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Pros and cons of cfDNA testing
WASHINGTON – The high trisomy 21 detection rate is among the selling points of noninvasive prenatal testing using cell-free DNA screening, though the test detects only a small number of abnormalities, Dr. Mary Norton said at the International Conference on Prenatal Diagnosis and Therapy.
During a symposium on introducing cfDNA screening into routine prenatal care, Dr. Norton, professor of obstetrics and gynecology at the University of California, San Francisco, said physicians are debating not only whether the cfDNA test should be used to screen low- versus high-risk women, but also whether cfDNA screening is appropriate as a primary screen for all pregnant women.
The use of noninvasive prenatal testing (NIPT) is growing in popularity, but its usefulness is narrow, focusing on three chromosomal abnormalities (trisomy 13, 21, and 18), while traditional diagnostic tests provide a broad screen for a wide array of abnormalities, she said.
One of the pros of using cfDNA as a primary screen is that “there’s no question” the detection rate for Down syndrome is better than with other methods, she said.
Other benefits include a lower false positive rate and a reduction in diagnostic tests.
In a prospective, international study published earlier this year that compared cfDNA testing to standard screening for trisomy 21, cfDNA testing identified trisomy 21 in all 38 women with the abnormality, compared to 30 of 38 with standard screening.
In the cfDNA group, the false positive rate was significantly lower (0.06% vs. 5.4%), and the positive predictive value was significantly higher (almost 81% vs. 3.4%) when compared with standard screening, according to Dr. Norton, who was the lead author of the study (N. Engl. J. Med. 2015;372:1589-97).
Another issue is positive predictive value, which is driven by prevalence of the abnormality screened, with lower prevalence corresponding to a lower PPV, she said. In a study of about 1,900 low-risk women whose mean maternal age was 30 years, cfDNA testing detected all cases of trisomy 21. The PPV for trisomy 21 was 45.5% compared with 4.2% with standard screening (N. Engl. J. Med. 2014;370:799-808).
But there are downsides to using the NIPT. For instance, cfDNA testing does not detect many other chromosome abnormalities.
In a study of more than 1.3 million women who had traditional prenatal screening between 2009 and 2012, about 17% of chromosome abnormalities identified were not detectable by current NIPT methods (Obset. Gynecol. 2014;124:979-86).
Other issues include test failure, which can occur because of a low fetal fraction (the amount of cfDNA in the maternal blood of fetal origin), as well as providers who offer cfDNA testing without a full understanding about the implications of positive results, Dr. Norton said.
In many communities, general ob.gyns. are confused about the meaning of the results, she said.
She pointed to a December 2014 investigative report on NIPT in the Boston Globe that said some women have terminated their pregnancies based on NIPT screening results without having a confirmatory diagnostic test.
And when using cfDNA screening, about 3% of samples do not provide a result, which can be associated with aneuploidy and cannot be ignored, Dr. Norton said.
The cfDNA testing is also expensive, Dr. Norton said. For patients who are young with a low risk for Down syndrome but higher risk for other abnormalities, it could be argued that a screening test should be “cheap and broad,” she said.
In the United States, there are many different ways serum and ultrasound screening is currently practiced, and cfDNA screening is being “integrated in very different ways in different settings,” she noted.
A recent American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine statement on cfDNA screening states that considering the performance of conventional screening methods, “the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first line screening for most women in the general obstetric population.”
The statement also notes that while any patient, regardless of her risk, can choose cfDNA testing, she should understand the “limitations and benefits of this screening paradigm” in the context of alternative screening and diagnostic options.
The ACOG/SMFM opinion adds that the cfDNA technology for prenatal aneuploidy screening is rapidly changing, and that “any recommendations regarding its use in screening also will likely evolve quickly.”
Dr. Norton disclosed having received research support from Natera and Ariosa.
WASHINGTON – The high trisomy 21 detection rate is among the selling points of noninvasive prenatal testing using cell-free DNA screening, though the test detects only a small number of abnormalities, Dr. Mary Norton said at the International Conference on Prenatal Diagnosis and Therapy.
During a symposium on introducing cfDNA screening into routine prenatal care, Dr. Norton, professor of obstetrics and gynecology at the University of California, San Francisco, said physicians are debating not only whether the cfDNA test should be used to screen low- versus high-risk women, but also whether cfDNA screening is appropriate as a primary screen for all pregnant women.
The use of noninvasive prenatal testing (NIPT) is growing in popularity, but its usefulness is narrow, focusing on three chromosomal abnormalities (trisomy 13, 21, and 18), while traditional diagnostic tests provide a broad screen for a wide array of abnormalities, she said.
One of the pros of using cfDNA as a primary screen is that “there’s no question” the detection rate for Down syndrome is better than with other methods, she said.
Other benefits include a lower false positive rate and a reduction in diagnostic tests.
In a prospective, international study published earlier this year that compared cfDNA testing to standard screening for trisomy 21, cfDNA testing identified trisomy 21 in all 38 women with the abnormality, compared to 30 of 38 with standard screening.
In the cfDNA group, the false positive rate was significantly lower (0.06% vs. 5.4%), and the positive predictive value was significantly higher (almost 81% vs. 3.4%) when compared with standard screening, according to Dr. Norton, who was the lead author of the study (N. Engl. J. Med. 2015;372:1589-97).
Another issue is positive predictive value, which is driven by prevalence of the abnormality screened, with lower prevalence corresponding to a lower PPV, she said. In a study of about 1,900 low-risk women whose mean maternal age was 30 years, cfDNA testing detected all cases of trisomy 21. The PPV for trisomy 21 was 45.5% compared with 4.2% with standard screening (N. Engl. J. Med. 2014;370:799-808).
But there are downsides to using the NIPT. For instance, cfDNA testing does not detect many other chromosome abnormalities.
In a study of more than 1.3 million women who had traditional prenatal screening between 2009 and 2012, about 17% of chromosome abnormalities identified were not detectable by current NIPT methods (Obset. Gynecol. 2014;124:979-86).
Other issues include test failure, which can occur because of a low fetal fraction (the amount of cfDNA in the maternal blood of fetal origin), as well as providers who offer cfDNA testing without a full understanding about the implications of positive results, Dr. Norton said.
In many communities, general ob.gyns. are confused about the meaning of the results, she said.
She pointed to a December 2014 investigative report on NIPT in the Boston Globe that said some women have terminated their pregnancies based on NIPT screening results without having a confirmatory diagnostic test.
And when using cfDNA screening, about 3% of samples do not provide a result, which can be associated with aneuploidy and cannot be ignored, Dr. Norton said.
The cfDNA testing is also expensive, Dr. Norton said. For patients who are young with a low risk for Down syndrome but higher risk for other abnormalities, it could be argued that a screening test should be “cheap and broad,” she said.
In the United States, there are many different ways serum and ultrasound screening is currently practiced, and cfDNA screening is being “integrated in very different ways in different settings,” she noted.
A recent American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine statement on cfDNA screening states that considering the performance of conventional screening methods, “the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first line screening for most women in the general obstetric population.”
The statement also notes that while any patient, regardless of her risk, can choose cfDNA testing, she should understand the “limitations and benefits of this screening paradigm” in the context of alternative screening and diagnostic options.
The ACOG/SMFM opinion adds that the cfDNA technology for prenatal aneuploidy screening is rapidly changing, and that “any recommendations regarding its use in screening also will likely evolve quickly.”
Dr. Norton disclosed having received research support from Natera and Ariosa.
WASHINGTON – The high trisomy 21 detection rate is among the selling points of noninvasive prenatal testing using cell-free DNA screening, though the test detects only a small number of abnormalities, Dr. Mary Norton said at the International Conference on Prenatal Diagnosis and Therapy.
During a symposium on introducing cfDNA screening into routine prenatal care, Dr. Norton, professor of obstetrics and gynecology at the University of California, San Francisco, said physicians are debating not only whether the cfDNA test should be used to screen low- versus high-risk women, but also whether cfDNA screening is appropriate as a primary screen for all pregnant women.
The use of noninvasive prenatal testing (NIPT) is growing in popularity, but its usefulness is narrow, focusing on three chromosomal abnormalities (trisomy 13, 21, and 18), while traditional diagnostic tests provide a broad screen for a wide array of abnormalities, she said.
One of the pros of using cfDNA as a primary screen is that “there’s no question” the detection rate for Down syndrome is better than with other methods, she said.
