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Surveillance for measles is a victim of the COVID pandemic
Although the estimated annual number of measles deaths decreased 94% from 2000 to 2020, the COVID-19 pandemic took a toll on both measles vaccination and surveillance, according to a recent report in Morbidity and Mortality Weekly Report.
The number of World Health Organization member states that achieved more than 90% coverage with the first dose of the measles vaccine (MCV1) declined 37% from 2019 to 2020. In 2020, 23 million infants did not receive MCV1 through routine immunization services, and another 93 million were affected by the postponement of mass immunizations or supplementary immunization activities because of the pandemic. Also, endemic transmission was reestablished in nine countries that had previously eliminated measles.
But perhaps the most overlooked aspect of COVID-19 is its effect on surveillance.
“The entire COVID pandemic really put a lot of strain on the surveillance systems, not only for measles but for all vaccine-preventable disease, because there’s a lot of overlap in the staff who work for surveillance,” said Katrina Kretsinger, MD, a medical epidemiologist at the Centers for Disease Control and Prevention, who contributed to the MMWR report.
Because of the stress on the systems, a lot fewer specimens were tested, she said in an interview. And it’s not just measles that is at risk. This has had an impact on the Global Polio Eradication Initiative, which lost staff.
In addition, many vaccination campaigns “were postponed and curtailed throughout 2020,” Dr. Kretsinger said. The strengthening of surveillance systems – and immunization systems, more broadly – needs to be a priority.
“It’s not clear that the children who were missed during that year were subsequently caught up,” she explained. Having a “cohort of children who have missed measles vaccine creates the reservoir of susceptibility that will provide the nidus for the next big outbreak.”
Measles is the indicator disease. That could mean a resurgence of other vaccine-preventable diseases as well.
This report “was written by some of the world’s experts in measles, and it raises concerns about potential resurgence of measles,” said Walter Orenstein, MD, professor of medicine, epidemiology, global health, and pediatrics at Emory University, Atlanta. “Measles is sort of a canary in the coal mine. If you look at vaccine-preventable diseases, measles is probably the most contagious, so the herd-immunity threshold is highest. Usually on the order of 92%-94% immunity is needed to stop transmission.”
“Measles is the indicator disease,” he said in an interview. “That could mean a resurgence of other vaccine-preventable diseases as well.” Outbreaks don’t just affect the countries where infections are occurring, they “also affect our own domestic health security.”
“Some sort of periodic intensified routine immunization” would be helpful, said Dr. Kretsinger, who recommends “going through and selectively doing some sort of intensified efforts to catch children up early for the entire range of vaccines that they may have missed.”
“Some of these capture campaigns in areas that are thought to have the major problem would be very, very important,” agreed Dr. Orenstein. “A school entry check is one way of trying to look at kids, let’s say at 4-6 years of age, in schools around the world,” offering doses if they’re unvaccinated or inadequately vaccinated. “Another is to try to improve surveillance and try to understand if the cases are vaccine failure or failure to vaccinate.”
“Where the health systems are the most fragile is where those gaps will be the last to be filled, if they are at all, and where we have the basic concerns,” Dr. Kretsinger explained.
“Years ago, WHO recognized that vaccine hesitancy is a top global health threat,” said Dr. Orenstein. “People may not see these diseases so they don’t mean much to them. Since vaccines, we’re victims of our own success.” There’s also a lot of incorrect information circulating.
“We need to realize – and it’s been shown with COVID – that a decision not to vaccinate is not just a decision for your own child. It’s a community decision,” he pointed out. “It’s not my freedom to drive drunk, because not only do I put myself at risk, but others can’t control the car. We have speed limits and other examples where we restrict personal choice because it can adversely affect individuals.”
“My favorite line is vaccines don’t save lives, vaccinations save lives,” Dr. Orenstein said. “The vaccine dose that remains in the vial is 0% effective, no matter what the clinical trials show. And the issue, I think, is that we need to determine how to convince the hesitant to get confident enough to accept vaccination. For that, there is behavioral research; there’s a whole bunch of things that need to be supported. Just purchasing the vaccine doesn’t get it into the bodies.”
Dr. Kretsinger and Dr. Orenstein disclosed no relevant financial relationships .
A version of this article first appeared on Medscape.com.
Although the estimated annual number of measles deaths decreased 94% from 2000 to 2020, the COVID-19 pandemic took a toll on both measles vaccination and surveillance, according to a recent report in Morbidity and Mortality Weekly Report.
The number of World Health Organization member states that achieved more than 90% coverage with the first dose of the measles vaccine (MCV1) declined 37% from 2019 to 2020. In 2020, 23 million infants did not receive MCV1 through routine immunization services, and another 93 million were affected by the postponement of mass immunizations or supplementary immunization activities because of the pandemic. Also, endemic transmission was reestablished in nine countries that had previously eliminated measles.
But perhaps the most overlooked aspect of COVID-19 is its effect on surveillance.
“The entire COVID pandemic really put a lot of strain on the surveillance systems, not only for measles but for all vaccine-preventable disease, because there’s a lot of overlap in the staff who work for surveillance,” said Katrina Kretsinger, MD, a medical epidemiologist at the Centers for Disease Control and Prevention, who contributed to the MMWR report.
Because of the stress on the systems, a lot fewer specimens were tested, she said in an interview. And it’s not just measles that is at risk. This has had an impact on the Global Polio Eradication Initiative, which lost staff.
In addition, many vaccination campaigns “were postponed and curtailed throughout 2020,” Dr. Kretsinger said. The strengthening of surveillance systems – and immunization systems, more broadly – needs to be a priority.
“It’s not clear that the children who were missed during that year were subsequently caught up,” she explained. Having a “cohort of children who have missed measles vaccine creates the reservoir of susceptibility that will provide the nidus for the next big outbreak.”
Measles is the indicator disease. That could mean a resurgence of other vaccine-preventable diseases as well.
This report “was written by some of the world’s experts in measles, and it raises concerns about potential resurgence of measles,” said Walter Orenstein, MD, professor of medicine, epidemiology, global health, and pediatrics at Emory University, Atlanta. “Measles is sort of a canary in the coal mine. If you look at vaccine-preventable diseases, measles is probably the most contagious, so the herd-immunity threshold is highest. Usually on the order of 92%-94% immunity is needed to stop transmission.”
“Measles is the indicator disease,” he said in an interview. “That could mean a resurgence of other vaccine-preventable diseases as well.” Outbreaks don’t just affect the countries where infections are occurring, they “also affect our own domestic health security.”
“Some sort of periodic intensified routine immunization” would be helpful, said Dr. Kretsinger, who recommends “going through and selectively doing some sort of intensified efforts to catch children up early for the entire range of vaccines that they may have missed.”
“Some of these capture campaigns in areas that are thought to have the major problem would be very, very important,” agreed Dr. Orenstein. “A school entry check is one way of trying to look at kids, let’s say at 4-6 years of age, in schools around the world,” offering doses if they’re unvaccinated or inadequately vaccinated. “Another is to try to improve surveillance and try to understand if the cases are vaccine failure or failure to vaccinate.”
“Where the health systems are the most fragile is where those gaps will be the last to be filled, if they are at all, and where we have the basic concerns,” Dr. Kretsinger explained.
“Years ago, WHO recognized that vaccine hesitancy is a top global health threat,” said Dr. Orenstein. “People may not see these diseases so they don’t mean much to them. Since vaccines, we’re victims of our own success.” There’s also a lot of incorrect information circulating.
“We need to realize – and it’s been shown with COVID – that a decision not to vaccinate is not just a decision for your own child. It’s a community decision,” he pointed out. “It’s not my freedom to drive drunk, because not only do I put myself at risk, but others can’t control the car. We have speed limits and other examples where we restrict personal choice because it can adversely affect individuals.”
“My favorite line is vaccines don’t save lives, vaccinations save lives,” Dr. Orenstein said. “The vaccine dose that remains in the vial is 0% effective, no matter what the clinical trials show. And the issue, I think, is that we need to determine how to convince the hesitant to get confident enough to accept vaccination. For that, there is behavioral research; there’s a whole bunch of things that need to be supported. Just purchasing the vaccine doesn’t get it into the bodies.”
Dr. Kretsinger and Dr. Orenstein disclosed no relevant financial relationships .
A version of this article first appeared on Medscape.com.
Although the estimated annual number of measles deaths decreased 94% from 2000 to 2020, the COVID-19 pandemic took a toll on both measles vaccination and surveillance, according to a recent report in Morbidity and Mortality Weekly Report.
The number of World Health Organization member states that achieved more than 90% coverage with the first dose of the measles vaccine (MCV1) declined 37% from 2019 to 2020. In 2020, 23 million infants did not receive MCV1 through routine immunization services, and another 93 million were affected by the postponement of mass immunizations or supplementary immunization activities because of the pandemic. Also, endemic transmission was reestablished in nine countries that had previously eliminated measles.
But perhaps the most overlooked aspect of COVID-19 is its effect on surveillance.
“The entire COVID pandemic really put a lot of strain on the surveillance systems, not only for measles but for all vaccine-preventable disease, because there’s a lot of overlap in the staff who work for surveillance,” said Katrina Kretsinger, MD, a medical epidemiologist at the Centers for Disease Control and Prevention, who contributed to the MMWR report.
Because of the stress on the systems, a lot fewer specimens were tested, she said in an interview. And it’s not just measles that is at risk. This has had an impact on the Global Polio Eradication Initiative, which lost staff.
In addition, many vaccination campaigns “were postponed and curtailed throughout 2020,” Dr. Kretsinger said. The strengthening of surveillance systems – and immunization systems, more broadly – needs to be a priority.
“It’s not clear that the children who were missed during that year were subsequently caught up,” she explained. Having a “cohort of children who have missed measles vaccine creates the reservoir of susceptibility that will provide the nidus for the next big outbreak.”
Measles is the indicator disease. That could mean a resurgence of other vaccine-preventable diseases as well.
This report “was written by some of the world’s experts in measles, and it raises concerns about potential resurgence of measles,” said Walter Orenstein, MD, professor of medicine, epidemiology, global health, and pediatrics at Emory University, Atlanta. “Measles is sort of a canary in the coal mine. If you look at vaccine-preventable diseases, measles is probably the most contagious, so the herd-immunity threshold is highest. Usually on the order of 92%-94% immunity is needed to stop transmission.”
“Measles is the indicator disease,” he said in an interview. “That could mean a resurgence of other vaccine-preventable diseases as well.” Outbreaks don’t just affect the countries where infections are occurring, they “also affect our own domestic health security.”
“Some sort of periodic intensified routine immunization” would be helpful, said Dr. Kretsinger, who recommends “going through and selectively doing some sort of intensified efforts to catch children up early for the entire range of vaccines that they may have missed.”
“Some of these capture campaigns in areas that are thought to have the major problem would be very, very important,” agreed Dr. Orenstein. “A school entry check is one way of trying to look at kids, let’s say at 4-6 years of age, in schools around the world,” offering doses if they’re unvaccinated or inadequately vaccinated. “Another is to try to improve surveillance and try to understand if the cases are vaccine failure or failure to vaccinate.”
“Where the health systems are the most fragile is where those gaps will be the last to be filled, if they are at all, and where we have the basic concerns,” Dr. Kretsinger explained.
“Years ago, WHO recognized that vaccine hesitancy is a top global health threat,” said Dr. Orenstein. “People may not see these diseases so they don’t mean much to them. Since vaccines, we’re victims of our own success.” There’s also a lot of incorrect information circulating.
“We need to realize – and it’s been shown with COVID – that a decision not to vaccinate is not just a decision for your own child. It’s a community decision,” he pointed out. “It’s not my freedom to drive drunk, because not only do I put myself at risk, but others can’t control the car. We have speed limits and other examples where we restrict personal choice because it can adversely affect individuals.”
“My favorite line is vaccines don’t save lives, vaccinations save lives,” Dr. Orenstein said. “The vaccine dose that remains in the vial is 0% effective, no matter what the clinical trials show. And the issue, I think, is that we need to determine how to convince the hesitant to get confident enough to accept vaccination. For that, there is behavioral research; there’s a whole bunch of things that need to be supported. Just purchasing the vaccine doesn’t get it into the bodies.”
Dr. Kretsinger and Dr. Orenstein disclosed no relevant financial relationships .
A version of this article first appeared on Medscape.com.
New trials in gynecologic cancers: Could your patient benefit?
A number of clinical trials in gynecologic cancers have opened in recent months. Maybe one of your patients could benefit from being enrolled.
Uterine precancer (endometrial intraepithelial neoplasia). A phase 2 study sponsored by the National Cancer Institute is seeking adults with endometrial intraepithelial neoplasia (also called complex atypical hyperplasia or atypical hyperplasia) who are scheduled for hysterectomy within 3 months. Researchers are using the window of opportunity before an already-scheduled hysterectomy to see whether adding metformin to megestrol acetate, a treatment standard for nonsurgical patients, increases the effectiveness of megestrol in slowing this type of neoplasia. Participants will receive twice-daily oral medication for 4 weeks then undergo hysterectomy. The trial aims to enroll 50 participants. It began recruiting on Sept. 21 at its Northwestern University site in Evanston, Ill.; sites in California, Colorado, and North Carolina are also planned. The primary outcome is the change in endometrial cell proliferation. Overall survival (OS) and quality of life (QoL) will not be measured. .
Maurie Markman, MD, president of medicine and science at Cancer Treatment Centers of America, who is not involved in this trial, was approached for comment. “This is an interesting study concept, and patients with endometrial atypical hyperplasia may certainly wish to consider participation,” Dr. Markman said. He noted the “limited sample size” of the study.
Advanced, recurrent or refractory ovarian, fallopian, and endometrial cancers overexpressing folate receptor (FR)–alpha. Patients with these types of cancers are eligible for a phase 1/2 study of a new-concept targeted therapy called ELU-001. The molecular structure of ELU001 – called a C’Dot drug conjugate – consists of a drug “payload” riding with an FR-alpha–targeting molecule. For the first 28 days of the study, patients will receive escalating intravenous doses of ELU001 to determine the highest tolerated dose of the drug. All participants will then receive the selected dose for up to 12 months until lesions disappear (complete response) or there is a 30% decrease in the sum of the tumors’ longest diameter (partial response). This “basket” study – a trial involving a “basket” of different cancers with one genetic target – is hosted by New Experimental Therapeutics of San Antonio, which started recruitment for 166 patients on Sept. 13. Neither OS nor QoL will be tracked. .
Dr. Markman commented: “There is considerable interest in examining antineoplastic agents directed to tumor antigens overexpressed in ovarian cancer.”
Locally recurrent, unresectable, or metastatic cervical or endometrial cancer positive for PD-L1. Adults with these types of cancers are invited to join another basket trial, this time testing MK-7684A, a new coformulation of pembrolizumab (Keytruda) and the investigational drug vibostolimab. Most participants will receive intravenous infusions of either MK-7684A, MK-7684A plus chemotherapy, or pembrolizumab alone every 3 weeks for up to 3 years. One group will be given MK-7684A every 3 weeks plus paclitaxel weekly. People with endometrial cancer will also take a daily capsule of lenvatinib (Lenvima). The primary outcomes are response rate and progression-free survival; OS and QoL are secondary outcomes. The study opened on Sept. 16 and hopes to recruit 480 participants in eight countries with several different cancers, including cervical and endometrial cancers. U.S. patients can join at the City of Hope National Medical Center, Duarte, Calif. .
Persistent or recurrent rare epithelial tumors of the ovary, fallopian tube, or peritoneum. Adults with these cancers are sought for a phase 2 trial comparing four targeted-therapy regimens. Participants will receive either ipatasertib plus paclitaxel (Taxol); cobimetinib (Cotellic); trastuzumab emtansine (Kadcyla); or atezolizumab (Tecentriq) plus bevacizumab (Avastin) for up to 5 years until disease progression or unacceptable toxicity. Ipatasertib and cobimetinib are oral medications; all the others are administered intravenously on schedules that vary from once every 3 weeks (atezolizumab, trastuzumab) to weekly infusions 3 weeks out of 4 (paclitaxel). The study opened on Oct. 7 and hopes to enroll 200 participants at sites in Arizona, California, Minnesota, Missouri, Texas, Virginia, and worldwide. OS will be tracked, QoL will not.
