% CI, 4.9-9%). This was true regardless of intervention and site. Overall, 1.4% of subjects experienced a thromboembolic event (95% CI, 0.9-2.1%), and there was no significant difference between the VKA group (1.3%; 95% CI, 0.8-2.2%) and the DOAC group (1.5%; 95% CI, 0.8-2.8%).

Clinically significant gastrointestinal bleeding occurred in 6.4% of subjects (95% CI, 5.3-7.7%); 2.7% of clinically significant gastrointestinal bleeding events were intraprocedural and 4.1% were delayed. The lowest risk of bleeding occurred with diagnostic endoscopy (1.1%) and biopsy (2.2%). The risk of bleeding for high-risk procedures was 11.5% (95% CI, 9.4-14%).

The overall mortality was 1.4%, with two deaths related to thromboembolic events, both in the DOAC group. The other deaths were considered to be unrelated to the procedure or periprocedural interruption of anticoagulants.

The researchers also examined the timing of anticoagulant resumption. Overall, 59.2% of subjects received bridging therapy, including 85% of the VKA group and 16% of the DOAC group (P < .001). This was not associated with increased endoscopy-related bleeding in either the VKA (3.3% with bridging therapy vs. 6.4% without; P = .14) or the DOAC group (8.3% vs. 6.4%; P = .48).

A total of 747 patients underwent a high-risk procedure, 46.3% of patients resumed anticoagulant therapy within 24 hours of the procedure, and 46.2% between 24 and 48 hours. After inverse probability of treatment weighting adjustment, a delay in anticoagulant resumption was not associated with a reduction in the frequency of postprocedural clinically significant gastrointestinal bleeding.

Still, the research left some questions unanswered. Most of the high-risk procedures were hot (41.8%) or cold snare polypectomies (39.8%). There weren’t enough data in the study to evaluate risk in patients undergoing other high-risk procedures such as balloon dilation for strictures, endoscopic ultrasound with fine-needle aspiration, and sphincterotomy. “That’s one group that we still don’t really have enough data about, particularly those patients who are on DOACs,” said Dr. Sealock.

The study also found a high number of patients on bridging therapy. “It highlighted the fact that we probably use bridging therapy too much in patients undergoing endoscopy,” said Dr. Sealock. He recommended using tools that generate recommendations for bridging therapy and timing for withholding and resuming anticoagulants based on procedure and patient characteristics.

SOURCE: de Santiago ER et al. Clin Gastroenterol Hepatol. 2020 Dec 03. doi: 10.1016/j.cgh.2020.11.037.

Among patients taking direct oral anticoagulants (DOACs), elective endoscopy procedures carry a risk of bleeding and thromboembolic events similar to that seen in those receiving vitamin K antagonists (VKAs), according to a multicenter, prospective observational study conducted at 12 Spanish academic and community centers.

DOACs have several advantages over VKAs, including more predictable pharmacokinetic profiles and fewer food and drug interactions, but they have not been well studied in the elective endoscopy setting. Some previous studies suggested a lower risk with DOACs than with VKAs, but they were retrospective or based on administrative databases.

It also remains unclear when anticoagulant therapy should be resumed following high-risk procedures. The new study, which was led by Enrique Rodríguez de Santiago of Universidad de Alcalá (Spain) and published in Clinical Gastroenterology and Hepatology, suggested that early resumption may be safe. “It certainly showed there was an acceptable rate of clinically significant rate of bleeding for patients on anticoagulants, and the thing I appreciated the most was that there was no statistically significant difference in terms of bleeding depending on when you resumed the anticoagulant,” said Robert Jay Sealock, MD, assistant professor of medicine at Baylor College of Medicine in Houston. Dr. Sealock was not involved in the study.

The researchers examined data from 1,623 patients who underwent 1,874 endoscopic procedures. Among these patients, 62.7% were taking VKAs, and 37.3% were taking DOACs; 58.9% were men, and the mean age was 74.2 years. Overall, 75.5% were on anticoagulant therapy for atrial fibrillation.

The most common procedures were colonoscopy (68.3%) and esophagogastroduodenoscopy (27.3%).

Within 30 days, The risk of bleeding was similar between patients taking VKAs (6.2%; 95% confidence interval, 4.8-7.8%) and DOACs (6.7%; 95% CI, 4.9-9%). This was true regardless of intervention and site. Overall, 1.4% of subjects experienced a thromboembolic event (95% CI, 0.9-2.1%), and there was no significant difference between the VKA group (1.3%; 95% CI, 0.8-2.2%) and the DOAC group (1.5%; 95% CI, 0.8-2.8%).

Clinically significant gastrointestinal bleeding occurred in 6.4% of subjects (95% CI, 5.3-7.7%); 2.7% of clinically significant gastrointestinal bleeding events were intraprocedural and 4.1% were delayed. The lowest risk of bleeding occurred with diagnostic endoscopy (1.1%) and biopsy (2.2%). The risk of bleeding for high-risk procedures was 11.5% (95% CI, 9.4-14%).

The overall mortality was 1.4%, with two deaths related to thromboembolic events, both in the DOAC group. The other deaths were considered to be unrelated to the procedure or periprocedural interruption of anticoagulants.

The researchers also examined the timing of anticoagulant resumption. Overall, 59.2% of subjects received bridging therapy, including 85% of the VKA group and 16% of the DOAC group (P < .001). This was not associated with increased endoscopy-related bleeding in either the VKA (3.3% with bridging therapy vs. 6.4% without; P = .14) or the DOAC group (8.3% vs. 6.4%; P = .48).

A total of 747 patients underwent a high-risk procedure, 46.3% of patients resumed anticoagulant therapy within 24 hours of the procedure, and 46.2% between 24 and 48 hours. After inverse probability of treatment weighting adjustment, a delay in anticoagulant resumption was not associated with a reduction in the frequency of postprocedural clinically significant gastrointestinal bleeding.

Still, the research left some questions unanswered. Most of the high-risk procedures were hot (41.8%) or cold snare polypectomies (39.8%). There weren’t enough data in the study to evaluate risk in patients undergoing other high-risk procedures such as balloon dilation for strictures, endoscopic ultrasound with fine-needle aspiration, and sphincterotomy. “That’s one group that we still don’t really have enough data about, particularly those patients who are on DOACs,” said Dr. Sealock.

The study also found a high number of patients on bridging therapy. “It highlighted the fact that we probably use bridging therapy too much in patients undergoing endoscopy,” said Dr. Sealock. He recommended using tools that generate recommendations for bridging therapy and timing for withholding and resuming anticoagulants based on procedure and patient characteristics.