Other benefits include a lower false positive rate and a reduction in diagnostic tests.
In a prospective, international study published earlier this year that compared cfDNA testing to standard screening for trisomy 21, cfDNA testing identified trisomy 21 in all 38 women with the abnormality, compared to 30 of 38 with standard screening.
In the cfDNA group, the false positive rate was significantly lower (0.06% vs. 5.4%), and the positive predictive value was significantly higher (almost 81% vs. 3.4%) when compared with standard screening, according to Dr. Norton, who was the lead author of the study (N. Engl. J. Med. 2015;372:1589-97).
Another issue is positive predictive value, which is driven by prevalence of the abnormality screened, with lower prevalence corresponding to a lower PPV, she said. In a study of about 1,900 low-risk women whose mean maternal age was 30 years, cfDNA testing detected all cases of trisomy 21. The PPV for trisomy 21 was 45.5% compared with 4.2% with standard screening (N. Engl. J. Med. 2014;370:799-808).
But there are downsides to using the NIPT. For instance, cfDNA testing does not detect many other chromosome abnormalities.
In a study of more than 1.3 million women who had traditional prenatal screening between 2009 and 2012, about 17% of chromosome abnormalities identified were not detectable by current NIPT methods (Obset. Gynecol. 2014;124:979-86).
Other issues include test failure, which can occur because of a low fetal fraction (the amount of cfDNA in the maternal blood of fetal origin), as well as providers who offer cfDNA testing without a full understanding about the implications of positive results, Dr. Norton said.
In many communities, general ob.gyns. are confused about the meaning of the results, she said.
She pointed to a December 2014 investigative report on NIPT in the Boston Globe that said some women have terminated their pregnancies based on NIPT screening results without having a confirmatory diagnostic test.
And when using cfDNA screening, about 3% of samples do not provide a result, which can be associated with aneuploidy and cannot be ignored, Dr. Norton said.
The cfDNA testing is also expensive, Dr. Norton said. For patients who are young with a low risk for Down syndrome but higher risk for other abnormalities, it could be argued that a screening test should be “cheap and broad,” she said.
In the United States, there are many different ways serum and ultrasound screening is currently practiced, and cfDNA screening is being “integrated in very different ways in different settings,” she noted.
A recent American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine statement on cfDNA screening states that considering the performance of conventional screening methods, “the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first line screening for most women in the general obstetric population.”
The statement also notes that while any patient, regardless of her risk, can choose cfDNA testing, she should understand the “limitations and benefits of this screening paradigm” in the context of alternative screening and diagnostic options.
The ACOG/SMFM opinion adds that the cfDNA technology for prenatal aneuploidy screening is rapidly changing, and that “any recommendations regarding its use in screening also will likely evolve quickly.”
Dr. Norton disclosed having received research support from Natera and Ariosa.
EXPERT ANALYSIS FROM ISPD 2015
False positive on cfDNA screen could mean maternal cancer
WASHINGTON – When the results of a noninvasive prenatal test are positive for aneuploidy but follow-up fetal karyotype results are normal, an undiagnosed maternal malignancy may be the reason why, Dr. Diana Bianchi reported at the International Conference on Prenatal Diagnosis and Therapy.
The conclusions are based on a study that evaluated several cases of cancers among apparently healthy women who had noninvasive prenatal testing (NIPT) during pregnancy with a cell-free DNA (cfDNA) test, which screens for fetal aneuploidy in chromosomes 13, 18, 21, X, and Y. In these cases, the NIPT results did not match the fetal karyotype results, which were obtained through amniocentesis or chorionic villus sampling.
While uncommon, “occult maternal malignancy is a potential biological explanation for discordant results,” between the fetal karyotype and NIPT, Dr. Bianchi, of the Mother Infant Research Institute at Tufts Medical Center, Boston, and lead author of the study, said at the meeting.
The study findings “underscore the need to perform a diagnostic procedure to ascertain the true fetal karyotype,” she added. The study was published July 13 in JAMA to coincide with Dr. Bianchi’s presentation at the International Conference on Prenatal Diagnosis and Therapy (doi:10.1001/jama.2015.7120).
In the study, she and her associates note that the discordant results are thought to be caused by cfDNA that is “released into the maternal circulation from apoptotic malignant cells.” The first case of a maternal cancer identified as the cause of discordant results between NIPT and fetal karyotype tests was identified in 2013, they said. Other explanations include the death of a twin or having received an organ transplant from a male donor. The researchers examined 125,426 NIPT results from asymptomatic pregnant women, which were processed at one lab between Feb. 15, 2012, and Sept. 30, 2014. Of these tests, 3,757 (3%) were positive for at least one aneuploidy involving chromosomes 13. 18, 21, X, or Y.
Among these cases, 10 women were subsequently diagnosed with cancer after abnormal NIPT results were reported (three cases of B-cell lymphoma and one case each of Hodgkin lymphoma; T-cell leukemia; unspecified adenocarcinoma; leiomyosarcoma; and neuroendocrine, colorectal, and anal carcinomas. Most (seven) had multiple aneuploidies, two had a single trisomy, and one had a single monosomy.
The investigators obtained more information from eight of the women. The other two women were critically ill and did not participate.
The mean age of the eight women was 35 years, and they were diagnosed with cancer while still pregnant or after delivery at a mean of 16 weeks after the first NIPT. Fetal karyotyping had been performed in seven of these cases and showed euploid results. The eight women were asymptomatic when they were screened, and the NIPT results “prompted” the diagnosis in three women, but whether earlier detection of the disease would have made a difference in the outcomes could not be determined, the authors wrote.
The follow-up of these patients was not complete, but the authors estimate that in 20%-44% of cases where multiple aneuploidies are detected and the results are discordant, an occult maternal cancer is the explanation. The study is described by the authors as “preliminary.” Limitations includes the retrospective design and incomplete follow-up information, they wrote.
During her presentation, Dr. Bianchi said that the highest risk group are women with multiple aneuploidies, “or suspiciously, a single autosomal monosomy,” the types of cases that “may warrant more detailed analysis of the whole genome.
“Further studies are needed to determine a recommended medical work-up for women” thought to be at high risk, she added. She referred to a recently published Belgian study, which evaluated a small group of women with the same types of suspicious NIPT results with MRI scans, which picked up evidence of tumors in all three of the women studied.
NIPT, considered an advanced screen not a diagnostic test, involves sequencing of cfDNA in maternal plasma, which contains placental DNA, “used as a proxy for the fetus,” and maternal DNA, the authors explained. NIPT is highly sensitive and specific for detecting trisomies 21, 18, and 13.
The cfDNA tests were manufactured by Illumina and were processed at the company’s clinical laboratory in Redwood City, Calif. Illumina funded the study, and sponsored research funding administered through Tufts Medical Center, which paid for the time that Dr. Bianchi spent working with Illumina employees to design the study, analyze the data, and prepare the manuscript.
This is “the first large-scale study that strengthens the premise that a false-positive NIPT result could be due to the presence of maternal malignancy,” Dr. Roberto Romero and Dr. Maurice Mahoney wrote in an editorial. “Since virtually all cancers have somatic genetic alterations that can be reflected in circulating cfDNA, and many of these derangements include chromosome 21, 18, and 13 (the focus of NIPT), it is plausible that discordant NIPT results could be explained by the presence of a maternal malignancy, particularly if the results of NIPT show multiple aneuploidies,” they wrote.
The results of the study need to be replicated and “the data emphasize the need for performing a diagnostic procedure to determine the fetal karyotype in all situations” where NIPT results are abnormal, especially since it is likely that the use of NIPT will increase in the next few years.
Dr. Romero is with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.; the University of Michigan, Ann Arbor; Michigan State University, East Lansing; and Wayne State University, Detroit. Dr. Mahoney is with the department of genetics, pediatrics, and obstetrics and gynecology at Yale University, New Haven, Conn. Their editorial was published July 13 in JAMA. Dr. Romero reported having no financial disclosures. Dr. Mahoney has been a principal investigator in a study of NIPT that used blood samples submitted to Natera under a contract with Yale University (JAMA 2015 July 13 [doi: 10.1001/jama.2015.7533]).