Dr. Markman commented: “This is an interesting early study of the potential efficacy of a novel AKT inhibitor [ipatasertib] in rare gynecologic cancers.”
Platinum-resistant or refractory high-grade serous ovarian cancer. Adult women whose high-grade serous ovarian cancer is platinum resistant or refractory and who do not have germline BRCA mutations are sought for a phase 3 study comparing alpelisib (Piqray) plus olaparib (Lynparza) to investigator’s choice of chemotherapy. Alpelisib is approved for breast cancer in combination with fulvestrant; olaparib is approved for advanced ovarian cancer in platinum-responsive patients and/or those with BRCA- or HRD-positive tumors, so this study could lead to labeling changes for these drugs. Participants will either take daily oral doses of alpelisib plus olaparib or receive intravenous chemo on the appropriate schedules for approximately 2 years. Progression-free survival is the primary outcome measure; OS and QoL are secondary outcomes. The trial opened on July 2 and hopes to recruit 358 individuals in Singapore, Australia, Europe, and the United States (Arizona, Illinois, and Texas). .
All trial information is from the National Institutes of Health U.S. National Library of Medicine (online at clinicaltrials.gov).
Dr. Markman is not involved with any of these trials. He is a regular contributor to Medscape Oncology. He has received income in an amount equal to or greater than $250 from Genentech, AstraZeneca Celgene, Clovis, Amgen.
A version of this article first appeared on Medscape.com.
A number of clinical trials in gynecologic cancers have opened in recent months. Maybe one of your patients could benefit from being enrolled.
Uterine precancer (endometrial intraepithelial neoplasia). A phase 2 study sponsored by the National Cancer Institute is seeking adults with endometrial intraepithelial neoplasia (also called complex atypical hyperplasia or atypical hyperplasia) who are scheduled for hysterectomy within 3 months. Researchers are using the window of opportunity before an already-scheduled hysterectomy to see whether adding metformin to megestrol acetate, a treatment standard for nonsurgical patients, increases the effectiveness of megestrol in slowing this type of neoplasia. Participants will receive twice-daily oral medication for 4 weeks then undergo hysterectomy. The trial aims to enroll 50 participants. It began recruiting on Sept. 21 at its Northwestern University site in Evanston, Ill.; sites in California, Colorado, and North Carolina are also planned. The primary outcome is the change in endometrial cell proliferation. Overall survival (OS) and quality of life (QoL) will not be measured. .
Maurie Markman, MD, president of medicine and science at Cancer Treatment Centers of America, who is not involved in this trial, was approached for comment. “This is an interesting study concept, and patients with endometrial atypical hyperplasia may certainly wish to consider participation,” Dr. Markman said. He noted the “limited sample size” of the study.
Advanced, recurrent or refractory ovarian, fallopian, and endometrial cancers overexpressing folate receptor (FR)–alpha. Patients with these types of cancers are eligible for a phase 1/2 study of a new-concept targeted therapy called ELU-001. The molecular structure of ELU001 – called a C’Dot drug conjugate – consists of a drug “payload” riding with an FR-alpha–targeting molecule. For the first 28 days of the study, patients will receive escalating intravenous doses of ELU001 to determine the highest tolerated dose of the drug. All participants will then receive the selected dose for up to 12 months until lesions disappear (complete response) or there is a 30% decrease in the sum of the tumors’ longest diameter (partial response). This “basket” study – a trial involving a “basket” of different cancers with one genetic target – is hosted by New Experimental Therapeutics of San Antonio, which started recruitment for 166 patients on Sept. 13. Neither OS nor QoL will be tracked. .
Dr. Markman commented: “There is considerable interest in examining antineoplastic agents directed to tumor antigens overexpressed in ovarian cancer.”
Locally recurrent, unresectable, or metastatic cervical or endometrial cancer positive for PD-L1. Adults with these types of cancers are invited to join another basket trial, this time testing MK-7684A, a new coformulation of pembrolizumab (Keytruda) and the investigational drug vibostolimab. Most participants will receive intravenous infusions of either MK-7684A, MK-7684A plus chemotherapy, or pembrolizumab alone every 3 weeks for up to 3 years. One group will be given MK-7684A every 3 weeks plus paclitaxel weekly. People with endometrial cancer will also take a daily capsule of lenvatinib (Lenvima). The primary outcomes are response rate and progression-free survival; OS and QoL are secondary outcomes. The study opened on Sept. 16 and hopes to recruit 480 participants in eight countries with several different cancers, including cervical and endometrial cancers. U.S. patients can join at the City of Hope National Medical Center, Duarte, Calif. .
Persistent or recurrent rare epithelial tumors of the ovary, fallopian tube, or peritoneum. Adults with these cancers are sought for a phase 2 trial comparing four targeted-therapy regimens. Participants will receive either ipatasertib plus paclitaxel (Taxol); cobimetinib (Cotellic); trastuzumab emtansine (Kadcyla); or atezolizumab (Tecentriq) plus bevacizumab (Avastin) for up to 5 years until disease progression or unacceptable toxicity. Ipatasertib and cobimetinib are oral medications; all the others are administered intravenously on schedules that vary from once every 3 weeks (atezolizumab, trastuzumab) to weekly infusions 3 weeks out of 4 (paclitaxel). The study opened on Oct. 7 and hopes to enroll 200 participants at sites in Arizona, California, Minnesota, Missouri, Texas, Virginia, and worldwide. OS will be tracked, QoL will not.
Dr. Markman commented: “This is an interesting early study of the potential efficacy of a novel AKT inhibitor [ipatasertib] in rare gynecologic cancers.”
Platinum-resistant or refractory high-grade serous ovarian cancer. Adult women whose high-grade serous ovarian cancer is platinum resistant or refractory and who do not have germline BRCA mutations are sought for a phase 3 study comparing alpelisib (Piqray) plus olaparib (Lynparza) to investigator’s choice of chemotherapy. Alpelisib is approved for breast cancer in combination with fulvestrant; olaparib is approved for advanced ovarian cancer in platinum-responsive patients and/or those with BRCA- or HRD-positive tumors, so this study could lead to labeling changes for these drugs. Participants will either take daily oral doses of alpelisib plus olaparib or receive intravenous chemo on the appropriate schedules for approximately 2 years. Progression-free survival is the primary outcome measure; OS and QoL are secondary outcomes. The trial opened on July 2 and hopes to recruit 358 individuals in Singapore, Australia, Europe, and the United States (Arizona, Illinois, and Texas). .
All trial information is from the National Institutes of Health U.S. National Library of Medicine (online at clinicaltrials.gov).
Dr. Markman is not involved with any of these trials. He is a regular contributor to Medscape Oncology. He has received income in an amount equal to or greater than $250 from Genentech, AstraZeneca Celgene, Clovis, Amgen.
A version of this article first appeared on Medscape.com.
A number of clinical trials in gynecologic cancers have opened in recent months. Maybe one of your patients could benefit from being enrolled.
Uterine precancer (endometrial intraepithelial neoplasia). A phase 2 study sponsored by the National Cancer Institute is seeking adults with endometrial intraepithelial neoplasia (also called complex atypical hyperplasia or atypical hyperplasia) who are scheduled for hysterectomy within 3 months. Researchers are using the window of opportunity before an already-scheduled hysterectomy to see whether adding metformin to megestrol acetate, a treatment standard for nonsurgical patients, increases the effectiveness of megestrol in slowing this type of neoplasia. Participants will receive twice-daily oral medication for 4 weeks then undergo hysterectomy. The trial aims to enroll 50 participants. It began recruiting on Sept. 21 at its Northwestern University site in Evanston, Ill.; sites in California, Colorado, and North Carolina are also planned. The primary outcome is the change in endometrial cell proliferation. Overall survival (OS) and quality of life (QoL) will not be measured. .
Maurie Markman, MD, president of medicine and science at Cancer Treatment Centers of America, who is not involved in this trial, was approached for comment. “This is an interesting study concept, and patients with endometrial atypical hyperplasia may certainly wish to consider participation,” Dr. Markman said. He noted the “limited sample size” of the study.
Advanced, recurrent or refractory ovarian, fallopian, and endometrial cancers overexpressing folate receptor (FR)–alpha. Patients with these types of cancers are eligible for a phase 1/2 study of a new-concept targeted therapy called ELU-001. The molecular structure of ELU001 – called a C’Dot drug conjugate – consists of a drug “payload” riding with an FR-alpha–targeting molecule. For the first 28 days of the study, patients will receive escalating intravenous doses of ELU001 to determine the highest tolerated dose of the drug. All participants will then receive the selected dose for up to 12 months until lesions disappear (complete response) or there is a 30% decrease in the sum of the tumors’ longest diameter (partial response). This “basket” study – a trial involving a “basket” of different cancers with one genetic target – is hosted by New Experimental Therapeutics of San Antonio, which started recruitment for 166 patients on Sept. 13. Neither OS nor QoL will be tracked. .
Dr. Markman commented: “There is considerable interest in examining antineoplastic agents directed to tumor antigens overexpressed in ovarian cancer.”
Locally recurrent, unresectable, or metastatic cervical or endometrial cancer positive for PD-L1. Adults with these types of cancers are invited to join another basket trial, this time testing MK-7684A, a new coformulation of pembrolizumab (Keytruda) and the investigational drug vibostolimab. Most participants will receive intravenous infusions of either MK-7684A, MK-7684A plus chemotherapy, or pembrolizumab alone every 3 weeks for up to 3 years. One group will be given MK-7684A every 3 weeks plus paclitaxel weekly. People with endometrial cancer will also take a daily capsule of lenvatinib (Lenvima). The primary outcomes are response rate and progression-free survival; OS and QoL are secondary outcomes. The study opened on Sept. 16 and hopes to recruit 480 participants in eight countries with several different cancers, including cervical and endometrial cancers. U.S. patients can join at the City of Hope National Medical Center, Duarte, Calif. .
Persistent or recurrent rare epithelial tumors of the ovary, fallopian tube, or peritoneum. Adults with these cancers are sought for a phase 2 trial comparing four targeted-therapy regimens. Participants will receive either ipatasertib plus paclitaxel (Taxol); cobimetinib (Cotellic); trastuzumab emtansine (Kadcyla); or atezolizumab (Tecentriq) plus bevacizumab (Avastin) for up to 5 years until disease progression or unacceptable toxicity. Ipatasertib and cobimetinib are oral medications; all the others are administered intravenously on schedules that vary from once every 3 weeks (atezolizumab, trastuzumab) to weekly infusions 3 weeks out of 4 (paclitaxel). The study opened on Oct. 7 and hopes to enroll 200 participants at sites in Arizona, California, Minnesota, Missouri, Texas, Virginia, and worldwide. OS will be tracked, QoL will not.
Dr. Markman commented: “This is an interesting early study of the potential efficacy of a novel AKT inhibitor [ipatasertib] in rare gynecologic cancers.”
Platinum-resistant or refractory high-grade serous ovarian cancer. Adult women whose high-grade serous ovarian cancer is platinum resistant or refractory and who do not have germline BRCA mutations are sought for a phase 3 study comparing alpelisib (Piqray) plus olaparib (Lynparza) to investigator’s choice of chemotherapy. Alpelisib is approved for breast cancer in combination with fulvestrant; olaparib is approved for advanced ovarian cancer in platinum-responsive patients and/or those with BRCA- or HRD-positive tumors, so this study could lead to labeling changes for these drugs. Participants will either take daily oral doses of alpelisib plus olaparib or receive intravenous chemo on the appropriate schedules for approximately 2 years. Progression-free survival is the primary outcome measure; OS and QoL are secondary outcomes. The trial opened on July 2 and hopes to recruit 358 individuals in Singapore, Australia, Europe, and the United States (Arizona, Illinois, and Texas). .
All trial information is from the National Institutes of Health U.S. National Library of Medicine (online at clinicaltrials.gov).
Dr. Markman is not involved with any of these trials. He is a regular contributor to Medscape Oncology. He has received income in an amount equal to or greater than $250 from Genentech, AstraZeneca Celgene, Clovis, Amgen.
A version of this article first appeared on Medscape.com.
New tool guides nutrition counseling in schizophrenia patients
A new tool designed by psychiatrists to help guide nutritional counseling in patients with schizophrenia spectrum disorders (SSD) has been released.
The worksheet and clinician guide were developed using results from a recent scoping review on the relationship between diet and mental health in patients with SSD, and a feedback process involving a focus group with psychiatrists and individuals who had lived experience with psychosis.
“Mental health clinicians already have the training to help our patients make behavioral changes,” lead author Laura LaChance, MD, lecturer, department of psychiatry, and a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said in an interview.
“We work every day with patients to help them to reduce their substance use, improve their sleep, take medications, etc., and nutrition should be added to the radar [since] eating well for mental health is part of self-care and can be included in mental health treatment plans,” she said.
The paper was published online Nov. 10 in BMC Psychiatry.
Nutrition frequently ignored
Dr. LaChance noted that “nutrition is largely absent from mental health training programs and often ignored in clinical practice.”
The investigators “wanted to create a tool to help incorporate basic nutritional counseling into the care of individuals with severe mental illness.” They wanted the tool “to be simple enough to understand for patients and simple enough to use for mental health care professionals who don’t have any official nutrition training.”
The team developed a worksheet that includes dietary recommendations, the majority of which are supported by the scoping review and consistent with Canada’s Food Guide. The review “identified all of the published literature related to the relationship between diet and psychiatric symptoms of SSD,” synthesizing the results of 822 prior articles.
and does not contradict generally accepted recommendations for weight management. It is suitable for all patients including those with low or normal body mass index and provides psychoeducation about the importance of quality nutrition as a determinant of mental health.
Positive tone
The worksheet was informed by social cognitive theory, which “highlights the important role of goal setting and behavior contracting, reinforcement, self-control, social norms, attitudes, and self-efficacy.”
It provides “basic education about important nutrition principles” as well as “very simple recommendations to increase knowledge about healthy eating” and “actionable tips for individuals to incorporate.” The researchers used a “positive” tone and included motivational interviewing questions.
“Delivery of the intervention by the patient’s mental health care provider is by design, in an attempt to address the widely held misbelief that nutrition intervention is of limited importance to mental health care and begin to change norms,” Dr. LaChance said.
The worksheet addresses monetary barriers to healthy eating; offers practical tips to “increase perceived control and self-efficacy”; is written in simple, accessible, nontechnical language; and includes foods from a range of cultural backgrounds.
To ensure that the worksheet and clinical guide met the needs of the target population, the researchers conducted a focus group with five psychiatrists and individual phone interviews with people who live with psychosis (n = 6).
Participants with psychosis were evenly divided between male and female and six age groups were represented: younger than 20 years; 21-30 years; 31-40 years; 41-50 years; 51-50 years; and older than 60 years. Of these participants, half scored in the “limited literacy” range, based on a nutritional literacy assessment tool (the Newest Vital Sign [NVS]).
A revised version of the worksheet, taking participants’ feedback into account, was mailed to all participants, who then provided further feedback on the revised version.
‘Unspoken area’
The clinician guide contains not only an overview and a suggested agenda to steer discussion, but also a sample visual representation of the recommended relative proportions of different food categories in an ideal meal as well as sample meals, a budgeting discussion, and a list of goals.
A closing statement encourages the clinician to “keep the messaging positive, celebrate small victories, and provide encouragement.”
Specific dietary recommendations include choosing complex carbohydrates and healthy fats, reducing highly processed foods and sugar, adding vegetables and fruits to meals and snacks, and eating protein-rich foods throughout the day.
A “noteworthy theme” that emerged in discussions with psychiatrists as well as participants with SSD was “the lack of nutrition training in medical education and psychiatric residency and the general absence of nutritional counseling in this field of medicine.”