SOURCE: de Santiago ER et al. Clin Gastroenterol Hepatol. 2020 Dec 03. doi: 10.1016/j.cgh.2020.11.037.

Among patients taking direct oral anticoagulants (DOACs), elective endoscopy procedures carry a risk of bleeding and thromboembolic events similar to that seen in those receiving vitamin K antagonists (VKAs), according to a multicenter, prospective observational study conducted at 12 Spanish academic and community centers.

DOACs have several advantages over VKAs, including more predictable pharmacokinetic profiles and fewer food and drug interactions, but they have not been well studied in the elective endoscopy setting. Some previous studies suggested a lower risk with DOACs than with VKAs, but they were retrospective or based on administrative databases.

It also remains unclear when anticoagulant therapy should be resumed following high-risk procedures. The new study, which was led by Enrique Rodríguez de Santiago of Universidad de Alcalá (Spain) and published in Clinical Gastroenterology and Hepatology, suggested that early resumption may be safe. “It certainly showed there was an acceptable rate of clinically significant rate of bleeding for patients on anticoagulants, and the thing I appreciated the most was that there was no statistically significant difference in terms of bleeding depending on when you resumed the anticoagulant,” said Robert Jay Sealock, MD, assistant professor of medicine at Baylor College of Medicine in Houston. Dr. Sealock was not involved in the study.

The researchers examined data from 1,623 patients who underwent 1,874 endoscopic procedures. Among these patients, 62.7% were taking VKAs, and 37.3% were taking DOACs; 58.9% were men, and the mean age was 74.2 years. Overall, 75.5% were on anticoagulant therapy for atrial fibrillation.

The most common procedures were colonoscopy (68.3%) and esophagogastroduodenoscopy (27.3%).

Within 30 days, The risk of bleeding was similar between patients taking VKAs (6.2%; 95% confidence interval, 4.8-7.8%) and DOACs (6.7%; 95% CI, 4.9-9%). This was true regardless of intervention and site. Overall, 1.4% of subjects experienced a thromboembolic event (95% CI, 0.9-2.1%), and there was no significant difference between the VKA group (1.3%; 95% CI, 0.8-2.2%) and the DOAC group (1.5%; 95% CI, 0.8-2.8%).

Clinically significant gastrointestinal bleeding occurred in 6.4% of subjects (95% CI, 5.3-7.7%); 2.7% of clinically significant gastrointestinal bleeding events were intraprocedural and 4.1% were delayed. The lowest risk of bleeding occurred with diagnostic endoscopy (1.1%) and biopsy (2.2%). The risk of bleeding for high-risk procedures was 11.5% (95% CI, 9.4-14%).

The overall mortality was 1.4%, with two deaths related to thromboembolic events, both in the DOAC group. The other deaths were considered to be unrelated to the procedure or periprocedural interruption of anticoagulants.

The researchers also examined the timing of anticoagulant resumption. Overall, 59.2% of subjects received bridging therapy, including 85% of the VKA group and 16% of the DOAC group (P < .001). This was not associated with increased endoscopy-related bleeding in either the VKA (3.3% with bridging therapy vs. 6.4% without; P = .14) or the DOAC group (8.3% vs. 6.4%; P = .48).

A total of 747 patients underwent a high-risk procedure, 46.3% of patients resumed anticoagulant therapy within 24 hours of the procedure, and 46.2% between 24 and 48 hours. After inverse probability of treatment weighting adjustment, a delay in anticoagulant resumption was not associated with a reduction in the frequency of postprocedural clinically significant gastrointestinal bleeding.

Still, the research left some questions unanswered. Most of the high-risk procedures were hot (41.8%) or cold snare polypectomies (39.8%). There weren’t enough data in the study to evaluate risk in patients undergoing other high-risk procedures such as balloon dilation for strictures, endoscopic ultrasound with fine-needle aspiration, and sphincterotomy. “That’s one group that we still don’t really have enough data about, particularly those patients who are on DOACs,” said Dr. Sealock.

The study also found a high number of patients on bridging therapy. “It highlighted the fact that we probably use bridging therapy too much in patients undergoing endoscopy,” said Dr. Sealock. He recommended using tools that generate recommendations for bridging therapy and timing for withholding and resuming anticoagulants based on procedure and patient characteristics.

SOURCE: de Santiago ER et al. Clin Gastroenterol Hepatol. 2020 Dec 03. doi: 10.1016/j.cgh.2020.11.037.

Millions of Americans with treatment-resistant hypertension are likely not being tested to determine whether their high blood pressure is driven by primary aldosteronism (PA), despite guidelines that call for such an approach, according to findings from the first reported large-scale, multicenter study of PA testing practices.

Researchers ran a retrospective review of PA testing among 269,010 patients who met the definition as having treatment-resistant hypertension and were managed at any one of 130 Veterans Health Administration (VHA) medical centers from 2000 to 2017.

The results showed that, despite the fact that primary aldosteronism is highly prevalent among patients with treatment-resistant hypertension, only 4,277 (1.6%) underwent assessment for PA during a median of 3.3 years’ follow-up after they first met the defining criteria, Jordana B. Cohen, MD, and her associates reported in a study published in Annals of Internal Medicine on December 28.

“Testing rates also did not change meaningfully over nearly 2 decades ... despite an increasing number of guidelines recommending testing for primary aldosteronism in this population,” including the most recent recommendations from the Endocrine Society, issued in 2016, noted Dr. Cohen, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia, and colleagues.

Most patients in the study (almost 90%) were seen by a primary care practitioner (PCP).

The small percentage of patients seen by a nephrologist or endocrinologist were more than twice as likely to be tested for PA than those seen by a PCP or cardiologist.

Those clinicians who did order a test for PA were much more likely to treat patients with the appropriate medication, a mineralocorticoid receptor antagonist (MRA). In addition, therapy was started sooner, the researchers found.

“Our results corroborate” earlier reports from smaller health systems and suggest that dramatic underuse of PA assessment “is an issue across the US,” Dr. Cohen said in an interview.

The VHA experience “is very representative of what we think goes on across U.S. practice” and contrasts with the VHA’s reputation for “doing a pretty good job managing hypertension” in general, she noted.
 

Missed diagnosis, missed treatment

Dr. Cohen believes a number of factors likely help drive the abysmally low rate of PA testing they observed in the VHA system. She believes rates of PA testing are low elsewhere as well.

First, optimal hypertension management “is often taken for granted” but is challenging in busy primary care practices, so many of patients likely fall through the cracks, she said.

Dr. Cohen cited efforts at her institution, as well as by the VHA system, to better employ electronic health records to flag patients with treatment-resistant hypertension – defined as patients whose systolic or diastolic blood pressure remains at or above 140/90 mm Hg on at least two successive measurements at least a month apart while the patient is undergoing treatment with three conventional antihypertensive drugs – and to guide clinicians to order the right tests and treatments for these patients.