This is “the first large-scale study that strengthens the premise that a false-positive NIPT result could be due to the presence of maternal malignancy,” Dr. Roberto Romero and Dr. Maurice Mahoney wrote in an editorial. “Since virtually all cancers have somatic genetic alterations that can be reflected in circulating cfDNA, and many of these derangements include chromosome 21, 18, and 13 (the focus of NIPT), it is plausible that discordant NIPT results could be explained by the presence of a maternal malignancy, particularly if the results of NIPT show multiple aneuploidies,” they wrote.
The results of the study need to be replicated and “the data emphasize the need for performing a diagnostic procedure to determine the fetal karyotype in all situations” where NIPT results are abnormal, especially since it is likely that the use of NIPT will increase in the next few years.
Dr. Romero is with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.; the University of Michigan, Ann Arbor; Michigan State University, East Lansing; and Wayne State University, Detroit. Dr. Mahoney is with the department of genetics, pediatrics, and obstetrics and gynecology at Yale University, New Haven, Conn. Their editorial was published July 13 in JAMA. Dr. Romero reported having no financial disclosures. Dr. Mahoney has been a principal investigator in a study of NIPT that used blood samples submitted to Natera under a contract with Yale University (JAMA 2015 July 13 [doi: 10.1001/jama.2015.7533]).
This is “the first large-scale study that strengthens the premise that a false-positive NIPT result could be due to the presence of maternal malignancy,” Dr. Roberto Romero and Dr. Maurice Mahoney wrote in an editorial. “Since virtually all cancers have somatic genetic alterations that can be reflected in circulating cfDNA, and many of these derangements include chromosome 21, 18, and 13 (the focus of NIPT), it is plausible that discordant NIPT results could be explained by the presence of a maternal malignancy, particularly if the results of NIPT show multiple aneuploidies,” they wrote.
The results of the study need to be replicated and “the data emphasize the need for performing a diagnostic procedure to determine the fetal karyotype in all situations” where NIPT results are abnormal, especially since it is likely that the use of NIPT will increase in the next few years.
Dr. Romero is with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.; the University of Michigan, Ann Arbor; Michigan State University, East Lansing; and Wayne State University, Detroit. Dr. Mahoney is with the department of genetics, pediatrics, and obstetrics and gynecology at Yale University, New Haven, Conn. Their editorial was published July 13 in JAMA. Dr. Romero reported having no financial disclosures. Dr. Mahoney has been a principal investigator in a study of NIPT that used blood samples submitted to Natera under a contract with Yale University (JAMA 2015 July 13 [doi: 10.1001/jama.2015.7533]).
WASHINGTON – When the results of a noninvasive prenatal test are positive for aneuploidy but follow-up fetal karyotype results are normal, an undiagnosed maternal malignancy may be the reason why, Dr. Diana Bianchi reported at the International Conference on Prenatal Diagnosis and Therapy.
The conclusions are based on a study that evaluated several cases of cancers among apparently healthy women who had noninvasive prenatal testing (NIPT) during pregnancy with a cell-free DNA (cfDNA) test, which screens for fetal aneuploidy in chromosomes 13, 18, 21, X, and Y. In these cases, the NIPT results did not match the fetal karyotype results, which were obtained through amniocentesis or chorionic villus sampling.
While uncommon, “occult maternal malignancy is a potential biological explanation for discordant results,” between the fetal karyotype and NIPT, Dr. Bianchi, of the Mother Infant Research Institute at Tufts Medical Center, Boston, and lead author of the study, said at the meeting.
The study findings “underscore the need to perform a diagnostic procedure to ascertain the true fetal karyotype,” she added. The study was published July 13 in JAMA to coincide with Dr. Bianchi’s presentation at the International Conference on Prenatal Diagnosis and Therapy (doi:10.1001/jama.2015.7120).
In the study, she and her associates note that the discordant results are thought to be caused by cfDNA that is “released into the maternal circulation from apoptotic malignant cells.” The first case of a maternal cancer identified as the cause of discordant results between NIPT and fetal karyotype tests was identified in 2013, they said. Other explanations include the death of a twin or having received an organ transplant from a male donor. The researchers examined 125,426 NIPT results from asymptomatic pregnant women, which were processed at one lab between Feb. 15, 2012, and Sept. 30, 2014. Of these tests, 3,757 (3%) were positive for at least one aneuploidy involving chromosomes 13. 18, 21, X, or Y.
Among these cases, 10 women were subsequently diagnosed with cancer after abnormal NIPT results were reported (three cases of B-cell lymphoma and one case each of Hodgkin lymphoma; T-cell leukemia; unspecified adenocarcinoma; leiomyosarcoma; and neuroendocrine, colorectal, and anal carcinomas. Most (seven) had multiple aneuploidies, two had a single trisomy, and one had a single monosomy.
The investigators obtained more information from eight of the women. The other two women were critically ill and did not participate.
The mean age of the eight women was 35 years, and they were diagnosed with cancer while still pregnant or after delivery at a mean of 16 weeks after the first NIPT. Fetal karyotyping had been performed in seven of these cases and showed euploid results. The eight women were asymptomatic when they were screened, and the NIPT results “prompted” the diagnosis in three women, but whether earlier detection of the disease would have made a difference in the outcomes could not be determined, the authors wrote.
The follow-up of these patients was not complete, but the authors estimate that in 20%-44% of cases where multiple aneuploidies are detected and the results are discordant, an occult maternal cancer is the explanation. The study is described by the authors as “preliminary.” Limitations includes the retrospective design and incomplete follow-up information, they wrote.
During her presentation, Dr. Bianchi said that the highest risk group are women with multiple aneuploidies, “or suspiciously, a single autosomal monosomy,” the types of cases that “may warrant more detailed analysis of the whole genome.
“Further studies are needed to determine a recommended medical work-up for women” thought to be at high risk, she added. She referred to a recently published Belgian study, which evaluated a small group of women with the same types of suspicious NIPT results with MRI scans, which picked up evidence of tumors in all three of the women studied.
NIPT, considered an advanced screen not a diagnostic test, involves sequencing of cfDNA in maternal plasma, which contains placental DNA, “used as a proxy for the fetus,” and maternal DNA, the authors explained. NIPT is highly sensitive and specific for detecting trisomies 21, 18, and 13.
The cfDNA tests were manufactured by Illumina and were processed at the company’s clinical laboratory in Redwood City, Calif. Illumina funded the study, and sponsored research funding administered through Tufts Medical Center, which paid for the time that Dr. Bianchi spent working with Illumina employees to design the study, analyze the data, and prepare the manuscript.
WASHINGTON – When the results of a noninvasive prenatal test are positive for aneuploidy but follow-up fetal karyotype results are normal, an undiagnosed maternal malignancy may be the reason why, Dr. Diana Bianchi reported at the International Conference on Prenatal Diagnosis and Therapy.
The conclusions are based on a study that evaluated several cases of cancers among apparently healthy women who had noninvasive prenatal testing (NIPT) during pregnancy with a cell-free DNA (cfDNA) test, which screens for fetal aneuploidy in chromosomes 13, 18, 21, X, and Y. In these cases, the NIPT results did not match the fetal karyotype results, which were obtained through amniocentesis or chorionic villus sampling.
While uncommon, “occult maternal malignancy is a potential biological explanation for discordant results,” between the fetal karyotype and NIPT, Dr. Bianchi, of the Mother Infant Research Institute at Tufts Medical Center, Boston, and lead author of the study, said at the meeting.
The study findings “underscore the need to perform a diagnostic procedure to ascertain the true fetal karyotype,” she added. The study was published July 13 in JAMA to coincide with Dr. Bianchi’s presentation at the International Conference on Prenatal Diagnosis and Therapy (doi:10.1001/jama.2015.7120).
In the study, she and her associates note that the discordant results are thought to be caused by cfDNA that is “released into the maternal circulation from apoptotic malignant cells.” The first case of a maternal cancer identified as the cause of discordant results between NIPT and fetal karyotype tests was identified in 2013, they said. Other explanations include the death of a twin or having received an organ transplant from a male donor. The researchers examined 125,426 NIPT results from asymptomatic pregnant women, which were processed at one lab between Feb. 15, 2012, and Sept. 30, 2014. Of these tests, 3,757 (3%) were positive for at least one aneuploidy involving chromosomes 13. 18, 21, X, or Y.