One participant described nutrition as “definitely an unspoken area” in schizophrenia – especially in institutional settings, where “you are overloaded with sugars, not healthy grain, not complex grain. You get white bread sandwiches, shitty juice.”
Powerful tool
Commenting on the paper for this news organization, Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and a nutrition educator at Harvard Medical School, both in Boston, said she appreciates that this paper “is seeking methods to expand treatment options for those with SSD and improve provider understanding/knowledge of therapeutic foods.”
She called the pilot evaluation “notably small,” but added that it “provides results to suggest that scaling this worksheet/guide may hold promise to better provide nutritional counseling to those with psychiatric illness.”
Dr. Naidoo, also a chef and the author of “This Is Your Brain on Food,” who was not involved in the study said, “I’ve seen the power of food as medicine in my own hospital practice and do believe that food is one of the most powerful tools we have in supporting mental fitness and emotional well-being.”
The project was funded by the Canadian CAM Research Fund. Dr. LaChance and Dr. Naidoo have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new tool designed by psychiatrists to help guide nutritional counseling in patients with schizophrenia spectrum disorders (SSD) has been released.
The worksheet and clinician guide were developed using results from a recent scoping review on the relationship between diet and mental health in patients with SSD, and a feedback process involving a focus group with psychiatrists and individuals who had lived experience with psychosis.
“Mental health clinicians already have the training to help our patients make behavioral changes,” lead author Laura LaChance, MD, lecturer, department of psychiatry, and a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said in an interview.
“We work every day with patients to help them to reduce their substance use, improve their sleep, take medications, etc., and nutrition should be added to the radar [since] eating well for mental health is part of self-care and can be included in mental health treatment plans,” she said.
The paper was published online Nov. 10 in BMC Psychiatry.
Nutrition frequently ignored
Dr. LaChance noted that “nutrition is largely absent from mental health training programs and often ignored in clinical practice.”
The investigators “wanted to create a tool to help incorporate basic nutritional counseling into the care of individuals with severe mental illness.” They wanted the tool “to be simple enough to understand for patients and simple enough to use for mental health care professionals who don’t have any official nutrition training.”
The team developed a worksheet that includes dietary recommendations, the majority of which are supported by the scoping review and consistent with Canada’s Food Guide. The review “identified all of the published literature related to the relationship between diet and psychiatric symptoms of SSD,” synthesizing the results of 822 prior articles.
and does not contradict generally accepted recommendations for weight management. It is suitable for all patients including those with low or normal body mass index and provides psychoeducation about the importance of quality nutrition as a determinant of mental health.
Positive tone
The worksheet was informed by social cognitive theory, which “highlights the important role of goal setting and behavior contracting, reinforcement, self-control, social norms, attitudes, and self-efficacy.”
It provides “basic education about important nutrition principles” as well as “very simple recommendations to increase knowledge about healthy eating” and “actionable tips for individuals to incorporate.” The researchers used a “positive” tone and included motivational interviewing questions.
“Delivery of the intervention by the patient’s mental health care provider is by design, in an attempt to address the widely held misbelief that nutrition intervention is of limited importance to mental health care and begin to change norms,” Dr. LaChance said.
The worksheet addresses monetary barriers to healthy eating; offers practical tips to “increase perceived control and self-efficacy”; is written in simple, accessible, nontechnical language; and includes foods from a range of cultural backgrounds.
To ensure that the worksheet and clinical guide met the needs of the target population, the researchers conducted a focus group with five psychiatrists and individual phone interviews with people who live with psychosis (n = 6).
Participants with psychosis were evenly divided between male and female and six age groups were represented: younger than 20 years; 21-30 years; 31-40 years; 41-50 years; 51-50 years; and older than 60 years. Of these participants, half scored in the “limited literacy” range, based on a nutritional literacy assessment tool (the Newest Vital Sign [NVS]).
A revised version of the worksheet, taking participants’ feedback into account, was mailed to all participants, who then provided further feedback on the revised version.
‘Unspoken area’
The clinician guide contains not only an overview and a suggested agenda to steer discussion, but also a sample visual representation of the recommended relative proportions of different food categories in an ideal meal as well as sample meals, a budgeting discussion, and a list of goals.
A closing statement encourages the clinician to “keep the messaging positive, celebrate small victories, and provide encouragement.”
Specific dietary recommendations include choosing complex carbohydrates and healthy fats, reducing highly processed foods and sugar, adding vegetables and fruits to meals and snacks, and eating protein-rich foods throughout the day.
A “noteworthy theme” that emerged in discussions with psychiatrists as well as participants with SSD was “the lack of nutrition training in medical education and psychiatric residency and the general absence of nutritional counseling in this field of medicine.”
One participant described nutrition as “definitely an unspoken area” in schizophrenia – especially in institutional settings, where “you are overloaded with sugars, not healthy grain, not complex grain. You get white bread sandwiches, shitty juice.”
Powerful tool
Commenting on the paper for this news organization, Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and a nutrition educator at Harvard Medical School, both in Boston, said she appreciates that this paper “is seeking methods to expand treatment options for those with SSD and improve provider understanding/knowledge of therapeutic foods.”
She called the pilot evaluation “notably small,” but added that it “provides results to suggest that scaling this worksheet/guide may hold promise to better provide nutritional counseling to those with psychiatric illness.”
Dr. Naidoo, also a chef and the author of “This Is Your Brain on Food,” who was not involved in the study said, “I’ve seen the power of food as medicine in my own hospital practice and do believe that food is one of the most powerful tools we have in supporting mental fitness and emotional well-being.”
The project was funded by the Canadian CAM Research Fund. Dr. LaChance and Dr. Naidoo have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new tool designed by psychiatrists to help guide nutritional counseling in patients with schizophrenia spectrum disorders (SSD) has been released.
The worksheet and clinician guide were developed using results from a recent scoping review on the relationship between diet and mental health in patients with SSD, and a feedback process involving a focus group with psychiatrists and individuals who had lived experience with psychosis.
“Mental health clinicians already have the training to help our patients make behavioral changes,” lead author Laura LaChance, MD, lecturer, department of psychiatry, and a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said in an interview.
“We work every day with patients to help them to reduce their substance use, improve their sleep, take medications, etc., and nutrition should be added to the radar [since] eating well for mental health is part of self-care and can be included in mental health treatment plans,” she said.
The paper was published online Nov. 10 in BMC Psychiatry.
Nutrition frequently ignored
Dr. LaChance noted that “nutrition is largely absent from mental health training programs and often ignored in clinical practice.”
The investigators “wanted to create a tool to help incorporate basic nutritional counseling into the care of individuals with severe mental illness.” They wanted the tool “to be simple enough to understand for patients and simple enough to use for mental health care professionals who don’t have any official nutrition training.”
The team developed a worksheet that includes dietary recommendations, the majority of which are supported by the scoping review and consistent with Canada’s Food Guide. The review “identified all of the published literature related to the relationship between diet and psychiatric symptoms of SSD,” synthesizing the results of 822 prior articles.
and does not contradict generally accepted recommendations for weight management. It is suitable for all patients including those with low or normal body mass index and provides psychoeducation about the importance of quality nutrition as a determinant of mental health.
Positive tone
The worksheet was informed by social cognitive theory, which “highlights the important role of goal setting and behavior contracting, reinforcement, self-control, social norms, attitudes, and self-efficacy.”
It provides “basic education about important nutrition principles” as well as “very simple recommendations to increase knowledge about healthy eating” and “actionable tips for individuals to incorporate.” The researchers used a “positive” tone and included motivational interviewing questions.
“Delivery of the intervention by the patient’s mental health care provider is by design, in an attempt to address the widely held misbelief that nutrition intervention is of limited importance to mental health care and begin to change norms,” Dr. LaChance said.
The worksheet addresses monetary barriers to healthy eating; offers practical tips to “increase perceived control and self-efficacy”; is written in simple, accessible, nontechnical language; and includes foods from a range of cultural backgrounds.
To ensure that the worksheet and clinical guide met the needs of the target population, the researchers conducted a focus group with five psychiatrists and individual phone interviews with people who live with psychosis (n = 6).
Participants with psychosis were evenly divided between male and female and six age groups were represented: younger than 20 years; 21-30 years; 31-40 years; 41-50 years; 51-50 years; and older than 60 years. Of these participants, half scored in the “limited literacy” range, based on a nutritional literacy assessment tool (the Newest Vital Sign [NVS]).
A revised version of the worksheet, taking participants’ feedback into account, was mailed to all participants, who then provided further feedback on the revised version.
‘Unspoken area’
The clinician guide contains not only an overview and a suggested agenda to steer discussion, but also a sample visual representation of the recommended relative proportions of different food categories in an ideal meal as well as sample meals, a budgeting discussion, and a list of goals.
A closing statement encourages the clinician to “keep the messaging positive, celebrate small victories, and provide encouragement.”
Specific dietary recommendations include choosing complex carbohydrates and healthy fats, reducing highly processed foods and sugar, adding vegetables and fruits to meals and snacks, and eating protein-rich foods throughout the day.
A “noteworthy theme” that emerged in discussions with psychiatrists as well as participants with SSD was “the lack of nutrition training in medical education and psychiatric residency and the general absence of nutritional counseling in this field of medicine.”
One participant described nutrition as “definitely an unspoken area” in schizophrenia – especially in institutional settings, where “you are overloaded with sugars, not healthy grain, not complex grain. You get white bread sandwiches, shitty juice.”
Powerful tool
Commenting on the paper for this news organization, Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and a nutrition educator at Harvard Medical School, both in Boston, said she appreciates that this paper “is seeking methods to expand treatment options for those with SSD and improve provider understanding/knowledge of therapeutic foods.”
She called the pilot evaluation “notably small,” but added that it “provides results to suggest that scaling this worksheet/guide may hold promise to better provide nutritional counseling to those with psychiatric illness.”
Dr. Naidoo, also a chef and the author of “This Is Your Brain on Food,” who was not involved in the study said, “I’ve seen the power of food as medicine in my own hospital practice and do believe that food is one of the most powerful tools we have in supporting mental fitness and emotional well-being.”
The project was funded by the Canadian CAM Research Fund. Dr. LaChance and Dr. Naidoo have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM BMC PSYCHIATRY
Hypertension may double the risk of late-onset epilepsy
new research suggests.
After excluding individuals with normal blood pressure who were taking antihypertensive medication, investigators found hypertension was linked to an almost 2.5-fold higher risk of epilepsy.
“Our findings further expand upon our knowledge of the negative effects hypertension has on brain health and, regarding epilepsy, that effect may be starting even in midlife,” said co–lead author Maria Stefanidou, MD, MSc, of Boston University.
“Practicing clinicians should be vigilant to diagnose hypertension, discuss with patients all potential long-term brain health outcomes, and need for treatment. Furthermore, in those presenting with new-onset epilepsy later in life, screening for potentially undiagnosed hypertension should be included in the initial workup,” she said.
The study was published online Nov. 17, 2021, in Epilepsia.
Unknown etiology
“New-onset epilepsy risk increases with increasing age over the age of 65 and can affect 15-20 per 1,000 older individuals. Although the most common causes for seizures in this age group are prior history of stroke and presence of dementia, for about 30%-40% of patients, the etiology of seizures remains unknown,” Dr. Stefanidou said.
“We wanted to study if modifiable vascular risk factors that are known to contribute both to vascular brain aging and to neurodegeneration may directly predict the development of epilepsy, even in the absence of clinical stroke or dementia,” she added.
To investigate, the researchers turned to data from participants in the Offspring Cohort of the Framingham Health Study (FHS). The original FHS was an ongoing longitudinal community-based study that first began in 1948. Offspring of the original cohort and their spouses (n = 5,124) were enrolled in the Offspring Cohort in 1971, with surveillance of these second-generation participants based on exam visits occurring every 4 years.
The study included participants who had attended exam 5 (1991-1995), were age 45 years or older, had available vascular risk factor (VRF) data, and available follow-up data on epilepsy status (n = 2,986; mean age, 58 years; 48% male).
The investigators conducted two statistical analyses. In the primary model, they adjusted for age and gender, while in a secondary model they also adjusted for prevalent and interim stroke. They also conducted an analysis that excluded participants treated with antihypertensive medication and had normal blood pressure.
Plausible mechanisms
During a mean follow-up of 19.2 years, 55 incident epilepsy cases were identified. The mean age of these patients was 73.8 years.
In the primary model, hypertension was associated with an almost twofold higher risk of developing epilepsy (hazard ratio, 1.97; 95% confidence interval, 1.13-3.45; P = .017).
Interestingly, the Framingham Stroke Risk Profile – a calculation based on an array of factors, including age/sex, systolic blood pressure, antihypertensive therapy, diabetes, history of cardiovascular disease, atrial fibrillation, and cigarette smoking – was not associated with incident epilepsy, and there was no other significant associated between any of the other VRFs when looked at independently.
When the researchers adjusted for prevalent and interim stroke, they continued to find an almost twofold higher risk of developing epilepsy (HR 1.93; 95% CI, 1.10-3.37; P = .022). An analysis that adjusted for competing risk of death obtained similar findings (HR, 1.98; 95% CI, 1.03-3.81; P = .042).
The model that excluded patients receiving antihypertensive treatment, whose blood pressure readings were normal (n = 2,162; 50 incident epilepsy cases) showed an even stronger association (HR, 2.44; 95% CI, 1.36-4.35; P = .003).
“Our results are based on an epidemiological, observational study, therefore our findings point to an association between hypertension and new-onset epilepsy later in life,” said Dr. Stefanidou.
She noted that because it was an observational study, “a cause-effect relationship cannot be established based on these results, but there is growing evidence from our, as well as other, similar cohorts that hypertension, a modifiable vascular risk factor, may indeed be an independent predictor of late-onset epilepsy.”
There are “plausible mechanisms” that support both a direct, and indirect, role of hypertension – for example, through accumulation of small vessel disease in the brain – but further research will be necessary to elucidate the exact mechanisms involved in the process,” she added.
‘Welcome addition’
In a joint comment, Hedley C.A. Emsley, PhD, professor of clinical neuroscience, Lancaster (England) University, and Jasmine Wall, MBBChir, academic clinical fellow in neurology, Lancaster University, described the study as a “welcome addition to this field,” noting that the Framingham Heart Study “lends itself well to an embedded observational study of this nature of late-onset epilepsy.”
Dr. Emsley and Dr. Wall, who were not involved in the research, said that the “apparent magnitude of increased late-onset epilepsy risk association with hypertension in the Stefanidou et al study is quite striking,” even allowing for the “relatively small sample size,” since their analysis and findings appear to “withstand exclusion of individuals who became normotensive on antihypertensive treatment.”
They noted that in recent years there has been a growing body of evidence highlighting the importance of hypertension in late-onset epilepsy epileptogenesis with subclinical cerebrovascular diseases, including “otherwise occult cerebral small vessel disease believed to be a frequent cause.”
The mechanisms “remain unclear,” but they could potentially include diffuse cerebral microangiopathy, structural and physiological changes, and/or blood-brain barrier dysfunction and leakage, they suggested.
“Although there is no current consensus over an age threshold that defines ‘late onset,’ we would argue that age thresholds used in such studies of late-onset epilepsy should be lower, to avoid missing younger adults at risk through vascular mechanisms,” Dr. Emsley and Dr. Wall added.
The study authors suggest that “potential pathophysiologic mechanisms can further be explored in future experimental studies and clinical trials.”
This study was funded by grants from the National Institutes of Health and Finding a Cure for Epilepsy/Seizures. Dr. Stefanidou disclosed relevant financial relationships. Dr. Emsley and Dr. Wall disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
After excluding individuals with normal blood pressure who were taking antihypertensive medication, investigators found hypertension was linked to an almost 2.5-fold higher risk of epilepsy.
“Our findings further expand upon our knowledge of the negative effects hypertension has on brain health and, regarding epilepsy, that effect may be starting even in midlife,” said co–lead author Maria Stefanidou, MD, MSc, of Boston University.