Many care providers mistakenly “see treatment-resistant hypertension as a disease of noncompliance,” although it is much more often the result of a missed diagnosis and inadequate intervention, she explained.
 

Physicians in denial; side effects of MRAs may deter prescribing

A second big cause of low PA testing rates is that doctors make the mistake of thinking a PA test result won’t change how they manage these patients.

The established treatment for most patients with treatment-resistant hypertension as well as PA is adding an MRA, either spironolactone or eplerenone (Inspra).

Many providers cling to the belief that they will start an MRA in these patients without first determining their PA status, says Dr. Cohen, but the data she and her colleagues collected show the opposite.

Overall, about 13% of all patients in the study began treatment with an MRA during follow-up. The likelihood of starting treatment with this drug class was fourfold higher among the patients tested for PA compared with those who were not tested.

PA testing also hastened the start of MRA use by more than a year, compared with untested patients.

“Providers think they prescribe an MRA” to treatment-resistant patients, “but it’s part of their denial. They are not using the evidence-based treatments [spironolactone or eplerenone], perhaps because of concerns about MRA side effects, although those have been pretty well overcome during the past 20 years,” she observed.

Dr. Cohen says gynecomastia is one adverse effect that gives pause to VHA clinicians who see a heavily male patient population. “It’s probably the biggest concern and why PA testing and MRA use is low” in the VHA system, she said.

“You can use a lower dosage of spironolactone, and the incidence is less common with eplerenone,” although using eplerenone does not completely eliminate all gynecomastia cases, she noted.

At the University of Pennsylvania hospitals, men often start on spironolactone first because it retains a significant price advantage, even though eplerenone is now generic, but “if there is a hint of gynecomastia, we quickly switch to eplerenone, which is usually well tolerated,” she explained.

And while eplerenone has a reputation of being less effective than spironolactone, “I’ve prescribed a lot of eplerenone and have had good results,” Dr. Cohen said. “Even if the blood pressure lowering is not as great compared with spironolactone, it still blunts the toxic effects of aldosterone on target organs.”

Hyperkalemia is the other big concern about spironolactone and eplerenone. Both agents cause it at roughly the same rate, although the rate is lower in patients without chronic kidney disease.

A new, nonsteroidal MRA, finerenone, caused substantially less hyperkalemia in a recent phase 3 trial, FIDELIO-DKD, and as a nonsteroidal MRA, it does not cause gynecomastia. Finerenone has promise as a potentially safer option for treating PA and treatment-resistant hypertension, noted Cohen, but so far, no advanced clinical trials have been launched to examine its efficacy for these indications.
 

PA testing allows a surgical option

A third reason to test patients with treatment-resistant hypertension for PA is that jumping straight to MRA treatment denies the patient assessment for a unilateral adrenal adenoma as the cause of excess aldosterone.

When unilateral adenomas exist, patients are candidates for adrenalectomy. Despite the potential advantage this gives patients to eliminate the cause of their PA without the need for additional drug treatment, some clinicians don’t see this as a compelling rationale to test for PA because they have a bias against surgery or have seen too many cases in which surgery failed to produce full hypertension resolution.

“It’s all about setting expectations appropriately” for the impact of this surgery, Dr. Cohen said.

“Adrenalectomy is not a cure; it just gets rid of the source of excess aldosterone.” But in patients with long-standing PA and hypertension, this is often not enough to completely resolve entrenched cardiovascular pathology.
 

PCPs, cardiologists in rural locations least likely to order PA testing

Of the 269,010 patients analyzed by Dr. Cohen and her coauthors, the average age was 65 years; 96% were men; half were obese; and 40% had diabetes. The researchers excluded patients who had already been tested for PA, as well as those who were already receiving treatment with an MRA.

For 88% of the patients, the main physician overseeing care was a PCP. A cardiologist was the main physician for 10%; a nephrologist, for 1%; and an endocrinologist, for fewer than 1%.

The rate of testing for PA varied across the 130 VHA centers that contributed data, ranging from 0% to 6%. The testing data showed that endocrinologists were most likely to order PA testing, doing it 2.48-fold more often than PCPs. Nephrologists were roughly twice as likely to order PA testing than PCPs, and cardiologists ordered testing at about the same rate as PCPs.

Patients managed at VHA centers in rural locations were nearly half as likely to undergo testing as patients managed at nonrural centers. The number of patients with treatment-resistant hypertension seen by a physician or at a center had no significant relationship to PA testing frequency.

The study received no commercial funding. Dr. Cohen has disclosed no relevant financial relationships.

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

Millions of Americans with treatment-resistant hypertension are likely not being tested to determine whether their high blood pressure is driven by primary aldosteronism (PA), despite guidelines that call for such an approach, according to findings from the first reported large-scale, multicenter study of PA testing practices.

Researchers ran a retrospective review of PA testing among 269,010 patients who met the definition as having treatment-resistant hypertension and were managed at any one of 130 Veterans Health Administration (VHA) medical centers from 2000 to 2017.

The results showed that, despite the fact that primary aldosteronism is highly prevalent among patients with treatment-resistant hypertension, only 4,277 (1.6%) underwent assessment for PA during a median of 3.3 years’ follow-up after they first met the defining criteria, Jordana B. Cohen, MD, and her associates reported in a study published in Annals of Internal Medicine on December 28.

“Testing rates also did not change meaningfully over nearly 2 decades ... despite an increasing number of guidelines recommending testing for primary aldosteronism in this population,” including the most recent recommendations from the Endocrine Society, issued in 2016, noted Dr. Cohen, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia, and colleagues.

Most patients in the study (almost 90%) were seen by a primary care practitioner (PCP).

The small percentage of patients seen by a nephrologist or endocrinologist were more than twice as likely to be tested for PA than those seen by a PCP or cardiologist.

Those clinicians who did order a test for PA were much more likely to treat patients with the appropriate medication, a mineralocorticoid receptor antagonist (MRA). In addition, therapy was started sooner, the researchers found.

“Our results corroborate” earlier reports from smaller health systems and suggest that dramatic underuse of PA assessment “is an issue across the US,” Dr. Cohen said in an interview.

The VHA experience “is very representative of what we think goes on across U.S. practice” and contrasts with the VHA’s reputation for “doing a pretty good job managing hypertension” in general, she noted.
 

Missed diagnosis, missed treatment

Dr. Cohen believes a number of factors likely help drive the abysmally low rate of PA testing they observed in the VHA system. She believes rates of PA testing are low elsewhere as well.