Among these cases, 10 women were subsequently diagnosed with cancer after abnormal NIPT results were reported (three cases of B-cell lymphoma and one case each of Hodgkin lymphoma; T-cell leukemia; unspecified adenocarcinoma; leiomyosarcoma; and neuroendocrine, colorectal, and anal carcinomas. Most (seven) had multiple aneuploidies, two had a single trisomy, and one had a single monosomy.
The investigators obtained more information from eight of the women. The other two women were critically ill and did not participate.
The mean age of the eight women was 35 years, and they were diagnosed with cancer while still pregnant or after delivery at a mean of 16 weeks after the first NIPT. Fetal karyotyping had been performed in seven of these cases and showed euploid results. The eight women were asymptomatic when they were screened, and the NIPT results “prompted” the diagnosis in three women, but whether earlier detection of the disease would have made a difference in the outcomes could not be determined, the authors wrote.
The follow-up of these patients was not complete, but the authors estimate that in 20%-44% of cases where multiple aneuploidies are detected and the results are discordant, an occult maternal cancer is the explanation. The study is described by the authors as “preliminary.” Limitations includes the retrospective design and incomplete follow-up information, they wrote.
During her presentation, Dr. Bianchi said that the highest risk group are women with multiple aneuploidies, “or suspiciously, a single autosomal monosomy,” the types of cases that “may warrant more detailed analysis of the whole genome.
“Further studies are needed to determine a recommended medical work-up for women” thought to be at high risk, she added. She referred to a recently published Belgian study, which evaluated a small group of women with the same types of suspicious NIPT results with MRI scans, which picked up evidence of tumors in all three of the women studied.
NIPT, considered an advanced screen not a diagnostic test, involves sequencing of cfDNA in maternal plasma, which contains placental DNA, “used as a proxy for the fetus,” and maternal DNA, the authors explained. NIPT is highly sensitive and specific for detecting trisomies 21, 18, and 13.
The cfDNA tests were manufactured by Illumina and were processed at the company’s clinical laboratory in Redwood City, Calif. Illumina funded the study, and sponsored research funding administered through Tufts Medical Center, which paid for the time that Dr. Bianchi spent working with Illumina employees to design the study, analyze the data, and prepare the manuscript.
AT ISPD 2015
Key clinical point: Discordant results between noninvasive prenatal testing (NIPT) for aneuploidy and fetal karyotype could be caused by an undiagnosed maternal malignancy.
Major finding: Of the 125,426 NIPT results, 3% (3,757) were positive for at least one aneuploidy involving chromosomes 13, 18, 21, X, or Y. Of these, 10 women were diagnosed with cancer.
Data source: A case series of 10 women diagnosed with cancer after abnormal NIPT results did not match the fetal karyotype, from a cohort of 125,426 NIPT tests processed at a single lab over a 2.5-year period.
Disclosures: The cfDNA tests were manufactured by Illumina and were processed at the company’s clinical laboratory in Redwood City, Calif. Illumina funded the study, and sponsored research funding administered through Tufts Medical Center, which paid for the time that Dr. Bianchi spent working with Illumina employees to design the study, analyze the data, and prepare the manuscript.
FDA panel says benefits of necitumumab for squamous NSCLC outweigh risks
SILVER SPRING, MD. – The majority of a Food and Drug Administration Advisory panel agreed that the benefits of adding necitumumab to gemcitabine and cisplatin for patients with squamous non–small cell lung cancer outweighed the risks.
At the meeting on July 9, the FDA’s Oncologic Drugs Advisory Committee reviewed data from a study that evaluated the anti–epidermal growth factor receptor monoclonal antibody in more than 1,000 patients with stage IV disease. The SQUIRE study was submitted to the FDA by Eli Lilly to support approval of necitumumab for the indication now under review: for use as a first-line treatment, in combination with gemcitabine and cisplatin, for patients with locally advanced or metastatic squamous non–small cell lung cancer (NSCLC). Necitumumab is a recombinant human IgG1 monoclonal antibody that is designed to block the ligand binding site of the human EGFR.
Despite a modest effect on overall survival, a very small but statistically significant effect on progression-free survival, and some safety concerns, 11 of the 12 panelists agreed that the efficacy and safety results of the trial supported a “positive benefit risk assessment” of necitumumab combined with gemcitabine and cisplatin for this group of patients, the main question they were asked by the FDA to discuss. The panel was not asked to specifically vote on whether to recommend approval.
The SQUIRE study, an international phase III study of 1,093 patients with stage IV squamous NSCLC, who had not received chemotherapy for advanced disease, evaluated the safety and efficacy of gemcitabine and cisplatin, with or without necitumumab, administered every 3 weeks, until disease progressed or toxicity became unacceptable, for a maximum of six cycles. The median age of patients was 62 years; they were mostly men and were heavy smokers; 36 patients were enrolled in the United States. (Patients were not selected based on EGFR protein expression but based on tissue pathology.)
Median overall survival (OS), the primary endpoint, was 11.5 months in the necitumumab-treated arm, vs. 9.9 months among controls, a 1.6 month difference that was statistically significant, representing a reduced risk of 16% (hazard ratio, 0.84). Progression-free survival (PFS) was a median of 5.7 months among those in the necitumumab-treated group, vs. 5.5 months, which was also statistically significant and represented a 15% reduced risk (HR, 0.85). There was no significant difference in the objective response rate (ORR), which was 31% among those in the necitumumab arm and 29% among those in the control arm. This is the first study to show an improvement in survival for a first-line treatment for squamous lung cancer, the company officials pointed out.
In the study, there were more venous thromboembolic events (VTEs; 9% vs. 5%) and more cases of sudden death and deaths “not otherwise specified” (2.2% vs. 0.5%) in the necitumumab-treated arm. There were also more cases of hypomagnesemia and skin rashes, and the FDA reviewers pointed out that several cases of sudden death occurred in patients with very low serum magnesium levels. VTEs and sudden or unexplained deaths were also higher among necitumumab-treated patients in another study that evaluated necitumumab in patients with nonsquamous NSCLC, which was stopped early because of the VTE increase; that study found no improvements in OS, PFS or ORR.
Among those agreeing that the risk-benefit assessment was positive, Dr. Michael Menefee of the Mayo Clinic, Jacksonville, Fla., said “Yes was the simple answer, but there are still caveats” regarding toxicity and the magnitude of the overall benefit.
“The survival benefit is modest but it’s real,” said Dr. Deborah Armstrong, the panel chair and professor of oncology, Johns Hopkins University, Baltimore, who also voted positively. She strongly encouraged continuing efforts to manage the toxicities of necitumumab, which she said might improve the risk-benefit balance further.
The panelist who did not agree was Dr. Tito Fojo, a senior investigator and director of the medical oncology fellowship program at the National Cancer Institute. He said that the study did not provide him with enough confidence. Noting it is a very difficult disease to treat, he said, “I just wish the data were much better.” His concerns included the possibility that those in the control arm, who received a median of five treatment cycles may have received less chemotherapy than those in the necitumumab arm, who received a median of six cycles.
Speaking on behalf of Eli Lilly at the meeting, Dr. David Gandara, director of the thoracic oncology program at the University of California Davis Comprehensive Cancer Center, said that although EGFR mutations are rare in squamous NSCLC, “the EGFR pathway itself is biologically relevant.” Necitumumab “attacks that pathway in ways independent of those associated with EGFR tyrosine-kinase inhibitors and independent of EGFR mutation status,” he added.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. The FDA decision is expected by the end of 2015, an Eli Lilly spokesperson said.
SILVER SPRING, MD. – The majority of a Food and Drug Administration Advisory panel agreed that the benefits of adding necitumumab to gemcitabine and cisplatin for patients with squamous non–small cell lung cancer outweighed the risks.
At the meeting on July 9, the FDA’s Oncologic Drugs Advisory Committee reviewed data from a study that evaluated the anti–epidermal growth factor receptor monoclonal antibody in more than 1,000 patients with stage IV disease. The SQUIRE study was submitted to the FDA by Eli Lilly to support approval of necitumumab for the indication now under review: for use as a first-line treatment, in combination with gemcitabine and cisplatin, for patients with locally advanced or metastatic squamous non–small cell lung cancer (NSCLC). Necitumumab is a recombinant human IgG1 monoclonal antibody that is designed to block the ligand binding site of the human EGFR.
Despite a modest effect on overall survival, a very small but statistically significant effect on progression-free survival, and some safety concerns, 11 of the 12 panelists agreed that the efficacy and safety results of the trial supported a “positive benefit risk assessment” of necitumumab combined with gemcitabine and cisplatin for this group of patients, the main question they were asked by the FDA to discuss. The panel was not asked to specifically vote on whether to recommend approval.