“Practicing clinicians should be vigilant to diagnose hypertension, discuss with patients all potential long-term brain health outcomes, and need for treatment. Furthermore, in those presenting with new-onset epilepsy later in life, screening for potentially undiagnosed hypertension should be included in the initial workup,” she said.
The study was published online Nov. 17, 2021, in Epilepsia.
Unknown etiology
“New-onset epilepsy risk increases with increasing age over the age of 65 and can affect 15-20 per 1,000 older individuals. Although the most common causes for seizures in this age group are prior history of stroke and presence of dementia, for about 30%-40% of patients, the etiology of seizures remains unknown,” Dr. Stefanidou said.
“We wanted to study if modifiable vascular risk factors that are known to contribute both to vascular brain aging and to neurodegeneration may directly predict the development of epilepsy, even in the absence of clinical stroke or dementia,” she added.
To investigate, the researchers turned to data from participants in the Offspring Cohort of the Framingham Health Study (FHS). The original FHS was an ongoing longitudinal community-based study that first began in 1948. Offspring of the original cohort and their spouses (n = 5,124) were enrolled in the Offspring Cohort in 1971, with surveillance of these second-generation participants based on exam visits occurring every 4 years.
The study included participants who had attended exam 5 (1991-1995), were age 45 years or older, had available vascular risk factor (VRF) data, and available follow-up data on epilepsy status (n = 2,986; mean age, 58 years; 48% male).
The investigators conducted two statistical analyses. In the primary model, they adjusted for age and gender, while in a secondary model they also adjusted for prevalent and interim stroke. They also conducted an analysis that excluded participants treated with antihypertensive medication and had normal blood pressure.
Plausible mechanisms
During a mean follow-up of 19.2 years, 55 incident epilepsy cases were identified. The mean age of these patients was 73.8 years.
In the primary model, hypertension was associated with an almost twofold higher risk of developing epilepsy (hazard ratio, 1.97; 95% confidence interval, 1.13-3.45; P = .017).
Interestingly, the Framingham Stroke Risk Profile – a calculation based on an array of factors, including age/sex, systolic blood pressure, antihypertensive therapy, diabetes, history of cardiovascular disease, atrial fibrillation, and cigarette smoking – was not associated with incident epilepsy, and there was no other significant associated between any of the other VRFs when looked at independently.
When the researchers adjusted for prevalent and interim stroke, they continued to find an almost twofold higher risk of developing epilepsy (HR 1.93; 95% CI, 1.10-3.37; P = .022). An analysis that adjusted for competing risk of death obtained similar findings (HR, 1.98; 95% CI, 1.03-3.81; P = .042).
The model that excluded patients receiving antihypertensive treatment, whose blood pressure readings were normal (n = 2,162; 50 incident epilepsy cases) showed an even stronger association (HR, 2.44; 95% CI, 1.36-4.35; P = .003).
“Our results are based on an epidemiological, observational study, therefore our findings point to an association between hypertension and new-onset epilepsy later in life,” said Dr. Stefanidou.
She noted that because it was an observational study, “a cause-effect relationship cannot be established based on these results, but there is growing evidence from our, as well as other, similar cohorts that hypertension, a modifiable vascular risk factor, may indeed be an independent predictor of late-onset epilepsy.”
There are “plausible mechanisms” that support both a direct, and indirect, role of hypertension – for example, through accumulation of small vessel disease in the brain – but further research will be necessary to elucidate the exact mechanisms involved in the process,” she added.
‘Welcome addition’
In a joint comment, Hedley C.A. Emsley, PhD, professor of clinical neuroscience, Lancaster (England) University, and Jasmine Wall, MBBChir, academic clinical fellow in neurology, Lancaster University, described the study as a “welcome addition to this field,” noting that the Framingham Heart Study “lends itself well to an embedded observational study of this nature of late-onset epilepsy.”
Dr. Emsley and Dr. Wall, who were not involved in the research, said that the “apparent magnitude of increased late-onset epilepsy risk association with hypertension in the Stefanidou et al study is quite striking,” even allowing for the “relatively small sample size,” since their analysis and findings appear to “withstand exclusion of individuals who became normotensive on antihypertensive treatment.”
They noted that in recent years there has been a growing body of evidence highlighting the importance of hypertension in late-onset epilepsy epileptogenesis with subclinical cerebrovascular diseases, including “otherwise occult cerebral small vessel disease believed to be a frequent cause.”
The mechanisms “remain unclear,” but they could potentially include diffuse cerebral microangiopathy, structural and physiological changes, and/or blood-brain barrier dysfunction and leakage, they suggested.
“Although there is no current consensus over an age threshold that defines ‘late onset,’ we would argue that age thresholds used in such studies of late-onset epilepsy should be lower, to avoid missing younger adults at risk through vascular mechanisms,” Dr. Emsley and Dr. Wall added.
The study authors suggest that “potential pathophysiologic mechanisms can further be explored in future experimental studies and clinical trials.”
This study was funded by grants from the National Institutes of Health and Finding a Cure for Epilepsy/Seizures. Dr. Stefanidou disclosed relevant financial relationships. Dr. Emsley and Dr. Wall disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
After excluding individuals with normal blood pressure who were taking antihypertensive medication, investigators found hypertension was linked to an almost 2.5-fold higher risk of epilepsy.
“Our findings further expand upon our knowledge of the negative effects hypertension has on brain health and, regarding epilepsy, that effect may be starting even in midlife,” said co–lead author Maria Stefanidou, MD, MSc, of Boston University.
“Practicing clinicians should be vigilant to diagnose hypertension, discuss with patients all potential long-term brain health outcomes, and need for treatment. Furthermore, in those presenting with new-onset epilepsy later in life, screening for potentially undiagnosed hypertension should be included in the initial workup,” she said.
The study was published online Nov. 17, 2021, in Epilepsia.
Unknown etiology
“New-onset epilepsy risk increases with increasing age over the age of 65 and can affect 15-20 per 1,000 older individuals. Although the most common causes for seizures in this age group are prior history of stroke and presence of dementia, for about 30%-40% of patients, the etiology of seizures remains unknown,” Dr. Stefanidou said.
“We wanted to study if modifiable vascular risk factors that are known to contribute both to vascular brain aging and to neurodegeneration may directly predict the development of epilepsy, even in the absence of clinical stroke or dementia,” she added.
To investigate, the researchers turned to data from participants in the Offspring Cohort of the Framingham Health Study (FHS). The original FHS was an ongoing longitudinal community-based study that first began in 1948. Offspring of the original cohort and their spouses (n = 5,124) were enrolled in the Offspring Cohort in 1971, with surveillance of these second-generation participants based on exam visits occurring every 4 years.
The study included participants who had attended exam 5 (1991-1995), were age 45 years or older, had available vascular risk factor (VRF) data, and available follow-up data on epilepsy status (n = 2,986; mean age, 58 years; 48% male).
The investigators conducted two statistical analyses. In the primary model, they adjusted for age and gender, while in a secondary model they also adjusted for prevalent and interim stroke. They also conducted an analysis that excluded participants treated with antihypertensive medication and had normal blood pressure.
Plausible mechanisms
During a mean follow-up of 19.2 years, 55 incident epilepsy cases were identified. The mean age of these patients was 73.8 years.
In the primary model, hypertension was associated with an almost twofold higher risk of developing epilepsy (hazard ratio, 1.97; 95% confidence interval, 1.13-3.45; P = .017).
Interestingly, the Framingham Stroke Risk Profile – a calculation based on an array of factors, including age/sex, systolic blood pressure, antihypertensive therapy, diabetes, history of cardiovascular disease, atrial fibrillation, and cigarette smoking – was not associated with incident epilepsy, and there was no other significant associated between any of the other VRFs when looked at independently.
When the researchers adjusted for prevalent and interim stroke, they continued to find an almost twofold higher risk of developing epilepsy (HR 1.93; 95% CI, 1.10-3.37; P = .022). An analysis that adjusted for competing risk of death obtained similar findings (HR, 1.98; 95% CI, 1.03-3.81; P = .042).
The model that excluded patients receiving antihypertensive treatment, whose blood pressure readings were normal (n = 2,162; 50 incident epilepsy cases) showed an even stronger association (HR, 2.44; 95% CI, 1.36-4.35; P = .003).
“Our results are based on an epidemiological, observational study, therefore our findings point to an association between hypertension and new-onset epilepsy later in life,” said Dr. Stefanidou.
She noted that because it was an observational study, “a cause-effect relationship cannot be established based on these results, but there is growing evidence from our, as well as other, similar cohorts that hypertension, a modifiable vascular risk factor, may indeed be an independent predictor of late-onset epilepsy.”
There are “plausible mechanisms” that support both a direct, and indirect, role of hypertension – for example, through accumulation of small vessel disease in the brain – but further research will be necessary to elucidate the exact mechanisms involved in the process,” she added.
‘Welcome addition’
In a joint comment, Hedley C.A. Emsley, PhD, professor of clinical neuroscience, Lancaster (England) University, and Jasmine Wall, MBBChir, academic clinical fellow in neurology, Lancaster University, described the study as a “welcome addition to this field,” noting that the Framingham Heart Study “lends itself well to an embedded observational study of this nature of late-onset epilepsy.”
Dr. Emsley and Dr. Wall, who were not involved in the research, said that the “apparent magnitude of increased late-onset epilepsy risk association with hypertension in the Stefanidou et al study is quite striking,” even allowing for the “relatively small sample size,” since their analysis and findings appear to “withstand exclusion of individuals who became normotensive on antihypertensive treatment.”
They noted that in recent years there has been a growing body of evidence highlighting the importance of hypertension in late-onset epilepsy epileptogenesis with subclinical cerebrovascular diseases, including “otherwise occult cerebral small vessel disease believed to be a frequent cause.”
The mechanisms “remain unclear,” but they could potentially include diffuse cerebral microangiopathy, structural and physiological changes, and/or blood-brain barrier dysfunction and leakage, they suggested.
“Although there is no current consensus over an age threshold that defines ‘late onset,’ we would argue that age thresholds used in such studies of late-onset epilepsy should be lower, to avoid missing younger adults at risk through vascular mechanisms,” Dr. Emsley and Dr. Wall added.
The study authors suggest that “potential pathophysiologic mechanisms can further be explored in future experimental studies and clinical trials.”
This study was funded by grants from the National Institutes of Health and Finding a Cure for Epilepsy/Seizures. Dr. Stefanidou disclosed relevant financial relationships. Dr. Emsley and Dr. Wall disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EPILEPSIA
Certain opioids hold promise for treating itch
Certain opioids are proving to be effective in treating a variety of itch conditions, according to Brian S. Kim, MD.
“We know that opioids or opiates do cause itch in a significant number of patients,” Dr. Kim, a dermatologist who is codirector of the Center for the Study of Itch & Sensory Disorders at Washington University, St. Louis, said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “It’s thought to do this by way of acting as a pruritogen at times and stimulating sensory neurons [that] then activate the itch cascade. But it’s also been well known that endogenous kappa opioids can activate sensory neurons that can then suppress itch and gate out signals from these opiates, but perhaps other pruritogens as well.”
Multiple drugs differentially target kappa-opioid receptor (KOR) and mu-opioid receptor (MOR) pathways, he continued. For example, oral naltrexone is a MOR antagonist, oral nalfurafine and intravenous difelikefalin are KOR agonists, while intranasal butorphanol and oral nalbuphine have a dual mechanism.
Difelikefalin is the first Food and Drug Administration–approved treatment for uremic pruritus associated with dialysis, approved in August 2021 for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis; it is administered intravenously. During the 2021 annual congress of the European Academy of Dermatology and Venereology, Dr. Kim and colleagues presented findings from a phase 2 trial of 401 people with atopic dermatitis (AD) and moderate to severe pruritus, who were randomized to receive oral difelikefalin at a dose of 0.25 mg, 0.5 mg, or 1.0 mg, or placebo over a 12-week treatment period. The primary endpoint, change from baseline in Itch Numerical Rating Scale score, was not met in any of the difelikefalin dose groups in the overall study population, but patients with a body surface area of less than 10% experienced a significant improvement in itch at week 12 in the combined difelikefalin dose group in (P = .039). A significant reduction in itch with difelikefalin was seen in this group of patients with itch-dominant AD, as early as the second day of treatment.
In another trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg, 60 mg, or placebo and treated for 8 weeks. The researchers found that nalbuphine 120 mg significantly reduced the itching intensity. Specifically, from a baseline numerical rate scale (NRS) of 6.9, the mean NRS declined by 3.5 and by 2.8 in the nalbuphine 120-mg and the placebo groups, respectively (P = .017).
In a separate, unpublished multicenter, randomized, phase 2/3 trial, researchers evaluated the safety and antipruritic efficacy of nalbuphine extended-release tablets dosed twice daily at 90 mg and 180 mg in 62 patients in the United States and Europe. The proportion of patients in the nalbuphine 180-mg arm who met 50% responder criteria at week 10 or last observed visit approached statistical significance (P = .083), and this arm met statistical significance for patients who completed treatment (P = .028).
Dr. Kim disclosed that he has served as a consultant for AbbVie, AstraZeneca, Cara Therapeutics, Galderma, GlaxoSmithKline, LEO Pharma, Lilly, Pfizer, Regeneron, Sanofi, Trevi Therapeutics. He also has conducted contracted research for Cara Therapeutics and LEO Pharma.
MedscapeLive and this news organization are owned by the same parent company.
Certain opioids are proving to be effective in treating a variety of itch conditions, according to Brian S. Kim, MD.
“We know that opioids or opiates do cause itch in a significant number of patients,” Dr. Kim, a dermatologist who is codirector of the Center for the Study of Itch & Sensory Disorders at Washington University, St. Louis, said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “It’s thought to do this by way of acting as a pruritogen at times and stimulating sensory neurons [that] then activate the itch cascade. But it’s also been well known that endogenous kappa opioids can activate sensory neurons that can then suppress itch and gate out signals from these opiates, but perhaps other pruritogens as well.”
Multiple drugs differentially target kappa-opioid receptor (KOR) and mu-opioid receptor (MOR) pathways, he continued. For example, oral naltrexone is a MOR antagonist, oral nalfurafine and intravenous difelikefalin are KOR agonists, while intranasal butorphanol and oral nalbuphine have a dual mechanism.
Difelikefalin is the first Food and Drug Administration–approved treatment for uremic pruritus associated with dialysis, approved in August 2021 for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis; it is administered intravenously. During the 2021 annual congress of the European Academy of Dermatology and Venereology, Dr. Kim and colleagues presented findings from a phase 2 trial of 401 people with atopic dermatitis (AD) and moderate to severe pruritus, who were randomized to receive oral difelikefalin at a dose of 0.25 mg, 0.5 mg, or 1.0 mg, or placebo over a 12-week treatment period. The primary endpoint, change from baseline in Itch Numerical Rating Scale score, was not met in any of the difelikefalin dose groups in the overall study population, but patients with a body surface area of less than 10% experienced a significant improvement in itch at week 12 in the combined difelikefalin dose group in (P = .039). A significant reduction in itch with difelikefalin was seen in this group of patients with itch-dominant AD, as early as the second day of treatment.
In another trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg, 60 mg, or placebo and treated for 8 weeks. The researchers found that nalbuphine 120 mg significantly reduced the itching intensity. Specifically, from a baseline numerical rate scale (NRS) of 6.9, the mean NRS declined by 3.5 and by 2.8 in the nalbuphine 120-mg and the placebo groups, respectively (P = .017).
In a separate, unpublished multicenter, randomized, phase 2/3 trial, researchers evaluated the safety and antipruritic efficacy of nalbuphine extended-release tablets dosed twice daily at 90 mg and 180 mg in 62 patients in the United States and Europe. The proportion of patients in the nalbuphine 180-mg arm who met 50% responder criteria at week 10 or last observed visit approached statistical significance (P = .083), and this arm met statistical significance for patients who completed treatment (P = .028).