First, optimal hypertension management “is often taken for granted” but is challenging in busy primary care practices, so many of patients likely fall through the cracks, she said.

Dr. Cohen cited efforts at her institution, as well as by the VHA system, to better employ electronic health records to flag patients with treatment-resistant hypertension – defined as patients whose systolic or diastolic blood pressure remains at or above 140/90 mm Hg on at least two successive measurements at least a month apart while the patient is undergoing treatment with three conventional antihypertensive drugs – and to guide clinicians to order the right tests and treatments for these patients.

Many care providers mistakenly “see treatment-resistant hypertension as a disease of noncompliance,” although it is much more often the result of a missed diagnosis and inadequate intervention, she explained.
 

Physicians in denial; side effects of MRAs may deter prescribing

A second big cause of low PA testing rates is that doctors make the mistake of thinking a PA test result won’t change how they manage these patients.

The established treatment for most patients with treatment-resistant hypertension as well as PA is adding an MRA, either spironolactone or eplerenone (Inspra).

Many providers cling to the belief that they will start an MRA in these patients without first determining their PA status, says Dr. Cohen, but the data she and her colleagues collected show the opposite.

Overall, about 13% of all patients in the study began treatment with an MRA during follow-up. The likelihood of starting treatment with this drug class was fourfold higher among the patients tested for PA compared with those who were not tested.

PA testing also hastened the start of MRA use by more than a year, compared with untested patients.

“Providers think they prescribe an MRA” to treatment-resistant patients, “but it’s part of their denial. They are not using the evidence-based treatments [spironolactone or eplerenone], perhaps because of concerns about MRA side effects, although those have been pretty well overcome during the past 20 years,” she observed.

Dr. Cohen says gynecomastia is one adverse effect that gives pause to VHA clinicians who see a heavily male patient population. “It’s probably the biggest concern and why PA testing and MRA use is low” in the VHA system, she said.

“You can use a lower dosage of spironolactone, and the incidence is less common with eplerenone,” although using eplerenone does not completely eliminate all gynecomastia cases, she noted.

At the University of Pennsylvania hospitals, men often start on spironolactone first because it retains a significant price advantage, even though eplerenone is now generic, but “if there is a hint of gynecomastia, we quickly switch to eplerenone, which is usually well tolerated,” she explained.

And while eplerenone has a reputation of being less effective than spironolactone, “I’ve prescribed a lot of eplerenone and have had good results,” Dr. Cohen said. “Even if the blood pressure lowering is not as great compared with spironolactone, it still blunts the toxic effects of aldosterone on target organs.”

Hyperkalemia is the other big concern about spironolactone and eplerenone. Both agents cause it at roughly the same rate, although the rate is lower in patients without chronic kidney disease.

A new, nonsteroidal MRA, finerenone, caused substantially less hyperkalemia in a recent phase 3 trial, FIDELIO-DKD, and as a nonsteroidal MRA, it does not cause gynecomastia. Finerenone has promise as a potentially safer option for treating PA and treatment-resistant hypertension, noted Cohen, but so far, no advanced clinical trials have been launched to examine its efficacy for these indications.
 

PA testing allows a surgical option

A third reason to test patients with treatment-resistant hypertension for PA is that jumping straight to MRA treatment denies the patient assessment for a unilateral adrenal adenoma as the cause of excess aldosterone.

When unilateral adenomas exist, patients are candidates for adrenalectomy. Despite the potential advantage this gives patients to eliminate the cause of their PA without the need for additional drug treatment, some clinicians don’t see this as a compelling rationale to test for PA because they have a bias against surgery or have seen too many cases in which surgery failed to produce full hypertension resolution.

“It’s all about setting expectations appropriately” for the impact of this surgery, Dr. Cohen said.

“Adrenalectomy is not a cure; it just gets rid of the source of excess aldosterone.” But in patients with long-standing PA and hypertension, this is often not enough to completely resolve entrenched cardiovascular pathology.
 

PCPs, cardiologists in rural locations least likely to order PA testing

Of the 269,010 patients analyzed by Dr. Cohen and her coauthors, the average age was 65 years; 96% were men; half were obese; and 40% had diabetes. The researchers excluded patients who had already been tested for PA, as well as those who were already receiving treatment with an MRA.

For 88% of the patients, the main physician overseeing care was a PCP. A cardiologist was the main physician for 10%; a nephrologist, for 1%; and an endocrinologist, for fewer than 1%.

The rate of testing for PA varied across the 130 VHA centers that contributed data, ranging from 0% to 6%. The testing data showed that endocrinologists were most likely to order PA testing, doing it 2.48-fold more often than PCPs. Nephrologists were roughly twice as likely to order PA testing than PCPs, and cardiologists ordered testing at about the same rate as PCPs.

Patients managed at VHA centers in rural locations were nearly half as likely to undergo testing as patients managed at nonrural centers. The number of patients with treatment-resistant hypertension seen by a physician or at a center had no significant relationship to PA testing frequency.

The study received no commercial funding. Dr. Cohen has disclosed no relevant financial relationships.

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

Millions of Americans with treatment-resistant hypertension are likely not being tested to determine whether their high blood pressure is driven by primary aldosteronism (PA), despite guidelines that call for such an approach, according to findings from the first reported large-scale, multicenter study of PA testing practices.

Researchers ran a retrospective review of PA testing among 269,010 patients who met the definition as having treatment-resistant hypertension and were managed at any one of 130 Veterans Health Administration (VHA) medical centers from 2000 to 2017.

The results showed that, despite the fact that primary aldosteronism is highly prevalent among patients with treatment-resistant hypertension, only 4,277 (1.6%) underwent assessment for PA during a median of 3.3 years’ follow-up after they first met the defining criteria, Jordana B. Cohen, MD, and her associates reported in a study published in Annals of Internal Medicine on December 28.

“Testing rates also did not change meaningfully over nearly 2 decades ... despite an increasing number of guidelines recommending testing for primary aldosteronism in this population,” including the most recent recommendations from the Endocrine Society, issued in 2016, noted Dr. Cohen, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia, and colleagues.

Most patients in the study (almost 90%) were seen by a primary care practitioner (PCP).

The small percentage of patients seen by a nephrologist or endocrinologist were more than twice as likely to be tested for PA than those seen by a PCP or cardiologist.

Those clinicians who did order a test for PA were much more likely to treat patients with the appropriate medication, a mineralocorticoid receptor antagonist (MRA). In addition, therapy was started sooner, the researchers found.

“Our results corroborate” earlier reports from smaller health systems and suggest that dramatic underuse of PA assessment “is an issue across the US,” Dr. Cohen said in an interview.

The VHA experience “is very representative of what we think goes on across U.S. practice” and contrasts with the VHA’s reputation for “doing a pretty good job managing hypertension” in general, she noted.
 