The SQUIRE study, an international phase III study of 1,093 patients with stage IV squamous NSCLC, who had not received chemotherapy for advanced disease, evaluated the safety and efficacy of gemcitabine and cisplatin, with or without necitumumab, administered every 3 weeks, until disease progressed or toxicity became unacceptable, for a maximum of six cycles. The median age of patients was 62 years; they were mostly men and were heavy smokers; 36 patients were enrolled in the United States. (Patients were not selected based on EGFR protein expression but based on tissue pathology.)
Median overall survival (OS), the primary endpoint, was 11.5 months in the necitumumab-treated arm, vs. 9.9 months among controls, a 1.6 month difference that was statistically significant, representing a reduced risk of 16% (hazard ratio, 0.84). Progression-free survival (PFS) was a median of 5.7 months among those in the necitumumab-treated group, vs. 5.5 months, which was also statistically significant and represented a 15% reduced risk (HR, 0.85). There was no significant difference in the objective response rate (ORR), which was 31% among those in the necitumumab arm and 29% among those in the control arm. This is the first study to show an improvement in survival for a first-line treatment for squamous lung cancer, the company officials pointed out.
In the study, there were more venous thromboembolic events (VTEs; 9% vs. 5%) and more cases of sudden death and deaths “not otherwise specified” (2.2% vs. 0.5%) in the necitumumab-treated arm. There were also more cases of hypomagnesemia and skin rashes, and the FDA reviewers pointed out that several cases of sudden death occurred in patients with very low serum magnesium levels. VTEs and sudden or unexplained deaths were also higher among necitumumab-treated patients in another study that evaluated necitumumab in patients with nonsquamous NSCLC, which was stopped early because of the VTE increase; that study found no improvements in OS, PFS or ORR.
Among those agreeing that the risk-benefit assessment was positive, Dr. Michael Menefee of the Mayo Clinic, Jacksonville, Fla., said “Yes was the simple answer, but there are still caveats” regarding toxicity and the magnitude of the overall benefit.
“The survival benefit is modest but it’s real,” said Dr. Deborah Armstrong, the panel chair and professor of oncology, Johns Hopkins University, Baltimore, who also voted positively. She strongly encouraged continuing efforts to manage the toxicities of necitumumab, which she said might improve the risk-benefit balance further.
The panelist who did not agree was Dr. Tito Fojo, a senior investigator and director of the medical oncology fellowship program at the National Cancer Institute. He said that the study did not provide him with enough confidence. Noting it is a very difficult disease to treat, he said, “I just wish the data were much better.” His concerns included the possibility that those in the control arm, who received a median of five treatment cycles may have received less chemotherapy than those in the necitumumab arm, who received a median of six cycles.
Speaking on behalf of Eli Lilly at the meeting, Dr. David Gandara, director of the thoracic oncology program at the University of California Davis Comprehensive Cancer Center, said that although EGFR mutations are rare in squamous NSCLC, “the EGFR pathway itself is biologically relevant.” Necitumumab “attacks that pathway in ways independent of those associated with EGFR tyrosine-kinase inhibitors and independent of EGFR mutation status,” he added.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. The FDA decision is expected by the end of 2015, an Eli Lilly spokesperson said.
SILVER SPRING, MD. – The majority of a Food and Drug Administration Advisory panel agreed that the benefits of adding necitumumab to gemcitabine and cisplatin for patients with squamous non–small cell lung cancer outweighed the risks.
At the meeting on July 9, the FDA’s Oncologic Drugs Advisory Committee reviewed data from a study that evaluated the anti–epidermal growth factor receptor monoclonal antibody in more than 1,000 patients with stage IV disease. The SQUIRE study was submitted to the FDA by Eli Lilly to support approval of necitumumab for the indication now under review: for use as a first-line treatment, in combination with gemcitabine and cisplatin, for patients with locally advanced or metastatic squamous non–small cell lung cancer (NSCLC). Necitumumab is a recombinant human IgG1 monoclonal antibody that is designed to block the ligand binding site of the human EGFR.
Despite a modest effect on overall survival, a very small but statistically significant effect on progression-free survival, and some safety concerns, 11 of the 12 panelists agreed that the efficacy and safety results of the trial supported a “positive benefit risk assessment” of necitumumab combined with gemcitabine and cisplatin for this group of patients, the main question they were asked by the FDA to discuss. The panel was not asked to specifically vote on whether to recommend approval.
The SQUIRE study, an international phase III study of 1,093 patients with stage IV squamous NSCLC, who had not received chemotherapy for advanced disease, evaluated the safety and efficacy of gemcitabine and cisplatin, with or without necitumumab, administered every 3 weeks, until disease progressed or toxicity became unacceptable, for a maximum of six cycles. The median age of patients was 62 years; they were mostly men and were heavy smokers; 36 patients were enrolled in the United States. (Patients were not selected based on EGFR protein expression but based on tissue pathology.)
Median overall survival (OS), the primary endpoint, was 11.5 months in the necitumumab-treated arm, vs. 9.9 months among controls, a 1.6 month difference that was statistically significant, representing a reduced risk of 16% (hazard ratio, 0.84). Progression-free survival (PFS) was a median of 5.7 months among those in the necitumumab-treated group, vs. 5.5 months, which was also statistically significant and represented a 15% reduced risk (HR, 0.85). There was no significant difference in the objective response rate (ORR), which was 31% among those in the necitumumab arm and 29% among those in the control arm. This is the first study to show an improvement in survival for a first-line treatment for squamous lung cancer, the company officials pointed out.
In the study, there were more venous thromboembolic events (VTEs; 9% vs. 5%) and more cases of sudden death and deaths “not otherwise specified” (2.2% vs. 0.5%) in the necitumumab-treated arm. There were also more cases of hypomagnesemia and skin rashes, and the FDA reviewers pointed out that several cases of sudden death occurred in patients with very low serum magnesium levels. VTEs and sudden or unexplained deaths were also higher among necitumumab-treated patients in another study that evaluated necitumumab in patients with nonsquamous NSCLC, which was stopped early because of the VTE increase; that study found no improvements in OS, PFS or ORR.
Among those agreeing that the risk-benefit assessment was positive, Dr. Michael Menefee of the Mayo Clinic, Jacksonville, Fla., said “Yes was the simple answer, but there are still caveats” regarding toxicity and the magnitude of the overall benefit.
“The survival benefit is modest but it’s real,” said Dr. Deborah Armstrong, the panel chair and professor of oncology, Johns Hopkins University, Baltimore, who also voted positively. She strongly encouraged continuing efforts to manage the toxicities of necitumumab, which she said might improve the risk-benefit balance further.
The panelist who did not agree was Dr. Tito Fojo, a senior investigator and director of the medical oncology fellowship program at the National Cancer Institute. He said that the study did not provide him with enough confidence. Noting it is a very difficult disease to treat, he said, “I just wish the data were much better.” His concerns included the possibility that those in the control arm, who received a median of five treatment cycles may have received less chemotherapy than those in the necitumumab arm, who received a median of six cycles.
Speaking on behalf of Eli Lilly at the meeting, Dr. David Gandara, director of the thoracic oncology program at the University of California Davis Comprehensive Cancer Center, said that although EGFR mutations are rare in squamous NSCLC, “the EGFR pathway itself is biologically relevant.” Necitumumab “attacks that pathway in ways independent of those associated with EGFR tyrosine-kinase inhibitors and independent of EGFR mutation status,” he added.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. The FDA decision is expected by the end of 2015, an Eli Lilly spokesperson said.
AT AN FDA ADVISORY COMMITTEE MEETING
FDA approval of sacubitril-valsartan combo opens ‘new chapter’ for heart failure
A combination of a new drug, sacubitril, a neprilysin inhibitor, and the angiotensin receptor blocker valsartan has been approved for treating heart failure, providing what experts are describing as a major advance in the treatment of heart failure.
The approval, announced by the Food and Drug Administration on July 7, was based on the results of the PARADIGM-HF study of about 8,400 patients with class II-IV heart failure and an ejection fraction of 40% or less. The study showed that the combination reduced the risk of cardiovascular death and hospitalization for heart failure by 20% and reduced the risk for all-cause mortality by 16%, compared with enalapril, with a favorable adverse event profile.