Dr. Kim disclosed that he has served as a consultant for AbbVie, AstraZeneca, Cara Therapeutics, Galderma, GlaxoSmithKline, LEO Pharma, Lilly, Pfizer, Regeneron, Sanofi, Trevi Therapeutics. He also has conducted contracted research for Cara Therapeutics and LEO Pharma.
MedscapeLive and this news organization are owned by the same parent company.
Certain opioids are proving to be effective in treating a variety of itch conditions, according to Brian S. Kim, MD.
“We know that opioids or opiates do cause itch in a significant number of patients,” Dr. Kim, a dermatologist who is codirector of the Center for the Study of Itch & Sensory Disorders at Washington University, St. Louis, said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “It’s thought to do this by way of acting as a pruritogen at times and stimulating sensory neurons [that] then activate the itch cascade. But it’s also been well known that endogenous kappa opioids can activate sensory neurons that can then suppress itch and gate out signals from these opiates, but perhaps other pruritogens as well.”
Multiple drugs differentially target kappa-opioid receptor (KOR) and mu-opioid receptor (MOR) pathways, he continued. For example, oral naltrexone is a MOR antagonist, oral nalfurafine and intravenous difelikefalin are KOR agonists, while intranasal butorphanol and oral nalbuphine have a dual mechanism.
Difelikefalin is the first Food and Drug Administration–approved treatment for uremic pruritus associated with dialysis, approved in August 2021 for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis; it is administered intravenously. During the 2021 annual congress of the European Academy of Dermatology and Venereology, Dr. Kim and colleagues presented findings from a phase 2 trial of 401 people with atopic dermatitis (AD) and moderate to severe pruritus, who were randomized to receive oral difelikefalin at a dose of 0.25 mg, 0.5 mg, or 1.0 mg, or placebo over a 12-week treatment period. The primary endpoint, change from baseline in Itch Numerical Rating Scale score, was not met in any of the difelikefalin dose groups in the overall study population, but patients with a body surface area of less than 10% experienced a significant improvement in itch at week 12 in the combined difelikefalin dose group in (P = .039). A significant reduction in itch with difelikefalin was seen in this group of patients with itch-dominant AD, as early as the second day of treatment.
In another trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg, 60 mg, or placebo and treated for 8 weeks. The researchers found that nalbuphine 120 mg significantly reduced the itching intensity. Specifically, from a baseline numerical rate scale (NRS) of 6.9, the mean NRS declined by 3.5 and by 2.8 in the nalbuphine 120-mg and the placebo groups, respectively (P = .017).
In a separate, unpublished multicenter, randomized, phase 2/3 trial, researchers evaluated the safety and antipruritic efficacy of nalbuphine extended-release tablets dosed twice daily at 90 mg and 180 mg in 62 patients in the United States and Europe. The proportion of patients in the nalbuphine 180-mg arm who met 50% responder criteria at week 10 or last observed visit approached statistical significance (P = .083), and this arm met statistical significance for patients who completed treatment (P = .028).
Dr. Kim disclosed that he has served as a consultant for AbbVie, AstraZeneca, Cara Therapeutics, Galderma, GlaxoSmithKline, LEO Pharma, Lilly, Pfizer, Regeneron, Sanofi, Trevi Therapeutics. He also has conducted contracted research for Cara Therapeutics and LEO Pharma.
MedscapeLive and this news organization are owned by the same parent company.
FROM THE MEDSCAPELIVE LAS VEGAS DERMATOLOGY SEMINAR
Comparing the efficacy and safety of common SIADH treatments
Background: Hyponatremia caused by SIADH is common in hospitalized patients, and most evidence for treatment comes from noncontrolled studies. This study aims to investigate the efficacy and safety of fluid restriction compared with furosemide, with or without NaCl supplementation, for treating SIADH.
Study design: Open-label randomized controlled trial.
Setting: Single center in Thailand.
Synopsis: There were 92 participants randomized to fluid restriction alone, fluid restriction and furosemide, or fluid restriction, furosemide, and NaCl supplementation. The authors assessed the primary outcome, change in sodium, at 4, 7, 14, and 28 days (baseline mean Na 125 mmol/L). By day 4, all groups had a significant increase in sodium (mean delta 5 mmol/L). The time to achieve a safe sodium level (Na less than 130 mmol/L) was not different among groups. Acute kidney injury was most common in patients who received furosemide and NaCl supplementation, compared with the fluid restriction and fluid restriction plus furosemide groups (32%, 10%, 17%, respectively; P = .07). Hypokalemia was also most common in the furosemide and NaCl group (42%, 13%, 23%, respectively; P = .01). Limitations include open-label study design, poor fluid restriction adherence (63% overall), and inflexible treatment regimens that excluded treatment with oral potassium.
Bottom line: In treatment of hyponatremia caused by SIADH, there was no benefit to adding furosemide with or without NaCl supplementation to fluid restriction. However, there was potential associated risk of acute kidney injury and hypokalemia.Citation: Krisanapan P et al. Efficacy of furosemide, oral sodium chloride, and fluid restriction for treatment of syndrome of inappropriate antidiuresis (SIADH): An open-label randomized controlled study (the EFFUSE-FLUID trial). Am J Kidney Dis. 2020 Aug;76(2):203-12. doi: 10.1053/j.ajkd.2019.11.012.
Dr. Welter is a hospitalist at Northwestern Memorial Hospital and instructor of medicine, Feinberg School of Medicine, both in Chicago.
Background: Hyponatremia caused by SIADH is common in hospitalized patients, and most evidence for treatment comes from noncontrolled studies. This study aims to investigate the efficacy and safety of fluid restriction compared with furosemide, with or without NaCl supplementation, for treating SIADH.
Study design: Open-label randomized controlled trial.
Setting: Single center in Thailand.
Synopsis: There were 92 participants randomized to fluid restriction alone, fluid restriction and furosemide, or fluid restriction, furosemide, and NaCl supplementation. The authors assessed the primary outcome, change in sodium, at 4, 7, 14, and 28 days (baseline mean Na 125 mmol/L). By day 4, all groups had a significant increase in sodium (mean delta 5 mmol/L). The time to achieve a safe sodium level (Na less than 130 mmol/L) was not different among groups. Acute kidney injury was most common in patients who received furosemide and NaCl supplementation, compared with the fluid restriction and fluid restriction plus furosemide groups (32%, 10%, 17%, respectively; P = .07). Hypokalemia was also most common in the furosemide and NaCl group (42%, 13%, 23%, respectively; P = .01). Limitations include open-label study design, poor fluid restriction adherence (63% overall), and inflexible treatment regimens that excluded treatment with oral potassium.
Bottom line: In treatment of hyponatremia caused by SIADH, there was no benefit to adding furosemide with or without NaCl supplementation to fluid restriction. However, there was potential associated risk of acute kidney injury and hypokalemia.Citation: Krisanapan P et al. Efficacy of furosemide, oral sodium chloride, and fluid restriction for treatment of syndrome of inappropriate antidiuresis (SIADH): An open-label randomized controlled study (the EFFUSE-FLUID trial). Am J Kidney Dis. 2020 Aug;76(2):203-12. doi: 10.1053/j.ajkd.2019.11.012.
Dr. Welter is a hospitalist at Northwestern Memorial Hospital and instructor of medicine, Feinberg School of Medicine, both in Chicago.
Background: Hyponatremia caused by SIADH is common in hospitalized patients, and most evidence for treatment comes from noncontrolled studies. This study aims to investigate the efficacy and safety of fluid restriction compared with furosemide, with or without NaCl supplementation, for treating SIADH.
Study design: Open-label randomized controlled trial.
Setting: Single center in Thailand.
Synopsis: There were 92 participants randomized to fluid restriction alone, fluid restriction and furosemide, or fluid restriction, furosemide, and NaCl supplementation. The authors assessed the primary outcome, change in sodium, at 4, 7, 14, and 28 days (baseline mean Na 125 mmol/L). By day 4, all groups had a significant increase in sodium (mean delta 5 mmol/L). The time to achieve a safe sodium level (Na less than 130 mmol/L) was not different among groups. Acute kidney injury was most common in patients who received furosemide and NaCl supplementation, compared with the fluid restriction and fluid restriction plus furosemide groups (32%, 10%, 17%, respectively; P = .07). Hypokalemia was also most common in the furosemide and NaCl group (42%, 13%, 23%, respectively; P = .01). Limitations include open-label study design, poor fluid restriction adherence (63% overall), and inflexible treatment regimens that excluded treatment with oral potassium.
Bottom line: In treatment of hyponatremia caused by SIADH, there was no benefit to adding furosemide with or without NaCl supplementation to fluid restriction. However, there was potential associated risk of acute kidney injury and hypokalemia.Citation: Krisanapan P et al. Efficacy of furosemide, oral sodium chloride, and fluid restriction for treatment of syndrome of inappropriate antidiuresis (SIADH): An open-label randomized controlled study (the EFFUSE-FLUID trial). Am J Kidney Dis. 2020 Aug;76(2):203-12. doi: 10.1053/j.ajkd.2019.11.012.
Dr. Welter is a hospitalist at Northwestern Memorial Hospital and instructor of medicine, Feinberg School of Medicine, both in Chicago.
Fueling an ‘already raging fire’: Fifth COVID surge approaches
“A significant rise in cases just before Thanksgiving is not what we want to be seeing,” said Stephen Kissler, PhD, a postdoctoral researcher and data modeler at the Harvard TH Chan School of Public Health in Boston.
Dr. Kissler said he’d rather see increases in daily cases coming 2 weeks after busy travel periods, as that would mean they could come back down as people returned to their routines.
Seeing big increases in cases ahead of the holidays, he said, “is sort of like adding fuel to an already raging fire.”
Last winter, vaccines hadn’t been rolled out as the nation prepared for Thanksgiving. COVID-19 was burning through family gatherings.
But now that two-thirds of Americans over age 5 are fully vaccinated and booster doses are approved for all adults, will a rise in cases translate, once again, into a strain on our still thinly stretched healthcare system?
Experts say the vaccines are keeping people out of the hospital, which will help. And new antiviral pills are coming that seem to be able to cut a COVID-19 infection off at the knees, at least according to early data. A U.S. Food and Drug Administration panel meets next week to discuss the first application for a pill by Merck.
But experts caution that the coming surge will almost certainly tax hospitals again, especially in areas with lower vaccination rates.
And even states where blood testing shows that significant numbers of people have antibodies after a COVID-19 infection aren’t out of the woods, in part because we still don’t know how long the immunity generated by infection may last.
“Erosion of immunity”
“It’s hard to know how much risk is out there,” said Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University’s Mailman School of Public Health in New York City, who has been modeling the trajectory of the pandemic.
“We’re estimating, unfortunately, and we have for many weeks now, that there is an erosion of immunity,” Dr. Shaman said. “I think it could get bad. How bad? I’m not sure.”
Ali Mokdad, PhD, a professor of health metrics sciences at the University of Washington’s Institute for Health Metrics and Evaluation in Seattle, agrees.
Because there are so few studies on how long immunity from natural infection lasts, Dr. Mokdad and his colleagues are assuming that waning immunity after infection happens at least as quickly as it does after vaccination.
Their model is predicting that the average number of daily cases will peak at around 100,000, with another 100,000 going undetected, and will stay at that level until the end of January, as some states recover from their surges and others pick up steam.
While the number of daily deaths won’t climb to the heights seen during the summer surge, Dr. Mokdad said their model is predicting that daily deaths will climb again to about 1,200 a day.
“We are almost there right now, and it will be with us for a while,” he said. “We are predicting 881,000 deaths by March 1.”
The United States has currently recorded 773,000 COVID-19 deaths, so Dr. Mokdad is predicting about 120,000 more deaths between now and then.
He said his model shows that more than half of those deaths could be prevented if 95% of Americans wore their masks while in close proximity to strangers.
Currently, only about 36% of Americans are consistently wearing masks, according to surveys. While people are moving around more now, mobility is at prepandemic levels in some states.
“The rise that you are seeing right now is high mobility and low mask wearing in the United States,” Dr. Mokdad said.
The solution, he said, is for all adults to get another dose of vaccine — he doesn’t like calling it a booster.
“Because they’re vaccinated and they have two doses they have a false sense of security that they are protected. We needed to come ahead of it immediately and say you need a third dose, and we were late to do so,” Dr. Mokdad said.
A version of this article first appeared on Medscape.com.
“A significant rise in cases just before Thanksgiving is not what we want to be seeing,” said Stephen Kissler, PhD, a postdoctoral researcher and data modeler at the Harvard TH Chan School of Public Health in Boston.
Dr. Kissler said he’d rather see increases in daily cases coming 2 weeks after busy travel periods, as that would mean they could come back down as people returned to their routines.
Seeing big increases in cases ahead of the holidays, he said, “is sort of like adding fuel to an already raging fire.”
Last winter, vaccines hadn’t been rolled out as the nation prepared for Thanksgiving. COVID-19 was burning through family gatherings.
But now that two-thirds of Americans over age 5 are fully vaccinated and booster doses are approved for all adults, will a rise in cases translate, once again, into a strain on our still thinly stretched healthcare system?
Experts say the vaccines are keeping people out of the hospital, which will help. And new antiviral pills are coming that seem to be able to cut a COVID-19 infection off at the knees, at least according to early data. A U.S. Food and Drug Administration panel meets next week to discuss the first application for a pill by Merck.
But experts caution that the coming surge will almost certainly tax hospitals again, especially in areas with lower vaccination rates.
And even states where blood testing shows that significant numbers of people have antibodies after a COVID-19 infection aren’t out of the woods, in part because we still don’t know how long the immunity generated by infection may last.
“Erosion of immunity”
“It’s hard to know how much risk is out there,” said Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University’s Mailman School of Public Health in New York City, who has been modeling the trajectory of the pandemic.
“We’re estimating, unfortunately, and we have for many weeks now, that there is an erosion of immunity,” Dr. Shaman said. “I think it could get bad. How bad? I’m not sure.”
Ali Mokdad, PhD, a professor of health metrics sciences at the University of Washington’s Institute for Health Metrics and Evaluation in Seattle, agrees.
Because there are so few studies on how long immunity from natural infection lasts, Dr. Mokdad and his colleagues are assuming that waning immunity after infection happens at least as quickly as it does after vaccination.
Their model is predicting that the average number of daily cases will peak at around 100,000, with another 100,000 going undetected, and will stay at that level until the end of January, as some states recover from their surges and others pick up steam.
While the number of daily deaths won’t climb to the heights seen during the summer surge, Dr. Mokdad said their model is predicting that daily deaths will climb again to about 1,200 a day.
“We are almost there right now, and it will be with us for a while,” he said. “We are predicting 881,000 deaths by March 1.”
The United States has currently recorded 773,000 COVID-19 deaths, so Dr. Mokdad is predicting about 120,000 more deaths between now and then.
He said his model shows that more than half of those deaths could be prevented if 95% of Americans wore their masks while in close proximity to strangers.
Currently, only about 36% of Americans are consistently wearing masks, according to surveys. While people are moving around more now, mobility is at prepandemic levels in some states.
“The rise that you are seeing right now is high mobility and low mask wearing in the United States,” Dr. Mokdad said.
The solution, he said, is for all adults to get another dose of vaccine — he doesn’t like calling it a booster.
“Because they’re vaccinated and they have two doses they have a false sense of security that they are protected. We needed to come ahead of it immediately and say you need a third dose, and we were late to do so,” Dr. Mokdad said.
A version of this article first appeared on Medscape.com.
“A significant rise in cases just before Thanksgiving is not what we want to be seeing,” said Stephen Kissler, PhD, a postdoctoral researcher and data modeler at the Harvard TH Chan School of Public Health in Boston.
Dr. Kissler said he’d rather see increases in daily cases coming 2 weeks after busy travel periods, as that would mean they could come back down as people returned to their routines.
Seeing big increases in cases ahead of the holidays, he said, “is sort of like adding fuel to an already raging fire.”
Last winter, vaccines hadn’t been rolled out as the nation prepared for Thanksgiving. COVID-19 was burning through family gatherings.