Missed diagnosis, missed treatment

Dr. Cohen believes a number of factors likely help drive the abysmally low rate of PA testing they observed in the VHA system. She believes rates of PA testing are low elsewhere as well.

First, optimal hypertension management “is often taken for granted” but is challenging in busy primary care practices, so many of patients likely fall through the cracks, she said.

Dr. Cohen cited efforts at her institution, as well as by the VHA system, to better employ electronic health records to flag patients with treatment-resistant hypertension – defined as patients whose systolic or diastolic blood pressure remains at or above 140/90 mm Hg on at least two successive measurements at least a month apart while the patient is undergoing treatment with three conventional antihypertensive drugs – and to guide clinicians to order the right tests and treatments for these patients.

Many care providers mistakenly “see treatment-resistant hypertension as a disease of noncompliance,” although it is much more often the result of a missed diagnosis and inadequate intervention, she explained.
 

Physicians in denial; side effects of MRAs may deter prescribing

A second big cause of low PA testing rates is that doctors make the mistake of thinking a PA test result won’t change how they manage these patients.

The established treatment for most patients with treatment-resistant hypertension as well as PA is adding an MRA, either spironolactone or eplerenone (Inspra).

Many providers cling to the belief that they will start an MRA in these patients without first determining their PA status, says Dr. Cohen, but the data she and her colleagues collected show the opposite.

Overall, about 13% of all patients in the study began treatment with an MRA during follow-up. The likelihood of starting treatment with this drug class was fourfold higher among the patients tested for PA compared with those who were not tested.

PA testing also hastened the start of MRA use by more than a year, compared with untested patients.

“Providers think they prescribe an MRA” to treatment-resistant patients, “but it’s part of their denial. They are not using the evidence-based treatments [spironolactone or eplerenone], perhaps because of concerns about MRA side effects, although those have been pretty well overcome during the past 20 years,” she observed.

Dr. Cohen says gynecomastia is one adverse effect that gives pause to VHA clinicians who see a heavily male patient population. “It’s probably the biggest concern and why PA testing and MRA use is low” in the VHA system, she said.

“You can use a lower dosage of spironolactone, and the incidence is less common with eplerenone,” although using eplerenone does not completely eliminate all gynecomastia cases, she noted.

At the University of Pennsylvania hospitals, men often start on spironolactone first because it retains a significant price advantage, even though eplerenone is now generic, but “if there is a hint of gynecomastia, we quickly switch to eplerenone, which is usually well tolerated,” she explained.

And while eplerenone has a reputation of being less effective than spironolactone, “I’ve prescribed a lot of eplerenone and have had good results,” Dr. Cohen said. “Even if the blood pressure lowering is not as great compared with spironolactone, it still blunts the toxic effects of aldosterone on target organs.”

Hyperkalemia is the other big concern about spironolactone and eplerenone. Both agents cause it at roughly the same rate, although the rate is lower in patients without chronic kidney disease.

A new, nonsteroidal MRA, finerenone, caused substantially less hyperkalemia in a recent phase 3 trial, FIDELIO-DKD, and as a nonsteroidal MRA, it does not cause gynecomastia. Finerenone has promise as a potentially safer option for treating PA and treatment-resistant hypertension, noted Cohen, but so far, no advanced clinical trials have been launched to examine its efficacy for these indications.
 

PA testing allows a surgical option

A third reason to test patients with treatment-resistant hypertension for PA is that jumping straight to MRA treatment denies the patient assessment for a unilateral adrenal adenoma as the cause of excess aldosterone.

When unilateral adenomas exist, patients are candidates for adrenalectomy. Despite the potential advantage this gives patients to eliminate the cause of their PA without the need for additional drug treatment, some clinicians don’t see this as a compelling rationale to test for PA because they have a bias against surgery or have seen too many cases in which surgery failed to produce full hypertension resolution.

“It’s all about setting expectations appropriately” for the impact of this surgery, Dr. Cohen said.

“Adrenalectomy is not a cure; it just gets rid of the source of excess aldosterone.” But in patients with long-standing PA and hypertension, this is often not enough to completely resolve entrenched cardiovascular pathology.
 

PCPs, cardiologists in rural locations least likely to order PA testing

Of the 269,010 patients analyzed by Dr. Cohen and her coauthors, the average age was 65 years; 96% were men; half were obese; and 40% had diabetes. The researchers excluded patients who had already been tested for PA, as well as those who were already receiving treatment with an MRA.

For 88% of the patients, the main physician overseeing care was a PCP. A cardiologist was the main physician for 10%; a nephrologist, for 1%; and an endocrinologist, for fewer than 1%.

The rate of testing for PA varied across the 130 VHA centers that contributed data, ranging from 0% to 6%. The testing data showed that endocrinologists were most likely to order PA testing, doing it 2.48-fold more often than PCPs. Nephrologists were roughly twice as likely to order PA testing than PCPs, and cardiologists ordered testing at about the same rate as PCPs.

Patients managed at VHA centers in rural locations were nearly half as likely to undergo testing as patients managed at nonrural centers. The number of patients with treatment-resistant hypertension seen by a physician or at a center had no significant relationship to PA testing frequency.

The study received no commercial funding. Dr. Cohen has disclosed no relevant financial relationships.

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

The U.S. Food and Drug Administration has approved the first-ever generic glucagon injection kit for the treatment of severe hypoglycemia in patients with diabetes and as a diagnostic aid.

The FDA determined that Amphastar’s Glucagon for Injection Emergency Kit, 1 mg, a synthetic peptide product, is bioequivalent and therapeutically equivalent to Eli Lilly’s recombinant DNA Glucagon Emergency Kit for Low Blood Sugar.

Both require a multistep mixing process that means they are complicated to use.

In 2019, FDA approved two branded, easier-to-use formulations of glucagon – one nasally administered (Baqsimi, Eli Lilly & Co) and the other a prefilled pen or syringe (Gvoke HypoPen and Gvoke PFS, respectively, Xeris Pharmaceuticals).

The new generic will have the advantage of lower cost, Amphastar spokesman Dan Dischner said in an interview.

“Our generic glucagon will be priced as a generic product so that patients will benefit from a lower price. As we are just at the beginning of the commercialization of the product, we are unable to discuss our specific product price,” he wrote.

As with the branded Lilly injectable glucagon, the new generic is also indicated as a diagnostic aid in gastrointestinal radiologic imaging, as glucagon slows gastric motility.

According to an FDA statement, glucagon is a “complex product” that has been difficult to manufacture generically despite the lifting of patent protection. This approval was the result of the FDA’s efforts to encourage the development and submission of applications for such drugs.