The approved indication for sacubitril-valsartan is to “reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure [New York Heart Association class II-IV] and reduced ejection fraction,” according to the prescribing information. The indications section includes the statement that it “is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB [angiotensin II receptor blocker].” It is contraindicated for use with ACE inhibitors, and when patients on an ACE inhibitor are switched to this drug a washout period of 36 hours before starting treatment is recommended.
Previously called LCZ696, the combination tablet formulation will be marketed by Novartis as Entresto, and will be available in three dosage strengths of sacubitril-valsartan: 24/26 mg, 49/51 mg, and 97/103 mg; in published studies of the combination, these doses are referred to as 50 mg, 100 mg, and 200 mg, respectively. The target dose is 97/103 mg twice a day.
“Many of us see this as a real sea change in heart failure management; we’re all eager to start using this new medicine in our patients, and I think clinicians will very rapidly get a feel for this drug,” Dr. Scott D. Solomon, professor of medicine, Harvard Medical School, Boston, and one of the authors of the study, said in an interview. Referring to the trial results, he noted that for at least 10 years, there has not been a new drug for heart failure that has had this impact on mortality, “so this is really quite an extraordinary finding.”
The availability of a new drug class, a neprilysin inhibitor, “opens up a new chapter in our treatment of heart failure,” said Dr. Mariell Jessup, professor of medicine at the University of Pennsylvania, Philadelphia, who was not involved in the study. “I’m very excited that we now have this new drug for use in our patients,” she said, pointing out that with the exception of ivabradine (Corlanor), approved in April, there has not been a new type of drug approved for heart failure in a long time.
Neprilysin is an endopeptidase that degrades several endogenous vasoactive peptides. Sacubitril “inhibits the breakdown of natriuretic peptides, among other vasoactive compounds, so the drug simultaneously blocks one of the neurohormonal systems that is abnormally activated in the setting of heart failure, and it also augments one of the neurohormonal systems that can be beneficial in patients with heart failure,” said Dr. Solomon, who is also director of noninvasive cardiology at Brigham and Women’s Hospital, Boston.
In PARADIGM-HF, conducted to determine if sacubitril-valsartan was superior to treatment with an ACE inhibitor, the recognized standard treatment for heart failure, a composite of death from cardiovascular causes or a first hospitalization for heart failure (the primary outcome), was 21.8% among those randomized to the combination vs. 26.5% of those on enalapril after a median 27-month follow-up, a highly statistically significant difference that represented a 20% reduced risk over the comparator (N. Engl. J. Med. 371:993-1004). A 20% reduced risk over enalapril was seen for the two components individually in the study, which was stopped early because of the magnitude of the effect over enalapril at a dose of the ACE inhibitor that the investigators pointed out had been shown to reduce mortality, compared with placebo.
Hypotension and nonserious cases of angioedema were higher among those on sacubitril-valsartan, while renal impairment, hyperkalemia, and cough were higher in the enalapril-treated patients.
As with ACE inhibitors, there is a small risk for angioedema, and while the number of cases was low in the study, physicians need to be aware of this issue, Dr. Solomon said. “To use this effectively, patients who are on ACE inhibitors or ARBs will need to be stopped, given 36 hours to wash out, and then started on this new agent,” he said.
In an interview, Dr. Jessup said that she hopes that physicians approach this new drug with the same caution they have with other drugs for patients with systolic heart failure and encouraged clinicians to carefully read the study and familiarize themselves with the prescribing information. Patients should not be taken off an ACE inhibitor and immediately switched to Entresto, she said.
She referred to the “famous” Canadian study that identified a significant increase in spironolactone prescriptions and in the rates of hyperkalemia and hyperkalemia-associated deaths after the positive Randomized Aldactone Evaluation Study (RALES) results were published in 1999 (N. Engl. J. Med. 2004;351:543-51). After the study, which found significant improvements in morbidity and mortality in patients with severe heart failure, was published, “physicians immediately started to put their patients on spironolactone and there was a spike in hyperkalemia and in deaths,” she noted.
The Entresto label includes a boxed warning about the risk of fetal toxicity, and the FDA statement recommends that health care professionals counsel patients about the risks to an unborn baby. One of the company’s postmarketing requirements is to conduct an epidemiologic study evaluating the incidence of angioedema in black patients treated with the combination, compared with another drug, according to the FDA’s approval letter.
The PARADIGM-HF results were reported in August 2014 at the European Society of Cardiology annual meeting in Barcelona. Dr. Solomon said that a large international study evaluating Entresto in patients with heart failure and preserved ejection fraction is currently underway.
The cost per day of Entresto is $12.50 (the wholesale acquisition cost), and the company anticipates that the product will be available in most pharmacies within weeks of the approval date, according to a Novartis spokesperson.
Valsartan, approved in 2001, is marketed as Diovan by Novartis and is available in generic form from Ranbaxy.
The PARADIGM-HF trial was funded by Novartis. Dr. Solomon, a member of the executive committee for the study, has received research support from Novartis for the conduct of this and other studies, and has served as a consultant to the company. Dr. Jessup had no related disclosures.
A combination of a new drug, sacubitril, a neprilysin inhibitor, and the angiotensin receptor blocker valsartan has been approved for treating heart failure, providing what experts are describing as a major advance in the treatment of heart failure.
The approval, announced by the Food and Drug Administration on July 7, was based on the results of the PARADIGM-HF study of about 8,400 patients with class II-IV heart failure and an ejection fraction of 40% or less. The study showed that the combination reduced the risk of cardiovascular death and hospitalization for heart failure by 20% and reduced the risk for all-cause mortality by 16%, compared with enalapril, with a favorable adverse event profile.
The approved indication for sacubitril-valsartan is to “reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure [New York Heart Association class II-IV] and reduced ejection fraction,” according to the prescribing information. The indications section includes the statement that it “is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB [angiotensin II receptor blocker].” It is contraindicated for use with ACE inhibitors, and when patients on an ACE inhibitor are switched to this drug a washout period of 36 hours before starting treatment is recommended.
Previously called LCZ696, the combination tablet formulation will be marketed by Novartis as Entresto, and will be available in three dosage strengths of sacubitril-valsartan: 24/26 mg, 49/51 mg, and 97/103 mg; in published studies of the combination, these doses are referred to as 50 mg, 100 mg, and 200 mg, respectively. The target dose is 97/103 mg twice a day.
“Many of us see this as a real sea change in heart failure management; we’re all eager to start using this new medicine in our patients, and I think clinicians will very rapidly get a feel for this drug,” Dr. Scott D. Solomon, professor of medicine, Harvard Medical School, Boston, and one of the authors of the study, said in an interview. Referring to the trial results, he noted that for at least 10 years, there has not been a new drug for heart failure that has had this impact on mortality, “so this is really quite an extraordinary finding.”
The availability of a new drug class, a neprilysin inhibitor, “opens up a new chapter in our treatment of heart failure,” said Dr. Mariell Jessup, professor of medicine at the University of Pennsylvania, Philadelphia, who was not involved in the study. “I’m very excited that we now have this new drug for use in our patients,” she said, pointing out that with the exception of ivabradine (Corlanor), approved in April, there has not been a new type of drug approved for heart failure in a long time.
Neprilysin is an endopeptidase that degrades several endogenous vasoactive peptides. Sacubitril “inhibits the breakdown of natriuretic peptides, among other vasoactive compounds, so the drug simultaneously blocks one of the neurohormonal systems that is abnormally activated in the setting of heart failure, and it also augments one of the neurohormonal systems that can be beneficial in patients with heart failure,” said Dr. Solomon, who is also director of noninvasive cardiology at Brigham and Women’s Hospital, Boston.
In PARADIGM-HF, conducted to determine if sacubitril-valsartan was superior to treatment with an ACE inhibitor, the recognized standard treatment for heart failure, a composite of death from cardiovascular causes or a first hospitalization for heart failure (the primary outcome), was 21.8% among those randomized to the combination vs. 26.5% of those on enalapril after a median 27-month follow-up, a highly statistically significant difference that represented a 20% reduced risk over the comparator (N. Engl. J. Med. 371:993-1004). A 20% reduced risk over enalapril was seen for the two components individually in the study, which was stopped early because of the magnitude of the effect over enalapril at a dose of the ACE inhibitor that the investigators pointed out had been shown to reduce mortality, compared with placebo.