But now that two-thirds of Americans over age 5 are fully vaccinated and booster doses are approved for all adults, will a rise in cases translate, once again, into a strain on our still thinly stretched healthcare system?
Experts say the vaccines are keeping people out of the hospital, which will help. And new antiviral pills are coming that seem to be able to cut a COVID-19 infection off at the knees, at least according to early data. A U.S. Food and Drug Administration panel meets next week to discuss the first application for a pill by Merck.
But experts caution that the coming surge will almost certainly tax hospitals again, especially in areas with lower vaccination rates.
And even states where blood testing shows that significant numbers of people have antibodies after a COVID-19 infection aren’t out of the woods, in part because we still don’t know how long the immunity generated by infection may last.
“Erosion of immunity”
“It’s hard to know how much risk is out there,” said Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University’s Mailman School of Public Health in New York City, who has been modeling the trajectory of the pandemic.
“We’re estimating, unfortunately, and we have for many weeks now, that there is an erosion of immunity,” Dr. Shaman said. “I think it could get bad. How bad? I’m not sure.”
Ali Mokdad, PhD, a professor of health metrics sciences at the University of Washington’s Institute for Health Metrics and Evaluation in Seattle, agrees.
Because there are so few studies on how long immunity from natural infection lasts, Dr. Mokdad and his colleagues are assuming that waning immunity after infection happens at least as quickly as it does after vaccination.
Their model is predicting that the average number of daily cases will peak at around 100,000, with another 100,000 going undetected, and will stay at that level until the end of January, as some states recover from their surges and others pick up steam.
While the number of daily deaths won’t climb to the heights seen during the summer surge, Dr. Mokdad said their model is predicting that daily deaths will climb again to about 1,200 a day.
“We are almost there right now, and it will be with us for a while,” he said. “We are predicting 881,000 deaths by March 1.”
The United States has currently recorded 773,000 COVID-19 deaths, so Dr. Mokdad is predicting about 120,000 more deaths between now and then.
He said his model shows that more than half of those deaths could be prevented if 95% of Americans wore their masks while in close proximity to strangers.
Currently, only about 36% of Americans are consistently wearing masks, according to surveys. While people are moving around more now, mobility is at prepandemic levels in some states.
“The rise that you are seeing right now is high mobility and low mask wearing in the United States,” Dr. Mokdad said.
The solution, he said, is for all adults to get another dose of vaccine — he doesn’t like calling it a booster.
“Because they’re vaccinated and they have two doses they have a false sense of security that they are protected. We needed to come ahead of it immediately and say you need a third dose, and we were late to do so,” Dr. Mokdad said.
A version of this article first appeared on Medscape.com.
Swell in off-label antipsychotic prescribing ‘not harmless’
A growing trend of off-label, low-dose antipsychotic prescribing to treat disorders such as anxiety and insomnia has been tied to an increased risk of cardiometabolic death, new research shows.
Investigators studied data from large Swedish registries on over 420,000 individuals without previous psychotic, bipolar, or cardiometabolic disorders and found that off-label treatment with olanzapine or quetiapine for 6 to 12 months – even at a low dose – was associated with an almost twofold higher risk of cardiometabolic mortality, compared to no treatment. The risk remained elevated after 12 months, but the finding was not deemed significant.
“Clinicians should be made aware that low-dose treatment with these drugs is probably not a harmless choice for insomnia and anxiety, and while they have the benefit of not being addictive and [are] seemingly effective, they might come at a cost of shortening patients’ life span,” study investigator Jonas Berge, MD, PhD, associate professor and resident psychiatrist, Lund University, Sweden, said in an interview.
“Clinicians should take this information into account when prescribing the drugs and also monitor the patients with regular physical examinations and blood tests in the same way as when treating patients with psychosis with higher doses of these drugs,” he said.
The study was published online Nov. 9 in the Journal of Psychiatric Research.
A growing trend
Use of low-dose antipsychotics to treat a variety of psychiatric and behavioral disturbances, including anxiety, insomnia, and agitation, has “surged in popularity,” the authors wrote.
Quetiapine and olanzapine “rank as two of the most frequently prescribed second-generation antipsychotics and, next to clozapine, are considered to exhort the highest risk for cardiometabolic sequelae, including components of metabolic syndrome,” they added.
Previous research examining the association between second-generation antipsychotics and placebo has either not focused on cardiometabolic-specific causes or has examined only cohorts with severe mental illness, so those findings “do not necessarily generalize to others treated off-label,” they noted.
“The motivation for the study came from my work as a psychiatrist, in which I’ve noticed that the off-label use of these medications [olanzapine and quetiapine] for anxiety and insomnia seems highly prevalent, and that many patients seem to gain a lot of weight, despite low doses,” Dr. Berge said.
There is “evidence to suggest that clinicians may underappreciate cardiometabolic risks owing to antipsychotic treatment, as routine screening is often incomplete or inconsistent,” the authors noted.
“To do a risk-benefit analysis of these drugs in low doses, the risks involved – as well as the effects, of course – need to be studied,” Dr. Berge stated.
To investigate the question, the researchers turned to three large cross-linked Swedish registers: the National Patient Register, containing demographic and medical data; the Prescribed Drug Register; and the Cause of Death Register.
They identified all individuals aged 18 years and older with at least one psychiatric visit (inpatient or outpatient) between July 1, 2006, and Dec. 31, 2016, to see how many were prescribed low-dose olanzapine or quetiapine (defined as ≤ 5 mg/day of olanzapine or olanzapine equivalent [OE]), which was used as a proxy marker for off-label treatment, since this dose is considered subtherapeutic for severe mental illness.
They calculated two time-dependent variables – cumulative dose and past annual average dose – and then used those to compute three different exposure valuables: those treated with low-dose OE; cumulative exposure (i.e., period treated with an average 5 mg/day); and a continuous variable “corresponding to each year exposed OE 5 mg/day.”
The primary outcome was set as mortality from cardiometabolic-related disorders, while secondary outcomes were disease-specific and all-cause mortality.
‘Weak’ association
The final cohort consisted of 428,525 individuals (mean [SD] age, 36.8 [15.4] years, 52.7% female) at baseline, with observation taking place over a mean of 4.8 years [range, 1 day to 10.5 years]) or a total of over 2 million (2,062,241) person-years.
Of the cohort, 4.3% (n = 18,317) had at least two prescriptions for either olanzapine or quetiapine (although subsequently, 86.5% were censored for exceeding the average OE dose of 5 mg/day).
By the end of the study, 3.1% of the cohort had died during the observation time, and of these, 69.5% were from disease-specific causes, while close to one-fifth (19.5%) were from cardiometabolic-specific causes.
On the whole, treatment status (i.e., treated vs. untreated) was not significantly associated with cardiometabolic mortality (adjusted hazard ratio [HR], .86 [95% confidence interval, 0.64-1.15]; P = .307).
Compared to no treatment, treatment with olanzapine or quetiapine for less than 6 months was significantly associated with a reduced risk of cardiovascular mortality (adjusted HR, .56 [.37 – .87]; P = .010). On the other hand, treatment for 6-12 months was significantly associated with an almost twofold increased risk (adjusted HR, 1.89 [1.22-2.92]; P = .004). The increased risk continued beyond 12 months, although the difference no longer remained significant.
“In the subgroup analysis consisting of individuals who had ever been treated with olanzapine/quetiapine, starting at the date of their first prescription, the hazard for cardiometabolic mortality increased significantly by 45% (6%-99%; P = .019) for every year exposed to an average 5 mg/day,” the authors reported.
The authors concluded that the association between low-dose olanzapine/quetiapine treatment and cardiometabolic mortality was present, but “weak.”
The hazard for disease-specific mortality also significantly increased with each year exposed to an average of 5 mg/day of OE (HR, 1.24 [1.03-1.50]; P = .026).
Treatment status similarly was associated with all-cause mortality (HR, 1.16 [1.03-1.30]; P = .012), although the increased hazard for all-cause mortality with each year of exposure was not considered significant.
“The findings of this study are consistent with the hypothesis that continuous low-dose treatment with these drugs is associated with increased cardiometabolic mortality, but ,” Dr. Berge said.
Seek alternatives
Commenting on the study for this news organization, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, called it a “timely paper” and “an important concept [because] low-doses of these antipsychotics are frequently prescribed across America and there has been less data on the safety [of these antipsychotics at lower doses].”
Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, said that this “important report reminds us that there are metabolic safety concerns, even at low doses, where these medications are often used off label.”
He advised clinicians to “seek alternatives, and alternatives that are on-label, for conditions like anxiety and sleep disturbances.”
This work was supported by the South Region Board ALF, Sweden. Dr. Berge and coauthors have disclosed no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is CEO of AltMed.
A version of this article first appeared on Medscape.com.
A growing trend of off-label, low-dose antipsychotic prescribing to treat disorders such as anxiety and insomnia has been tied to an increased risk of cardiometabolic death, new research shows.
Investigators studied data from large Swedish registries on over 420,000 individuals without previous psychotic, bipolar, or cardiometabolic disorders and found that off-label treatment with olanzapine or quetiapine for 6 to 12 months – even at a low dose – was associated with an almost twofold higher risk of cardiometabolic mortality, compared to no treatment. The risk remained elevated after 12 months, but the finding was not deemed significant.
“Clinicians should be made aware that low-dose treatment with these drugs is probably not a harmless choice for insomnia and anxiety, and while they have the benefit of not being addictive and [are] seemingly effective, they might come at a cost of shortening patients’ life span,” study investigator Jonas Berge, MD, PhD, associate professor and resident psychiatrist, Lund University, Sweden, said in an interview.
“Clinicians should take this information into account when prescribing the drugs and also monitor the patients with regular physical examinations and blood tests in the same way as when treating patients with psychosis with higher doses of these drugs,” he said.
The study was published online Nov. 9 in the Journal of Psychiatric Research.
A growing trend
Use of low-dose antipsychotics to treat a variety of psychiatric and behavioral disturbances, including anxiety, insomnia, and agitation, has “surged in popularity,” the authors wrote.
Quetiapine and olanzapine “rank as two of the most frequently prescribed second-generation antipsychotics and, next to clozapine, are considered to exhort the highest risk for cardiometabolic sequelae, including components of metabolic syndrome,” they added.
Previous research examining the association between second-generation antipsychotics and placebo has either not focused on cardiometabolic-specific causes or has examined only cohorts with severe mental illness, so those findings “do not necessarily generalize to others treated off-label,” they noted.
“The motivation for the study came from my work as a psychiatrist, in which I’ve noticed that the off-label use of these medications [olanzapine and quetiapine] for anxiety and insomnia seems highly prevalent, and that many patients seem to gain a lot of weight, despite low doses,” Dr. Berge said.
There is “evidence to suggest that clinicians may underappreciate cardiometabolic risks owing to antipsychotic treatment, as routine screening is often incomplete or inconsistent,” the authors noted.
“To do a risk-benefit analysis of these drugs in low doses, the risks involved – as well as the effects, of course – need to be studied,” Dr. Berge stated.
To investigate the question, the researchers turned to three large cross-linked Swedish registers: the National Patient Register, containing demographic and medical data; the Prescribed Drug Register; and the Cause of Death Register.
They identified all individuals aged 18 years and older with at least one psychiatric visit (inpatient or outpatient) between July 1, 2006, and Dec. 31, 2016, to see how many were prescribed low-dose olanzapine or quetiapine (defined as ≤ 5 mg/day of olanzapine or olanzapine equivalent [OE]), which was used as a proxy marker for off-label treatment, since this dose is considered subtherapeutic for severe mental illness.
They calculated two time-dependent variables – cumulative dose and past annual average dose – and then used those to compute three different exposure valuables: those treated with low-dose OE; cumulative exposure (i.e., period treated with an average 5 mg/day); and a continuous variable “corresponding to each year exposed OE 5 mg/day.”
The primary outcome was set as mortality from cardiometabolic-related disorders, while secondary outcomes were disease-specific and all-cause mortality.
‘Weak’ association
The final cohort consisted of 428,525 individuals (mean [SD] age, 36.8 [15.4] years, 52.7% female) at baseline, with observation taking place over a mean of 4.8 years [range, 1 day to 10.5 years]) or a total of over 2 million (2,062,241) person-years.
Of the cohort, 4.3% (n = 18,317) had at least two prescriptions for either olanzapine or quetiapine (although subsequently, 86.5% were censored for exceeding the average OE dose of 5 mg/day).
By the end of the study, 3.1% of the cohort had died during the observation time, and of these, 69.5% were from disease-specific causes, while close to one-fifth (19.5%) were from cardiometabolic-specific causes.
On the whole, treatment status (i.e., treated vs. untreated) was not significantly associated with cardiometabolic mortality (adjusted hazard ratio [HR], .86 [95% confidence interval, 0.64-1.15]; P = .307).
Compared to no treatment, treatment with olanzapine or quetiapine for less than 6 months was significantly associated with a reduced risk of cardiovascular mortality (adjusted HR, .56 [.37 – .87]; P = .010). On the other hand, treatment for 6-12 months was significantly associated with an almost twofold increased risk (adjusted HR, 1.89 [1.22-2.92]; P = .004). The increased risk continued beyond 12 months, although the difference no longer remained significant.
“In the subgroup analysis consisting of individuals who had ever been treated with olanzapine/quetiapine, starting at the date of their first prescription, the hazard for cardiometabolic mortality increased significantly by 45% (6%-99%; P = .019) for every year exposed to an average 5 mg/day,” the authors reported.
The authors concluded that the association between low-dose olanzapine/quetiapine treatment and cardiometabolic mortality was present, but “weak.”
The hazard for disease-specific mortality also significantly increased with each year exposed to an average of 5 mg/day of OE (HR, 1.24 [1.03-1.50]; P = .026).
Treatment status similarly was associated with all-cause mortality (HR, 1.16 [1.03-1.30]; P = .012), although the increased hazard for all-cause mortality with each year of exposure was not considered significant.
“The findings of this study are consistent with the hypothesis that continuous low-dose treatment with these drugs is associated with increased cardiometabolic mortality, but ,” Dr. Berge said.
Seek alternatives
Commenting on the study for this news organization, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, called it a “timely paper” and “an important concept [because] low-doses of these antipsychotics are frequently prescribed across America and there has been less data on the safety [of these antipsychotics at lower doses].”
Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, said that this “important report reminds us that there are metabolic safety concerns, even at low doses, where these medications are often used off label.”
He advised clinicians to “seek alternatives, and alternatives that are on-label, for conditions like anxiety and sleep disturbances.”
This work was supported by the South Region Board ALF, Sweden. Dr. Berge and coauthors have disclosed no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is CEO of AltMed.
A version of this article first appeared on Medscape.com.
A growing trend of off-label, low-dose antipsychotic prescribing to treat disorders such as anxiety and insomnia has been tied to an increased risk of cardiometabolic death, new research shows.
Investigators studied data from large Swedish registries on over 420,000 individuals without previous psychotic, bipolar, or cardiometabolic disorders and found that off-label treatment with olanzapine or quetiapine for 6 to 12 months – even at a low dose – was associated with an almost twofold higher risk of cardiometabolic mortality, compared to no treatment. The risk remained elevated after 12 months, but the finding was not deemed significant.
“Clinicians should be made aware that low-dose treatment with these drugs is probably not a harmless choice for insomnia and anxiety, and while they have the benefit of not being addictive and [are] seemingly effective, they might come at a cost of shortening patients’ life span,” study investigator Jonas Berge, MD, PhD, associate professor and resident psychiatrist, Lund University, Sweden, said in an interview.
“Clinicians should take this information into account when prescribing the drugs and also monitor the patients with regular physical examinations and blood tests in the same way as when treating patients with psychosis with higher doses of these drugs,” he said.
The study was published online Nov. 9 in the Journal of Psychiatric Research.
A growing trend
Use of low-dose antipsychotics to treat a variety of psychiatric and behavioral disturbances, including anxiety, insomnia, and agitation, has “surged in popularity,” the authors wrote.