Amphastar specializes in “developing, manufacturing, marketing, and selling technically-challenging generic and proprietary injectable, inhalation, and intranasal products,” the company website says.

Mr. Dischner said, “Glucagon is a complex product that requires R&D and manufacturing capabilities to develop a highly purified synthetic peptide product bioequivalent and therapeutically equivalent to the recombinant DNA origin Glucagon. Given that this product has been through various review cycles, its complexity, and the technological capabilities required to manufacture, it is no surprise that there hasn’t been a generic of glucagon until now.”

Side effects of injected glucagon include nausea, vomiting, transient increase in heart rate, and redness/swelling of the injection site.

Mr. Dischner added, “We are confident that our generic to Lilly’s time-tested glucagon will provide a favorable option, at a reasonable price, to patients who rely on this product.”

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

The U.S. Food and Drug Administration has approved the first-ever generic glucagon injection kit for the treatment of severe hypoglycemia in patients with diabetes and as a diagnostic aid.

The FDA determined that Amphastar’s Glucagon for Injection Emergency Kit, 1 mg, a synthetic peptide product, is bioequivalent and therapeutically equivalent to Eli Lilly’s recombinant DNA Glucagon Emergency Kit for Low Blood Sugar.

Both require a multistep mixing process that means they are complicated to use.

In 2019, FDA approved two branded, easier-to-use formulations of glucagon – one nasally administered (Baqsimi, Eli Lilly & Co) and the other a prefilled pen or syringe (Gvoke HypoPen and Gvoke PFS, respectively, Xeris Pharmaceuticals).

The new generic will have the advantage of lower cost, Amphastar spokesman Dan Dischner said in an interview.

“Our generic glucagon will be priced as a generic product so that patients will benefit from a lower price. As we are just at the beginning of the commercialization of the product, we are unable to discuss our specific product price,” he wrote.

As with the branded Lilly injectable glucagon, the new generic is also indicated as a diagnostic aid in gastrointestinal radiologic imaging, as glucagon slows gastric motility.

According to an FDA statement, glucagon is a “complex product” that has been difficult to manufacture generically despite the lifting of patent protection. This approval was the result of the FDA’s efforts to encourage the development and submission of applications for such drugs.

Amphastar specializes in “developing, manufacturing, marketing, and selling technically-challenging generic and proprietary injectable, inhalation, and intranasal products,” the company website says.

Mr. Dischner said, “Glucagon is a complex product that requires R&D and manufacturing capabilities to develop a highly purified synthetic peptide product bioequivalent and therapeutically equivalent to the recombinant DNA origin Glucagon. Given that this product has been through various review cycles, its complexity, and the technological capabilities required to manufacture, it is no surprise that there hasn’t been a generic of glucagon until now.”

Side effects of injected glucagon include nausea, vomiting, transient increase in heart rate, and redness/swelling of the injection site.

Mr. Dischner added, “We are confident that our generic to Lilly’s time-tested glucagon will provide a favorable option, at a reasonable price, to patients who rely on this product.”

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

The U.S. Food and Drug Administration has approved the first-ever generic glucagon injection kit for the treatment of severe hypoglycemia in patients with diabetes and as a diagnostic aid.

The FDA determined that Amphastar’s Glucagon for Injection Emergency Kit, 1 mg, a synthetic peptide product, is bioequivalent and therapeutically equivalent to Eli Lilly’s recombinant DNA Glucagon Emergency Kit for Low Blood Sugar.

Both require a multistep mixing process that means they are complicated to use.

In 2019, FDA approved two branded, easier-to-use formulations of glucagon – one nasally administered (Baqsimi, Eli Lilly & Co) and the other a prefilled pen or syringe (Gvoke HypoPen and Gvoke PFS, respectively, Xeris Pharmaceuticals).

The new generic will have the advantage of lower cost, Amphastar spokesman Dan Dischner said in an interview.

“Our generic glucagon will be priced as a generic product so that patients will benefit from a lower price. As we are just at the beginning of the commercialization of the product, we are unable to discuss our specific product price,” he wrote.

As with the branded Lilly injectable glucagon, the new generic is also indicated as a diagnostic aid in gastrointestinal radiologic imaging, as glucagon slows gastric motility.

According to an FDA statement, glucagon is a “complex product” that has been difficult to manufacture generically despite the lifting of patent protection. This approval was the result of the FDA’s efforts to encourage the development and submission of applications for such drugs.

Amphastar specializes in “developing, manufacturing, marketing, and selling technically-challenging generic and proprietary injectable, inhalation, and intranasal products,” the company website says.

Mr. Dischner said, “Glucagon is a complex product that requires R&D and manufacturing capabilities to develop a highly purified synthetic peptide product bioequivalent and therapeutically equivalent to the recombinant DNA origin Glucagon. Given that this product has been through various review cycles, its complexity, and the technological capabilities required to manufacture, it is no surprise that there hasn’t been a generic of glucagon until now.”

Side effects of injected glucagon include nausea, vomiting, transient increase in heart rate, and redness/swelling of the injection site.

Mr. Dischner added, “We are confident that our generic to Lilly’s time-tested glucagon will provide a favorable option, at a reasonable price, to patients who rely on this product.”

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

Women treated with oral bisphosphonate drugs for osteoporosis for 5 years get no additional benefit – in terms of hip fracture risk – if the treatment is extended for another 5 years, new research shows.

Raycat/Getty Images

“We found that hip fracture risk in women did not differ if women stopped bisphosphonate use after 5 years or stayed on the medication for 10 years,” coauthor Joan C. Lo, MD, Kaiser Permanente Northern California, Oakland, said in an interview.

The new study, published Dec. 7 in JAMA Network Open, did show a small benefit in continuing the treatment through 7 years vs. 5 years, but it wasn’t clear if this was significant.

“Whether there is a benefit to staying on the drug for 7 years needs to be further studied in randomized trials,” Dr. Lo stressed.

It is well established that oral bisphosphonates are effective in reducing the risk for fracture within the first 3-5 years of treatment; however, evidence on the effects of treatment beyond 5 years is lacking.

The most recent guidance from the American Society of Bone and Mineral Research (ASBMR) on the issue, which were released in 2015, recommends continuation of bisphosphonates beyond 5 years for high-risk patients, but it recommends a “drug holiday” for low-risk patients.
 

Study adds important new evidence

However, that guidance acknowledges that data are limited regarding long-term use. This large new study adds important new evidence to the discussion, Robert A. Adler, MD, who was a member of the ASBMR Task Force for the recent guidance, said in an interview.