Hypotension and nonserious cases of angioedema were higher among those on sacubitril-valsartan, while renal impairment, hyperkalemia, and cough were higher in the enalapril-treated patients.
As with ACE inhibitors, there is a small risk for angioedema, and while the number of cases was low in the study, physicians need to be aware of this issue, Dr. Solomon said. “To use this effectively, patients who are on ACE inhibitors or ARBs will need to be stopped, given 36 hours to wash out, and then started on this new agent,” he said.
In an interview, Dr. Jessup said that she hopes that physicians approach this new drug with the same caution they have with other drugs for patients with systolic heart failure and encouraged clinicians to carefully read the study and familiarize themselves with the prescribing information. Patients should not be taken off an ACE inhibitor and immediately switched to Entresto, she said.
She referred to the “famous” Canadian study that identified a significant increase in spironolactone prescriptions and in the rates of hyperkalemia and hyperkalemia-associated deaths after the positive Randomized Aldactone Evaluation Study (RALES) results were published in 1999 (N. Engl. J. Med. 2004;351:543-51). After the study, which found significant improvements in morbidity and mortality in patients with severe heart failure, was published, “physicians immediately started to put their patients on spironolactone and there was a spike in hyperkalemia and in deaths,” she noted.
The Entresto label includes a boxed warning about the risk of fetal toxicity, and the FDA statement recommends that health care professionals counsel patients about the risks to an unborn baby. One of the company’s postmarketing requirements is to conduct an epidemiologic study evaluating the incidence of angioedema in black patients treated with the combination, compared with another drug, according to the FDA’s approval letter.
The PARADIGM-HF results were reported in August 2014 at the European Society of Cardiology annual meeting in Barcelona. Dr. Solomon said that a large international study evaluating Entresto in patients with heart failure and preserved ejection fraction is currently underway.
The cost per day of Entresto is $12.50 (the wholesale acquisition cost), and the company anticipates that the product will be available in most pharmacies within weeks of the approval date, according to a Novartis spokesperson.
Valsartan, approved in 2001, is marketed as Diovan by Novartis and is available in generic form from Ranbaxy.
The PARADIGM-HF trial was funded by Novartis. Dr. Solomon, a member of the executive committee for the study, has received research support from Novartis for the conduct of this and other studies, and has served as a consultant to the company. Dr. Jessup had no related disclosures.
A combination of a new drug, sacubitril, a neprilysin inhibitor, and the angiotensin receptor blocker valsartan has been approved for treating heart failure, providing what experts are describing as a major advance in the treatment of heart failure.
The approval, announced by the Food and Drug Administration on July 7, was based on the results of the PARADIGM-HF study of about 8,400 patients with class II-IV heart failure and an ejection fraction of 40% or less. The study showed that the combination reduced the risk of cardiovascular death and hospitalization for heart failure by 20% and reduced the risk for all-cause mortality by 16%, compared with enalapril, with a favorable adverse event profile.
The approved indication for sacubitril-valsartan is to “reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure [New York Heart Association class II-IV] and reduced ejection fraction,” according to the prescribing information. The indications section includes the statement that it “is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB [angiotensin II receptor blocker].” It is contraindicated for use with ACE inhibitors, and when patients on an ACE inhibitor are switched to this drug a washout period of 36 hours before starting treatment is recommended.
Previously called LCZ696, the combination tablet formulation will be marketed by Novartis as Entresto, and will be available in three dosage strengths of sacubitril-valsartan: 24/26 mg, 49/51 mg, and 97/103 mg; in published studies of the combination, these doses are referred to as 50 mg, 100 mg, and 200 mg, respectively. The target dose is 97/103 mg twice a day.
“Many of us see this as a real sea change in heart failure management; we’re all eager to start using this new medicine in our patients, and I think clinicians will very rapidly get a feel for this drug,” Dr. Scott D. Solomon, professor of medicine, Harvard Medical School, Boston, and one of the authors of the study, said in an interview. Referring to the trial results, he noted that for at least 10 years, there has not been a new drug for heart failure that has had this impact on mortality, “so this is really quite an extraordinary finding.”
The availability of a new drug class, a neprilysin inhibitor, “opens up a new chapter in our treatment of heart failure,” said Dr. Mariell Jessup, professor of medicine at the University of Pennsylvania, Philadelphia, who was not involved in the study. “I’m very excited that we now have this new drug for use in our patients,” she said, pointing out that with the exception of ivabradine (Corlanor), approved in April, there has not been a new type of drug approved for heart failure in a long time.
Neprilysin is an endopeptidase that degrades several endogenous vasoactive peptides. Sacubitril “inhibits the breakdown of natriuretic peptides, among other vasoactive compounds, so the drug simultaneously blocks one of the neurohormonal systems that is abnormally activated in the setting of heart failure, and it also augments one of the neurohormonal systems that can be beneficial in patients with heart failure,” said Dr. Solomon, who is also director of noninvasive cardiology at Brigham and Women’s Hospital, Boston.
In PARADIGM-HF, conducted to determine if sacubitril-valsartan was superior to treatment with an ACE inhibitor, the recognized standard treatment for heart failure, a composite of death from cardiovascular causes or a first hospitalization for heart failure (the primary outcome), was 21.8% among those randomized to the combination vs. 26.5% of those on enalapril after a median 27-month follow-up, a highly statistically significant difference that represented a 20% reduced risk over the comparator (N. Engl. J. Med. 371:993-1004). A 20% reduced risk over enalapril was seen for the two components individually in the study, which was stopped early because of the magnitude of the effect over enalapril at a dose of the ACE inhibitor that the investigators pointed out had been shown to reduce mortality, compared with placebo.
Hypotension and nonserious cases of angioedema were higher among those on sacubitril-valsartan, while renal impairment, hyperkalemia, and cough were higher in the enalapril-treated patients.
As with ACE inhibitors, there is a small risk for angioedema, and while the number of cases was low in the study, physicians need to be aware of this issue, Dr. Solomon said. “To use this effectively, patients who are on ACE inhibitors or ARBs will need to be stopped, given 36 hours to wash out, and then started on this new agent,” he said.
In an interview, Dr. Jessup said that she hopes that physicians approach this new drug with the same caution they have with other drugs for patients with systolic heart failure and encouraged clinicians to carefully read the study and familiarize themselves with the prescribing information. Patients should not be taken off an ACE inhibitor and immediately switched to Entresto, she said.
She referred to the “famous” Canadian study that identified a significant increase in spironolactone prescriptions and in the rates of hyperkalemia and hyperkalemia-associated deaths after the positive Randomized Aldactone Evaluation Study (RALES) results were published in 1999 (N. Engl. J. Med. 2004;351:543-51). After the study, which found significant improvements in morbidity and mortality in patients with severe heart failure, was published, “physicians immediately started to put their patients on spironolactone and there was a spike in hyperkalemia and in deaths,” she noted.
The Entresto label includes a boxed warning about the risk of fetal toxicity, and the FDA statement recommends that health care professionals counsel patients about the risks to an unborn baby. One of the company’s postmarketing requirements is to conduct an epidemiologic study evaluating the incidence of angioedema in black patients treated with the combination, compared with another drug, according to the FDA’s approval letter.
The PARADIGM-HF results were reported in August 2014 at the European Society of Cardiology annual meeting in Barcelona. Dr. Solomon said that a large international study evaluating Entresto in patients with heart failure and preserved ejection fraction is currently underway.
The cost per day of Entresto is $12.50 (the wholesale acquisition cost), and the company anticipates that the product will be available in most pharmacies within weeks of the approval date, according to a Novartis spokesperson.
Valsartan, approved in 2001, is marketed as Diovan by Novartis and is available in generic form from Ranbaxy.
The PARADIGM-HF trial was funded by Novartis. Dr. Solomon, a member of the executive committee for the study, has received research support from Novartis for the conduct of this and other studies, and has served as a consultant to the company. Dr. Jessup had no related disclosures.
DDW: Study finds pancreatic cancer misdiagnosis rate at 31%
WASHINGTON – Initial misdiagnoses were common and were associated with a later disease stage at diagnosis, in a study of 313 patients diagnosed with pancreatic cancer, Dr. Douglas Swords said at the annual Digestive Disease Week.