Quetiapine and olanzapine “rank as two of the most frequently prescribed second-generation antipsychotics and, next to clozapine, are considered to exhort the highest risk for cardiometabolic sequelae, including components of metabolic syndrome,” they added.
Previous research examining the association between second-generation antipsychotics and placebo has either not focused on cardiometabolic-specific causes or has examined only cohorts with severe mental illness, so those findings “do not necessarily generalize to others treated off-label,” they noted.
“The motivation for the study came from my work as a psychiatrist, in which I’ve noticed that the off-label use of these medications [olanzapine and quetiapine] for anxiety and insomnia seems highly prevalent, and that many patients seem to gain a lot of weight, despite low doses,” Dr. Berge said.
There is “evidence to suggest that clinicians may underappreciate cardiometabolic risks owing to antipsychotic treatment, as routine screening is often incomplete or inconsistent,” the authors noted.
“To do a risk-benefit analysis of these drugs in low doses, the risks involved – as well as the effects, of course – need to be studied,” Dr. Berge stated.
To investigate the question, the researchers turned to three large cross-linked Swedish registers: the National Patient Register, containing demographic and medical data; the Prescribed Drug Register; and the Cause of Death Register.
They identified all individuals aged 18 years and older with at least one psychiatric visit (inpatient or outpatient) between July 1, 2006, and Dec. 31, 2016, to see how many were prescribed low-dose olanzapine or quetiapine (defined as ≤ 5 mg/day of olanzapine or olanzapine equivalent [OE]), which was used as a proxy marker for off-label treatment, since this dose is considered subtherapeutic for severe mental illness.
They calculated two time-dependent variables – cumulative dose and past annual average dose – and then used those to compute three different exposure valuables: those treated with low-dose OE; cumulative exposure (i.e., period treated with an average 5 mg/day); and a continuous variable “corresponding to each year exposed OE 5 mg/day.”
The primary outcome was set as mortality from cardiometabolic-related disorders, while secondary outcomes were disease-specific and all-cause mortality.
‘Weak’ association
The final cohort consisted of 428,525 individuals (mean [SD] age, 36.8 [15.4] years, 52.7% female) at baseline, with observation taking place over a mean of 4.8 years [range, 1 day to 10.5 years]) or a total of over 2 million (2,062,241) person-years.
Of the cohort, 4.3% (n = 18,317) had at least two prescriptions for either olanzapine or quetiapine (although subsequently, 86.5% were censored for exceeding the average OE dose of 5 mg/day).
By the end of the study, 3.1% of the cohort had died during the observation time, and of these, 69.5% were from disease-specific causes, while close to one-fifth (19.5%) were from cardiometabolic-specific causes.
On the whole, treatment status (i.e., treated vs. untreated) was not significantly associated with cardiometabolic mortality (adjusted hazard ratio [HR], .86 [95% confidence interval, 0.64-1.15]; P = .307).
Compared to no treatment, treatment with olanzapine or quetiapine for less than 6 months was significantly associated with a reduced risk of cardiovascular mortality (adjusted HR, .56 [.37 – .87]; P = .010). On the other hand, treatment for 6-12 months was significantly associated with an almost twofold increased risk (adjusted HR, 1.89 [1.22-2.92]; P = .004). The increased risk continued beyond 12 months, although the difference no longer remained significant.
“In the subgroup analysis consisting of individuals who had ever been treated with olanzapine/quetiapine, starting at the date of their first prescription, the hazard for cardiometabolic mortality increased significantly by 45% (6%-99%; P = .019) for every year exposed to an average 5 mg/day,” the authors reported.
The authors concluded that the association between low-dose olanzapine/quetiapine treatment and cardiometabolic mortality was present, but “weak.”
The hazard for disease-specific mortality also significantly increased with each year exposed to an average of 5 mg/day of OE (HR, 1.24 [1.03-1.50]; P = .026).
Treatment status similarly was associated with all-cause mortality (HR, 1.16 [1.03-1.30]; P = .012), although the increased hazard for all-cause mortality with each year of exposure was not considered significant.
“The findings of this study are consistent with the hypothesis that continuous low-dose treatment with these drugs is associated with increased cardiometabolic mortality, but ,” Dr. Berge said.
Seek alternatives
Commenting on the study for this news organization, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, called it a “timely paper” and “an important concept [because] low-doses of these antipsychotics are frequently prescribed across America and there has been less data on the safety [of these antipsychotics at lower doses].”
Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, said that this “important report reminds us that there are metabolic safety concerns, even at low doses, where these medications are often used off label.”
He advised clinicians to “seek alternatives, and alternatives that are on-label, for conditions like anxiety and sleep disturbances.”
This work was supported by the South Region Board ALF, Sweden. Dr. Berge and coauthors have disclosed no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is CEO of AltMed.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF PSYCHIATRIC RESEARCH
30% of docs say they don’t want own kids 5-11 to get COVID vaccine
A Medscape
Among physician respondents who have children in that age group, 30% said they would not want their children to be vaccinated; 9% were unsure. For nurses/advanced practice registered nurses (APRNs), more (45%) said they did not want their kids to get the COVID-19 vaccine; 13% were unsure. Among pharmacists, 31% said they would not get them vaccinated and 9% were unsure.
Clinicians were more likely to want vaccinations for their kids 5-11 than were 510 consumers polled by WebMD at the same time. Overall, 49% of the consumers who had kids that age did not want them to get the COVID-19 vaccine.
On November 2, Centers for Disease Control and Prevention (CDC) Director Rochelle P. Walensky, MD, MPH, endorsed the CDC Advisory Committee on Immunization Practices’ recommendation that children 5-11 be vaccinated with the Pfizer-BioNTech pediatric vaccine. That decision expanded vaccine recommendations to about 28 million children in the United States.
The CDC states that, in clinical trials, the Pfizer vaccine had more than 90% efficacy in preventing laboratory-confirmed COVID-19 infection in children 5 to 15 years old, and that the immune response in children ages 5-15 equaled the immune response in people 16 to 25 years old.
The Medscape poll, fielded from November 3 to November 11, included 325 physicians, 793 nurses/APRNs, and 151 pharmacists.
How safe is the vaccine?
Clinicians were asked how confident they were that the vaccine is safe for that age group, and 66% of physicians, 52% of nurses/APRNs, and 66% of pharmacists said they were somewhat or very confident.
Among consumers overall in the WebMD poll, 56% said they were confident or somewhat confident that the vaccine is safe in that age group.
Among adolescents and young adults, rare cases of myocarditis and pericarditis in adolescents and young adults have been reported. According to the CDC, “[I]n one study, the risk of myocarditis after the second dose of Pfizer-BioNTech in the week following vaccination was around 54 cases per million doses administered to males ages 12-17 years.”
Known and potential benefits of COVID-19 vaccination outweigh the risks, including the possible risk for myocarditis or pericarditis, the CDC states.
Across clinician types, women edged out their male counterparts on confidence in the vaccine’ s safety: 71% vs 65% among physicians, 55% vs 45% among nurses/APRNs, and 68% vs 60% among pharmacists.
Among both physicians and nurses, younger physicians (under 45) tended to have greater confidence in the vaccine’ s safety: 72% vs 64% (physicians), 54% vs 51% (nurses/APRNs), and 71% vs 59% (pharmacists).
The difference in confidence was clear between vaccinated and unvaccinated physicians. All of the unvaccinated physicians who responded to the poll said they had no confidence in the vaccine for kids. Among unvaccinated nurses/APRNs, 2% were somewhat confident in the vaccine for kids under 12.
Knowledge about smaller dosage
The clinicians were asked about whether they were aware, before reading the poll question, that the Pfizer vaccine for children and the proposed Moderna vaccine for children in this age group (5-11) would have a different dosage.
The dose for kids 5-11 is 10 micrograms rather than 30 micrograms for people at least 12 years old. Children 5-11 receive a second dose 21 days or more after their first shot. The formulation comes with an orange cap, and a smaller needle is used.
Knowledge on the lower dose was highest among pharmacists (91% said they knew), followed by physicians (84%) and nurses (79%).
The poll also asked whether the COVID-19 vaccine should be added to the list of childhood immunizations. Responses varied widely and uncertainty was evident.
Notably, female physicians were more likely to say it should be added to the list of immunizations than were their male counterparts: 46% vs 35% (physicians), 26% vs 22% (nurses/APRNs), and 33% vs 30% (pharmacists).
A version of this article first appeared on Medscape.com.
A Medscape
Among physician respondents who have children in that age group, 30% said they would not want their children to be vaccinated; 9% were unsure. For nurses/advanced practice registered nurses (APRNs), more (45%) said they did not want their kids to get the COVID-19 vaccine; 13% were unsure. Among pharmacists, 31% said they would not get them vaccinated and 9% were unsure.
Clinicians were more likely to want vaccinations for their kids 5-11 than were 510 consumers polled by WebMD at the same time. Overall, 49% of the consumers who had kids that age did not want them to get the COVID-19 vaccine.
On November 2, Centers for Disease Control and Prevention (CDC) Director Rochelle P. Walensky, MD, MPH, endorsed the CDC Advisory Committee on Immunization Practices’ recommendation that children 5-11 be vaccinated with the Pfizer-BioNTech pediatric vaccine. That decision expanded vaccine recommendations to about 28 million children in the United States.
The CDC states that, in clinical trials, the Pfizer vaccine had more than 90% efficacy in preventing laboratory-confirmed COVID-19 infection in children 5 to 15 years old, and that the immune response in children ages 5-15 equaled the immune response in people 16 to 25 years old.
The Medscape poll, fielded from November 3 to November 11, included 325 physicians, 793 nurses/APRNs, and 151 pharmacists.
How safe is the vaccine?
Clinicians were asked how confident they were that the vaccine is safe for that age group, and 66% of physicians, 52% of nurses/APRNs, and 66% of pharmacists said they were somewhat or very confident.
Among consumers overall in the WebMD poll, 56% said they were confident or somewhat confident that the vaccine is safe in that age group.
Among adolescents and young adults, rare cases of myocarditis and pericarditis in adolescents and young adults have been reported. According to the CDC, “[I]n one study, the risk of myocarditis after the second dose of Pfizer-BioNTech in the week following vaccination was around 54 cases per million doses administered to males ages 12-17 years.”
Known and potential benefits of COVID-19 vaccination outweigh the risks, including the possible risk for myocarditis or pericarditis, the CDC states.
Across clinician types, women edged out their male counterparts on confidence in the vaccine’ s safety: 71% vs 65% among physicians, 55% vs 45% among nurses/APRNs, and 68% vs 60% among pharmacists.
Among both physicians and nurses, younger physicians (under 45) tended to have greater confidence in the vaccine’ s safety: 72% vs 64% (physicians), 54% vs 51% (nurses/APRNs), and 71% vs 59% (pharmacists).
The difference in confidence was clear between vaccinated and unvaccinated physicians. All of the unvaccinated physicians who responded to the poll said they had no confidence in the vaccine for kids. Among unvaccinated nurses/APRNs, 2% were somewhat confident in the vaccine for kids under 12.
Knowledge about smaller dosage
The clinicians were asked about whether they were aware, before reading the poll question, that the Pfizer vaccine for children and the proposed Moderna vaccine for children in this age group (5-11) would have a different dosage.
The dose for kids 5-11 is 10 micrograms rather than 30 micrograms for people at least 12 years old. Children 5-11 receive a second dose 21 days or more after their first shot. The formulation comes with an orange cap, and a smaller needle is used.
Knowledge on the lower dose was highest among pharmacists (91% said they knew), followed by physicians (84%) and nurses (79%).
The poll also asked whether the COVID-19 vaccine should be added to the list of childhood immunizations. Responses varied widely and uncertainty was evident.
Notably, female physicians were more likely to say it should be added to the list of immunizations than were their male counterparts: 46% vs 35% (physicians), 26% vs 22% (nurses/APRNs), and 33% vs 30% (pharmacists).
A version of this article first appeared on Medscape.com.
A Medscape
Among physician respondents who have children in that age group, 30% said they would not want their children to be vaccinated; 9% were unsure. For nurses/advanced practice registered nurses (APRNs), more (45%) said they did not want their kids to get the COVID-19 vaccine; 13% were unsure. Among pharmacists, 31% said they would not get them vaccinated and 9% were unsure.
Clinicians were more likely to want vaccinations for their kids 5-11 than were 510 consumers polled by WebMD at the same time. Overall, 49% of the consumers who had kids that age did not want them to get the COVID-19 vaccine.
On November 2, Centers for Disease Control and Prevention (CDC) Director Rochelle P. Walensky, MD, MPH, endorsed the CDC Advisory Committee on Immunization Practices’ recommendation that children 5-11 be vaccinated with the Pfizer-BioNTech pediatric vaccine. That decision expanded vaccine recommendations to about 28 million children in the United States.
The CDC states that, in clinical trials, the Pfizer vaccine had more than 90% efficacy in preventing laboratory-confirmed COVID-19 infection in children 5 to 15 years old, and that the immune response in children ages 5-15 equaled the immune response in people 16 to 25 years old.
The Medscape poll, fielded from November 3 to November 11, included 325 physicians, 793 nurses/APRNs, and 151 pharmacists.
How safe is the vaccine?
Clinicians were asked how confident they were that the vaccine is safe for that age group, and 66% of physicians, 52% of nurses/APRNs, and 66% of pharmacists said they were somewhat or very confident.
Among consumers overall in the WebMD poll, 56% said they were confident or somewhat confident that the vaccine is safe in that age group.
Among adolescents and young adults, rare cases of myocarditis and pericarditis in adolescents and young adults have been reported. According to the CDC, “[I]n one study, the risk of myocarditis after the second dose of Pfizer-BioNTech in the week following vaccination was around 54 cases per million doses administered to males ages 12-17 years.”
Known and potential benefits of COVID-19 vaccination outweigh the risks, including the possible risk for myocarditis or pericarditis, the CDC states.
Across clinician types, women edged out their male counterparts on confidence in the vaccine’ s safety: 71% vs 65% among physicians, 55% vs 45% among nurses/APRNs, and 68% vs 60% among pharmacists.
Among both physicians and nurses, younger physicians (under 45) tended to have greater confidence in the vaccine’ s safety: 72% vs 64% (physicians), 54% vs 51% (nurses/APRNs), and 71% vs 59% (pharmacists).
The difference in confidence was clear between vaccinated and unvaccinated physicians. All of the unvaccinated physicians who responded to the poll said they had no confidence in the vaccine for kids. Among unvaccinated nurses/APRNs, 2% were somewhat confident in the vaccine for kids under 12.
Knowledge about smaller dosage
The clinicians were asked about whether they were aware, before reading the poll question, that the Pfizer vaccine for children and the proposed Moderna vaccine for children in this age group (5-11) would have a different dosage.
The dose for kids 5-11 is 10 micrograms rather than 30 micrograms for people at least 12 years old. Children 5-11 receive a second dose 21 days or more after their first shot. The formulation comes with an orange cap, and a smaller needle is used.
Knowledge on the lower dose was highest among pharmacists (91% said they knew), followed by physicians (84%) and nurses (79%).
The poll also asked whether the COVID-19 vaccine should be added to the list of childhood immunizations. Responses varied widely and uncertainty was evident.
Notably, female physicians were more likely to say it should be added to the list of immunizations than were their male counterparts: 46% vs 35% (physicians), 26% vs 22% (nurses/APRNs), and 33% vs 30% (pharmacists).
A version of this article first appeared on Medscape.com.
Treating unexplained infertility – avoiding trial and error
Physicians who care for women having difficulty conceiving must understand the devastation their patients feel while knowing how to define infertility, when (and when not) to advise an evaluation, and offer evidence-based treatment options. Analogous to a mother desiring an antibiotic prescription for her child’s common cold, infertility patients can be desperate for an evaluation and treatment, despite the lack of an indication. This month’s article addresses the diagnosis and management of unexplained infertility.