“[With the lack of recent research,] this new study from Kaiser Permanente is of great interest,” said Dr. Adler, chief of endocrinology and metabolism at Central Virginia Veterans Affairs Health Care System and professor of internal medicine and of epidemiology at Virginia Commonwealth University, Richmond.

“It is new data and suggests we might temper our enthusiasm for long-term treatment with bisphosphonates,” he said.

“Importantly, it is the first large observational trial and is closer to a real-world setting than a randomized controlled trial,” he said.

But, Dr. Adler emphasized: “The take-home message is that while this suggests that patients can probably be given a drug holiday for a couple of years ... they should be retested, and if they appear to be at an increased risk of fracture, they probably should restart again.

“Osteoporosis is a chronic disorder,” he emphasized. “It isn’t cured by any of our treatments, and as people get older, they are at a higher fracture risk.

“So we really need to follow our patients for a lifetime and reassess their fracture risk every couple of years – whether they are still on therapy or on a drug holiday.”
 

Possible that 7 years is better than 5 but remains to be proven

The new study involved data from Kaiser Permanente Northern and Southern California on 29,685 women who had completed 5 years of treatment with oral bisphosphonates, including alendronate, risedronate, or ibandronate, between 2002 and 2014.

Among the women, 11,105 (37%) continued taking the drugs beyond 5 years to 7 years, and 2,725 (9.2%) completed a total of 10 years of treatment.

Their median age was 71. Among those for whom bone mineral density data were available, 37% had osteoporosis after the first 5 years of treatment.

During these 5 years of treatment, 507 hip fractures occurred.

The cumulative incidence of hip fracture among for those who discontinued study therapy at entry, i.e., those who underwent treatment for 5 years, was 23.0 per 1,000 individuals.

After 7 years of treatment, the rate was 20.8 per 1000. For those who continued therapy for 10 years, the rate was 26.8 per 1000 individuals.

The rate in the 7-year treatment group was based on patients taking a 6-month drug holiday after the initial 5 years, but the results are hard to interpret, Dr. Lo said.

“It’s possible that 7 years is better than 5, but this is not a randomized trial, and some of the data analyses done in the study suggest more research should be done to look at a benefit after 7 years.

“At the end of the day, doctors and women need to decide at 5 years what an individual woman’s risk fracture risk is and determine if she should stay on the drug longer,” Dr. Lo emphasized.
 

Limitations: Subgroups not identified, adherence hard to assess

The uncertainty of any benefit of treatment with bisphosphonates beyond 5 years is further reflected in U.S. recommendations – the Food and Drug Administration has concluded on the basis of pooled data from the extension phase of major clinical trials that any advantages of treatment beyond 3-5 years are unclear.

Key limitations of the current study include the fact that the incidence of hip fracture was not evaluated in low-risk vs. high-risk subgroups; therefore, “these findings may not be applicable to older women at higher risk of osteoporotic fracture,” the authors wrote.

Furthermore, the study did not assess outcomes of fractures other than hip fractures, such as vertebral fractures, they noted.

Dr. Adler pointed out that another limitation is that adherence in the trial was defined as taking 60% of prescribed pills.

“I think this is the biggest weakness with the study,” he said. “Particularly with medications like oral bisphosphonates that don’t really make patients feel any different, it’s a real challenge to make sure patients continue to take these drugs properly.”

The findings should give some reassurance for patients who take a break from the drugs after 5 years. However, reassessment of their risk is critical, Dr. Adler reiterated.

The study was supported by a grant from the National Institute on Aging and the National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the National Institutes of Health. The authors and Adler have disclosed no relevant financial relationships.

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

Women treated with oral bisphosphonate drugs for osteoporosis for 5 years get no additional benefit – in terms of hip fracture risk – if the treatment is extended for another 5 years, new research shows.

Raycat/Getty Images

“We found that hip fracture risk in women did not differ if women stopped bisphosphonate use after 5 years or stayed on the medication for 10 years,” coauthor Joan C. Lo, MD, Kaiser Permanente Northern California, Oakland, said in an interview.

The new study, published Dec. 7 in JAMA Network Open, did show a small benefit in continuing the treatment through 7 years vs. 5 years, but it wasn’t clear if this was significant.

“Whether there is a benefit to staying on the drug for 7 years needs to be further studied in randomized trials,” Dr. Lo stressed.

It is well established that oral bisphosphonates are effective in reducing the risk for fracture within the first 3-5 years of treatment; however, evidence on the effects of treatment beyond 5 years is lacking.

The most recent guidance from the American Society of Bone and Mineral Research (ASBMR) on the issue, which were released in 2015, recommends continuation of bisphosphonates beyond 5 years for high-risk patients, but it recommends a “drug holiday” for low-risk patients.
 

Study adds important new evidence

However, that guidance acknowledges that data are limited regarding long-term use. This large new study adds important new evidence to the discussion, Robert A. Adler, MD, who was a member of the ASBMR Task Force for the recent guidance, said in an interview.

“[With the lack of recent research,] this new study from Kaiser Permanente is of great interest,” said Dr. Adler, chief of endocrinology and metabolism at Central Virginia Veterans Affairs Health Care System and professor of internal medicine and of epidemiology at Virginia Commonwealth University, Richmond.

“It is new data and suggests we might temper our enthusiasm for long-term treatment with bisphosphonates,” he said.

“Importantly, it is the first large observational trial and is closer to a real-world setting than a randomized controlled trial,” he said.

But, Dr. Adler emphasized: “The take-home message is that while this suggests that patients can probably be given a drug holiday for a couple of years ... they should be retested, and if they appear to be at an increased risk of fracture, they probably should restart again.

“Osteoporosis is a chronic disorder,” he emphasized. “It isn’t cured by any of our treatments, and as people get older, they are at a higher fracture risk.

“So we really need to follow our patients for a lifetime and reassess their fracture risk every couple of years – whether they are still on therapy or on a drug holiday.”
 

Possible that 7 years is better than 5 but remains to be proven

The new study involved data from Kaiser Permanente Northern and Southern California on 29,685 women who had completed 5 years of treatment with oral bisphosphonates, including alendronate, risedronate, or ibandronate, between 2002 and 2014.

Among the women, 11,105 (37%) continued taking the drugs beyond 5 years to 7 years, and 2,725 (9.2%) completed a total of 10 years of treatment.

Their median age was 71. Among those for whom bone mineral density data were available, 37% had osteoporosis after the first 5 years of treatment.

During these 5 years of treatment, 507 hip fractures occurred.

The cumulative incidence of hip fracture among for those who discontinued study therapy at entry, i.e., those who underwent treatment for 5 years, was 23.0 per 1,000 individuals.

After 7 years of treatment, the rate was 20.8 per 1000. For those who continued therapy for 10 years, the rate was 26.8 per 1000 individuals.

The rate in the 7-year treatment group was based on patients taking a 6-month drug holiday after the initial 5 years, but the results are hard to interpret, Dr. Lo said.

“It’s possible that 7 years is better than 5, but this is not a randomized trial, and some of the data analyses done in the study suggest more research should be done to look at a benefit after 7 years.

“At the end of the day, doctors and women need to decide at 5 years what an individual woman’s risk fracture risk is and determine if she should stay on the drug longer,” Dr. Lo emphasized.
 

Limitations: Subgroups not identified, adherence hard to assess

The uncertainty of any benefit of treatment with bisphosphonates beyond 5 years is further reflected in U.S. recommendations – the Food and Drug Administration has concluded on the basis of pooled data from the extension phase of major clinical trials that any advantages of treatment beyond 3-5 years are unclear.

Key limitations of the current study include the fact that the incidence of hip fracture was not evaluated in low-risk vs. high-risk subgroups; therefore, “these findings may not be applicable to older women at higher risk of osteoporotic fracture,” the authors wrote.

Furthermore, the study did not assess outcomes of fractures other than hip fractures, such as vertebral fractures, they noted.

Dr. Adler pointed out that another limitation is that adherence in the trial was defined as taking 60% of prescribed pills.

“I think this is the biggest weakness with the study,” he said. “Particularly with medications like oral bisphosphonates that don’t really make patients feel any different, it’s a real challenge to make sure patients continue to take these drugs properly.”

The findings should give some reassurance for patients who take a break from the drugs after 5 years. However, reassessment of their risk is critical, Dr. Adler reiterated.

The study was supported by a grant from the National Institute on Aging and the National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the National Institutes of Health. The authors and Adler have disclosed no relevant financial relationships.

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

Women treated with oral bisphosphonate drugs for osteoporosis for 5 years get no additional benefit – in terms of hip fracture risk – if the treatment is extended for another 5 years, new research shows.

Raycat/Getty Images

“We found that hip fracture risk in women did not differ if women stopped bisphosphonate use after 5 years or stayed on the medication for 10 years,” coauthor Joan C. Lo, MD, Kaiser Permanente Northern California, Oakland, said in an interview.

The new study, published Dec. 7 in JAMA Network Open, did show a small benefit in continuing the treatment through 7 years vs. 5 years, but it wasn’t clear if this was significant.

“Whether there is a benefit to staying on the drug for 7 years needs to be further studied in randomized trials,” Dr. Lo stressed.

It is well established that oral bisphosphonates are effective in reducing the risk for fracture within the first 3-5 years of treatment; however, evidence on the effects of treatment beyond 5 years is lacking.

The most recent guidance from the American Society of Bone and Mineral Research (ASBMR) on the issue, which were released in 2015, recommends continuation of bisphosphonates beyond 5 years for high-risk patients, but it recommends a “drug holiday” for low-risk patients.
 

Study adds important new evidence

However, that guidance acknowledges that data are limited regarding long-term use. This large new study adds important new evidence to the discussion, Robert A. Adler, MD, who was a member of the ASBMR Task Force for the recent guidance, said in an interview.

“[With the lack of recent research,] this new study from Kaiser Permanente is of great interest,” said Dr. Adler, chief of endocrinology and metabolism at Central Virginia Veterans Affairs Health Care System and professor of internal medicine and of epidemiology at Virginia Commonwealth University, Richmond.

“It is new data and suggests we might temper our enthusiasm for long-term treatment with bisphosphonates,” he said.

“Importantly, it is the first large observational trial and is closer to a real-world setting than a randomized controlled trial,” he said.

But, Dr. Adler emphasized: “The take-home message is that while this suggests that patients can probably be given a drug holiday for a couple of years ... they should be retested, and if they appear to be at an increased risk of fracture, they probably should restart again.

“Osteoporosis is a chronic disorder,” he emphasized. “It isn’t cured by any of our treatments, and as people get older, they are at a higher fracture risk.

“So we really need to follow our patients for a lifetime and reassess their fracture risk every couple of years – whether they are still on therapy or on a drug holiday.”
 

Possible that 7 years is better than 5 but remains to be proven

The new study involved data from Kaiser Permanente Northern and Southern California on 29,685 women who had completed 5 years of treatment with oral bisphosphonates, including alendronate, risedronate, or ibandronate, between 2002 and 2014.

Among the women, 11,105 (37%) continued taking the drugs beyond 5 years to 7 years, and 2,725 (9.2%) completed a total of 10 years of treatment.

Their median age was 71. Among those for whom bone mineral density data were available, 37% had osteoporosis after the first 5 years of treatment.

During these 5 years of treatment, 507 hip fractures occurred.

The cumulative incidence of hip fracture among for those who discontinued study therapy at entry, i.e., those who underwent treatment for 5 years, was 23.0 per 1,000 individuals.

After 7 years of treatment, the rate was 20.8 per 1000. For those who continued therapy for 10 years, the rate was 26.8 per 1000 individuals.

The rate in the 7-year treatment group was based on patients taking a 6-month drug holiday after the initial 5 years, but the results are hard to interpret, Dr. Lo said.

“It’s possible that 7 years is better than 5, but this is not a randomized trial, and some of the data analyses done in the study suggest more research should be done to look at a benefit after 7 years.

“At the end of the day, doctors and women need to decide at 5 years what an individual woman’s risk fracture risk is and determine if she should stay on the drug longer,” Dr. Lo emphasized.
 

Limitations: Subgroups not identified, adherence hard to assess

The uncertainty of any benefit of treatment with bisphosphonates beyond 5 years is further reflected in U.S. recommendations – the Food and Drug Administration has concluded on the basis of pooled data from the extension phase of major clinical trials that any advantages of treatment beyond 3-5 years are unclear.

Key limitations of the current study include the fact that the incidence of hip fracture was not evaluated in low-risk vs. high-risk subgroups; therefore, “these findings may not be applicable to older women at higher risk of osteoporotic fracture,” the authors wrote.

Furthermore, the study did not assess outcomes of fractures other than hip fractures, such as vertebral fractures, they noted.

Dr. Adler pointed out that another limitation is that adherence in the trial was defined as taking 60% of prescribed pills.

“I think this is the biggest weakness with the study,” he said. “Particularly with medications like oral bisphosphonates that don’t really make patients feel any different, it’s a real challenge to make sure patients continue to take these drugs properly.”

The findings should give some reassurance for patients who take a break from the drugs after 5 years. However, reassessment of their risk is critical, Dr. Adler reiterated.

The study was supported by a grant from the National Institute on Aging and the National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the National Institutes of Health. The authors and Adler have disclosed no relevant financial relationships.

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