The chronological age of a woman is the leading prognostic factor for successful reproduction. The definition of infertility remains 1 year of an inability to conceive in a couple who have no demonstrable risk factors, such as ovulation dysfunction, prior infertility, or known male factor. In women less than age 30, monthly fecundity rates are between 20% and 37% during the first 3 months of trying to conceive. The chance of success increases to 80% after 1 year and 90% after 2 years of trying to conceive, according to the American Society of Reproductive Medicine. Nevertheless, following unsuccessful attempts at conception by a couple, the physician should offer an evaluation based on the woman’s age – 1 year for women less than age 35, 6 months for women aged 35-39, and 3 months for women aged 40 and older. Testing can be initiated earlier if there are predisposing factors impairing fertility.
The basic infertility evaluation consists of a thorough history of the couple, a review of medical records, and an assessment of ovulation, fallopian tube patency, and sperm parameters on analysis. In the interest of efficiency, given that couples are typically anxious, these three areas can be evaluated within 1 month. In years past, a diagnostic laparoscopy was considered the gold standard of necessity to provide the diagnosis of exclusion, that is, unexplained infertility. This surgical procedure has fallen out of favor given the low diagnostic yield in a woman with a normal hysterosalpingogram, pelvic ultrasound, and no risk for a pelvic factor; for example, prior abdominal myomectomy, bowel surgery, or strong suspicion for endometriosis based on symptoms including significant pelvic pain affecting activities of daily living.
Initial laboratory testing should be judiciously ordered by recommending only those that will affect management, that is, prenatal labs to assess immunity to rubella and varicella along with a baseline thyroid-stimulating hormone, CBC, blood type, and Rh and antibody screen. In a woman with monthly ovulatory menstrual cycles and no signs of hirsutism or galactorrhea, the clinical utility of obtaining follicle-stimulating hormone, luteinizing hormone (LH), estradiol, prolactin, total and free testosterone, and dehydroepiandrosterone lack evidence. Further, a random anti-Müllerian hormone (without prior chemotherapy, radiation, or ovarian surgery) lacks value as the natural pregnancy rate does not appear to be affected, although low AMH has been associated with an increased risk for miscarriage.
Although not typically screened, measles can cause significant complications in pregnancy including an increased risk of maternal hospitalization and pneumonia, as well as miscarriage, stillbirth, low birth weight, and increased risk of preterm delivery.
Education is an important tool to guide patients and begins with an explanation of urine LH timed intercourse. From the onset of the LH surge, the oocyte is released in 24-36 hours, i.e., the actual day of ovulation is estimated to be the day after the urine LH surge. The “fertile window” appears to be the 5 days before plus the day of ovulation but the highest chance of conception occurs within the 2 days before and including the day of ovulation.
Empiric treatment may be offered when no demonstrable etiology has been identified, lifestyle factors have been addressed (for example, elevated female body mass index, tobacco use by the couple), and medical conditions have been optimized. Reproductive capability declines with continued attempts at conception such that, by 2 years, the approximate monthly fecundity rate is 3%-4%.
The first-line treatment of unexplained infertility is clomiphene citrate (CC) with intrauterine insemination. Letrozole, while not Food and Drug Administration approved for infertility treatment, has been shown in multiple studies to be equally effective as CC and to have a good safety profile. In a recent study, the cumulative live-birth rate over three cycles with CC and IUI, compared with expectant management was 31% versus 9%, respectively. Further, multiple studies failed to show a difference in pregnancy outcomes when comparing CC and IUI with letrozole and IUI.
It is vital to note that, for women who ovulate, studies do not support the use of CC without the addition of intrauterine insemination (IUI). The monthly fecundity rate of a cycle of CC without IUI is similar to natural conception attempts with urine LH timed intercourse, that is, without ovarian stimulation.
Recommendations (along with the level of evidence) from ASRM guidelines
- 1. Natural cycle, that is, without ovarian stimulation, timed with IUI is equivalent to expectant management (strong)
- 2. CC or letrozole with timed intercourse is no more effective than a natural cycle (good)
- 3. Pregnancy rates using gonadotropins with timed intercourse have not been shown to be superior to oral ovarian stimulating medications but risks multiple gestation (insufficient)
- 4. CC plus standard-dose gonadotropins results in higher pregnancy rates, there is good evidence for an increased risk of multiple gestation (fair)
- 5. Treatment with gonadotropins alone with IUI is superior to CC or letrozole with IUI; the risk of a multiple gestation rate remains significant (insufficient)
- 6. IUI can be performed between 0 and 36 hours following human chorionic gonadotropin trigger and performing one IUI in a cycle has equivalent success as two (fair)
- 7. Immediate IVF in women older than 38 years may be associated with a higher pregnancy rate and shorter time to pregnancy, compared with ovarian stimulation/IUI cycles before IVF (good)
Conclusion
It is recommended that couples with unexplained infertility initially undergo a course (typically three or four cycles) of ovarian stimulation with IUI using oral agents (CC or letrozole). For those unsuccessful with ovarian stimulation and IUI treatments with oral agents, in vitro fertilization is recommended rather than ovarian stimulation and IUI with gonadotropins to reduce the risk of a multiple gestation.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at obnews@mdedge.com.
Physicians who care for women having difficulty conceiving must understand the devastation their patients feel while knowing how to define infertility, when (and when not) to advise an evaluation, and offer evidence-based treatment options. Analogous to a mother desiring an antibiotic prescription for her child’s common cold, infertility patients can be desperate for an evaluation and treatment, despite the lack of an indication. This month’s article addresses the diagnosis and management of unexplained infertility.
The chronological age of a woman is the leading prognostic factor for successful reproduction. The definition of infertility remains 1 year of an inability to conceive in a couple who have no demonstrable risk factors, such as ovulation dysfunction, prior infertility, or known male factor. In women less than age 30, monthly fecundity rates are between 20% and 37% during the first 3 months of trying to conceive. The chance of success increases to 80% after 1 year and 90% after 2 years of trying to conceive, according to the American Society of Reproductive Medicine. Nevertheless, following unsuccessful attempts at conception by a couple, the physician should offer an evaluation based on the woman’s age – 1 year for women less than age 35, 6 months for women aged 35-39, and 3 months for women aged 40 and older. Testing can be initiated earlier if there are predisposing factors impairing fertility.
The basic infertility evaluation consists of a thorough history of the couple, a review of medical records, and an assessment of ovulation, fallopian tube patency, and sperm parameters on analysis. In the interest of efficiency, given that couples are typically anxious, these three areas can be evaluated within 1 month. In years past, a diagnostic laparoscopy was considered the gold standard of necessity to provide the diagnosis of exclusion, that is, unexplained infertility. This surgical procedure has fallen out of favor given the low diagnostic yield in a woman with a normal hysterosalpingogram, pelvic ultrasound, and no risk for a pelvic factor; for example, prior abdominal myomectomy, bowel surgery, or strong suspicion for endometriosis based on symptoms including significant pelvic pain affecting activities of daily living.
Initial laboratory testing should be judiciously ordered by recommending only those that will affect management, that is, prenatal labs to assess immunity to rubella and varicella along with a baseline thyroid-stimulating hormone, CBC, blood type, and Rh and antibody screen. In a woman with monthly ovulatory menstrual cycles and no signs of hirsutism or galactorrhea, the clinical utility of obtaining follicle-stimulating hormone, luteinizing hormone (LH), estradiol, prolactin, total and free testosterone, and dehydroepiandrosterone lack evidence. Further, a random anti-Müllerian hormone (without prior chemotherapy, radiation, or ovarian surgery) lacks value as the natural pregnancy rate does not appear to be affected, although low AMH has been associated with an increased risk for miscarriage.
Although not typically screened, measles can cause significant complications in pregnancy including an increased risk of maternal hospitalization and pneumonia, as well as miscarriage, stillbirth, low birth weight, and increased risk of preterm delivery.
Education is an important tool to guide patients and begins with an explanation of urine LH timed intercourse. From the onset of the LH surge, the oocyte is released in 24-36 hours, i.e., the actual day of ovulation is estimated to be the day after the urine LH surge. The “fertile window” appears to be the 5 days before plus the day of ovulation but the highest chance of conception occurs within the 2 days before and including the day of ovulation.
Empiric treatment may be offered when no demonstrable etiology has been identified, lifestyle factors have been addressed (for example, elevated female body mass index, tobacco use by the couple), and medical conditions have been optimized. Reproductive capability declines with continued attempts at conception such that, by 2 years, the approximate monthly fecundity rate is 3%-4%.
The first-line treatment of unexplained infertility is clomiphene citrate (CC) with intrauterine insemination. Letrozole, while not Food and Drug Administration approved for infertility treatment, has been shown in multiple studies to be equally effective as CC and to have a good safety profile. In a recent study, the cumulative live-birth rate over three cycles with CC and IUI, compared with expectant management was 31% versus 9%, respectively. Further, multiple studies failed to show a difference in pregnancy outcomes when comparing CC and IUI with letrozole and IUI.
It is vital to note that, for women who ovulate, studies do not support the use of CC without the addition of intrauterine insemination (IUI). The monthly fecundity rate of a cycle of CC without IUI is similar to natural conception attempts with urine LH timed intercourse, that is, without ovarian stimulation.
Recommendations (along with the level of evidence) from ASRM guidelines
- 1. Natural cycle, that is, without ovarian stimulation, timed with IUI is equivalent to expectant management (strong)
- 2. CC or letrozole with timed intercourse is no more effective than a natural cycle (good)
- 3. Pregnancy rates using gonadotropins with timed intercourse have not been shown to be superior to oral ovarian stimulating medications but risks multiple gestation (insufficient)
- 4. CC plus standard-dose gonadotropins results in higher pregnancy rates, there is good evidence for an increased risk of multiple gestation (fair)
- 5. Treatment with gonadotropins alone with IUI is superior to CC or letrozole with IUI; the risk of a multiple gestation rate remains significant (insufficient)
- 6. IUI can be performed between 0 and 36 hours following human chorionic gonadotropin trigger and performing one IUI in a cycle has equivalent success as two (fair)
- 7. Immediate IVF in women older than 38 years may be associated with a higher pregnancy rate and shorter time to pregnancy, compared with ovarian stimulation/IUI cycles before IVF (good)
Conclusion
It is recommended that couples with unexplained infertility initially undergo a course (typically three or four cycles) of ovarian stimulation with IUI using oral agents (CC or letrozole). For those unsuccessful with ovarian stimulation and IUI treatments with oral agents, in vitro fertilization is recommended rather than ovarian stimulation and IUI with gonadotropins to reduce the risk of a multiple gestation.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at obnews@mdedge.com.
Physicians who care for women having difficulty conceiving must understand the devastation their patients feel while knowing how to define infertility, when (and when not) to advise an evaluation, and offer evidence-based treatment options. Analogous to a mother desiring an antibiotic prescription for her child’s common cold, infertility patients can be desperate for an evaluation and treatment, despite the lack of an indication. This month’s article addresses the diagnosis and management of unexplained infertility.
The chronological age of a woman is the leading prognostic factor for successful reproduction. The definition of infertility remains 1 year of an inability to conceive in a couple who have no demonstrable risk factors, such as ovulation dysfunction, prior infertility, or known male factor. In women less than age 30, monthly fecundity rates are between 20% and 37% during the first 3 months of trying to conceive. The chance of success increases to 80% after 1 year and 90% after 2 years of trying to conceive, according to the American Society of Reproductive Medicine. Nevertheless, following unsuccessful attempts at conception by a couple, the physician should offer an evaluation based on the woman’s age – 1 year for women less than age 35, 6 months for women aged 35-39, and 3 months for women aged 40 and older. Testing can be initiated earlier if there are predisposing factors impairing fertility.
The basic infertility evaluation consists of a thorough history of the couple, a review of medical records, and an assessment of ovulation, fallopian tube patency, and sperm parameters on analysis. In the interest of efficiency, given that couples are typically anxious, these three areas can be evaluated within 1 month. In years past, a diagnostic laparoscopy was considered the gold standard of necessity to provide the diagnosis of exclusion, that is, unexplained infertility. This surgical procedure has fallen out of favor given the low diagnostic yield in a woman with a normal hysterosalpingogram, pelvic ultrasound, and no risk for a pelvic factor; for example, prior abdominal myomectomy, bowel surgery, or strong suspicion for endometriosis based on symptoms including significant pelvic pain affecting activities of daily living.
Initial laboratory testing should be judiciously ordered by recommending only those that will affect management, that is, prenatal labs to assess immunity to rubella and varicella along with a baseline thyroid-stimulating hormone, CBC, blood type, and Rh and antibody screen. In a woman with monthly ovulatory menstrual cycles and no signs of hirsutism or galactorrhea, the clinical utility of obtaining follicle-stimulating hormone, luteinizing hormone (LH), estradiol, prolactin, total and free testosterone, and dehydroepiandrosterone lack evidence. Further, a random anti-Müllerian hormone (without prior chemotherapy, radiation, or ovarian surgery) lacks value as the natural pregnancy rate does not appear to be affected, although low AMH has been associated with an increased risk for miscarriage.
Although not typically screened, measles can cause significant complications in pregnancy including an increased risk of maternal hospitalization and pneumonia, as well as miscarriage, stillbirth, low birth weight, and increased risk of preterm delivery.
Education is an important tool to guide patients and begins with an explanation of urine LH timed intercourse. From the onset of the LH surge, the oocyte is released in 24-36 hours, i.e., the actual day of ovulation is estimated to be the day after the urine LH surge. The “fertile window” appears to be the 5 days before plus the day of ovulation but the highest chance of conception occurs within the 2 days before and including the day of ovulation.
Empiric treatment may be offered when no demonstrable etiology has been identified, lifestyle factors have been addressed (for example, elevated female body mass index, tobacco use by the couple), and medical conditions have been optimized. Reproductive capability declines with continued attempts at conception such that, by 2 years, the approximate monthly fecundity rate is 3%-4%.
The first-line treatment of unexplained infertility is clomiphene citrate (CC) with intrauterine insemination. Letrozole, while not Food and Drug Administration approved for infertility treatment, has been shown in multiple studies to be equally effective as CC and to have a good safety profile. In a recent study, the cumulative live-birth rate over three cycles with CC and IUI, compared with expectant management was 31% versus 9%, respectively. Further, multiple studies failed to show a difference in pregnancy outcomes when comparing CC and IUI with letrozole and IUI.
It is vital to note that, for women who ovulate, studies do not support the use of CC without the addition of intrauterine insemination (IUI). The monthly fecundity rate of a cycle of CC without IUI is similar to natural conception attempts with urine LH timed intercourse, that is, without ovarian stimulation.
Recommendations (along with the level of evidence) from ASRM guidelines
- 1. Natural cycle, that is, without ovarian stimulation, timed with IUI is equivalent to expectant management (strong)
- 2. CC or letrozole with timed intercourse is no more effective than a natural cycle (good)
- 3. Pregnancy rates using gonadotropins with timed intercourse have not been shown to be superior to oral ovarian stimulating medications but risks multiple gestation (insufficient)
- 4. CC plus standard-dose gonadotropins results in higher pregnancy rates, there is good evidence for an increased risk of multiple gestation (fair)
- 5. Treatment with gonadotropins alone with IUI is superior to CC or letrozole with IUI; the risk of a multiple gestation rate remains significant (insufficient)
- 6. IUI can be performed between 0 and 36 hours following human chorionic gonadotropin trigger and performing one IUI in a cycle has equivalent success as two (fair)
- 7. Immediate IVF in women older than 38 years may be associated with a higher pregnancy rate and shorter time to pregnancy, compared with ovarian stimulation/IUI cycles before IVF (good)
Conclusion
It is recommended that couples with unexplained infertility initially undergo a course (typically three or four cycles) of ovarian stimulation with IUI using oral agents (CC or letrozole). For those unsuccessful with ovarian stimulation and IUI treatments with oral agents, in vitro fertilization is recommended rather than ovarian stimulation and IUI with gonadotropins to reduce the risk of a multiple gestation.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at obnews@mdedge.com.