“By far, the most common misdiagnosis was gallbladder disease,” and there was about a 3-month longer time period, on average, from the first visit to a physician to the actual cancer diagnosis, in patients who were initially misdiagnosed, said Dr. Swords, a surgery resident at the University of Utah, Salt Lake City.
In the series of 313 patients diagnosed with pancreatic cancer, 98 (31.3%) were initially misdiagnosed, with a total of 119 diagnoses other than pancreatic cancer, he said. The most common misdiagnosis was gallbladder disease, which led to a cholecystectomy in 38 cases, followed by gastroesophageal reflux disease in 15 cases, and peptic ulcer disease in 11 cases. Those initially misdiagnosed were an average of about 5 years younger.
Patients with an initial misdiagnosis had significantly greater rates of abdominal pain (about 85% vs. about 60%), weight loss (about 85% vs. about 75%), nausea/vomiting (50% vs. almost 40%), and pancreatitis (almost 30% vs. less than 5%), Dr. Swords said. In addition, patients with an initial misdiagnosis had significantly lower rates of jaundice (about 50% vs. almost 80%). The rates of diarrhea and anorexia were not significantly different between the two groups.
The study also looked at the time intervals from when the patient developed symptoms to the physician visit, from the physician visit to the cancer diagnosis, and from the physician visit to the performance of axial imaging. There was no difference in the time of symptom onset to the first visit with a physician in the two groups (0.5 month among those initially misdiagnosed and 0.7 month among those correctly diagnosed).
However, the time from the physician visit to the cancer diagnosis was 3.5 months among those initially misdiagnosed, vs. less than a month (0.6 month) among those who were correctly diagnosed, a statistically significant difference (P <.001), he said.
In addition, for those patients initially misdiagnosed, it took about 1 month longer from the physician visit to the time a CT scan or other type of axial imaging was ordered (an average of 1.1 months vs. 0.1 month, P <.001).
There was also a statistically significant association between a more advanced stage and initial misdiagnosis. Patients who were initially misdiagnosed had a 1.4-fold greater risk of having stage III or IV disease at the time of the pancreatic cancer diagnosis, Dr. Swords said.
Almost 40% (39) of those who were initially misdiagnosed were diagnosed with stage IV disease when they were correctly diagnosed, compared with 23.7% (51 patients) of those who were correctly diagnosed. The proportion diagnosed with stage III disease was similar, 21.4% among those initially misdiagnosed and 20% of those correctly diagnosed. Almost 51% of those correctly diagnosed were diagnosed with stage II disease, vs. 33.7% of those who were initially misdiagnosed. Of those initially misdiagnosed, 5.1% were diagnosed with stage I disease, compared with 5.6% of those correctly diagnosed.
However, the earlier stage at diagnosis for those with an initial correct diagnosis “did not translate into a survival difference,” Dr. Swords said, noting that there was a trend toward shorter survival among those who were initially misdiagnosed (median overall survival of 9.6 vs. 10.3 months).
Based on these results, Dr. Swords said, “surgeons should consider the diagnosis of pancreatic cancer when a patient referred for cholecystectomy has vague or atypical symptoms.”
He said he had no relevant financial disclosures.
WASHINGTON – Initial misdiagnoses were common and were associated with a later disease stage at diagnosis, in a study of 313 patients diagnosed with pancreatic cancer, Dr. Douglas Swords said at the annual Digestive Disease Week.
“By far, the most common misdiagnosis was gallbladder disease,” and there was about a 3-month longer time period, on average, from the first visit to a physician to the actual cancer diagnosis, in patients who were initially misdiagnosed, said Dr. Swords, a surgery resident at the University of Utah, Salt Lake City.
In the series of 313 patients diagnosed with pancreatic cancer, 98 (31.3%) were initially misdiagnosed, with a total of 119 diagnoses other than pancreatic cancer, he said. The most common misdiagnosis was gallbladder disease, which led to a cholecystectomy in 38 cases, followed by gastroesophageal reflux disease in 15 cases, and peptic ulcer disease in 11 cases. Those initially misdiagnosed were an average of about 5 years younger.
Patients with an initial misdiagnosis had significantly greater rates of abdominal pain (about 85% vs. about 60%), weight loss (about 85% vs. about 75%), nausea/vomiting (50% vs. almost 40%), and pancreatitis (almost 30% vs. less than 5%), Dr. Swords said. In addition, patients with an initial misdiagnosis had significantly lower rates of jaundice (about 50% vs. almost 80%). The rates of diarrhea and anorexia were not significantly different between the two groups.
The study also looked at the time intervals from when the patient developed symptoms to the physician visit, from the physician visit to the cancer diagnosis, and from the physician visit to the performance of axial imaging. There was no difference in the time of symptom onset to the first visit with a physician in the two groups (0.5 month among those initially misdiagnosed and 0.7 month among those correctly diagnosed).
However, the time from the physician visit to the cancer diagnosis was 3.5 months among those initially misdiagnosed, vs. less than a month (0.6 month) among those who were correctly diagnosed, a statistically significant difference (P <.001), he said.
In addition, for those patients initially misdiagnosed, it took about 1 month longer from the physician visit to the time a CT scan or other type of axial imaging was ordered (an average of 1.1 months vs. 0.1 month, P <.001).
There was also a statistically significant association between a more advanced stage and initial misdiagnosis. Patients who were initially misdiagnosed had a 1.4-fold greater risk of having stage III or IV disease at the time of the pancreatic cancer diagnosis, Dr. Swords said.
Almost 40% (39) of those who were initially misdiagnosed were diagnosed with stage IV disease when they were correctly diagnosed, compared with 23.7% (51 patients) of those who were correctly diagnosed. The proportion diagnosed with stage III disease was similar, 21.4% among those initially misdiagnosed and 20% of those correctly diagnosed. Almost 51% of those correctly diagnosed were diagnosed with stage II disease, vs. 33.7% of those who were initially misdiagnosed. Of those initially misdiagnosed, 5.1% were diagnosed with stage I disease, compared with 5.6% of those correctly diagnosed.
However, the earlier stage at diagnosis for those with an initial correct diagnosis “did not translate into a survival difference,” Dr. Swords said, noting that there was a trend toward shorter survival among those who were initially misdiagnosed (median overall survival of 9.6 vs. 10.3 months).
Based on these results, Dr. Swords said, “surgeons should consider the diagnosis of pancreatic cancer when a patient referred for cholecystectomy has vague or atypical symptoms.”
He said he had no relevant financial disclosures.
WASHINGTON – Initial misdiagnoses were common and were associated with a later disease stage at diagnosis, in a study of 313 patients diagnosed with pancreatic cancer, Dr. Douglas Swords said at the annual Digestive Disease Week.
“By far, the most common misdiagnosis was gallbladder disease,” and there was about a 3-month longer time period, on average, from the first visit to a physician to the actual cancer diagnosis, in patients who were initially misdiagnosed, said Dr. Swords, a surgery resident at the University of Utah, Salt Lake City.
In the series of 313 patients diagnosed with pancreatic cancer, 98 (31.3%) were initially misdiagnosed, with a total of 119 diagnoses other than pancreatic cancer, he said. The most common misdiagnosis was gallbladder disease, which led to a cholecystectomy in 38 cases, followed by gastroesophageal reflux disease in 15 cases, and peptic ulcer disease in 11 cases. Those initially misdiagnosed were an average of about 5 years younger.
Patients with an initial misdiagnosis had significantly greater rates of abdominal pain (about 85% vs. about 60%), weight loss (about 85% vs. about 75%), nausea/vomiting (50% vs. almost 40%), and pancreatitis (almost 30% vs. less than 5%), Dr. Swords said. In addition, patients with an initial misdiagnosis had significantly lower rates of jaundice (about 50% vs. almost 80%). The rates of diarrhea and anorexia were not significantly different between the two groups.
The study also looked at the time intervals from when the patient developed symptoms to the physician visit, from the physician visit to the cancer diagnosis, and from the physician visit to the performance of axial imaging. There was no difference in the time of symptom onset to the first visit with a physician in the two groups (0.5 month among those initially misdiagnosed and 0.7 month among those correctly diagnosed).
However, the time from the physician visit to the cancer diagnosis was 3.5 months among those initially misdiagnosed, vs. less than a month (0.6 month) among those who were correctly diagnosed, a statistically significant difference (P <.001), he said.
In addition, for those patients initially misdiagnosed, it took about 1 month longer from the physician visit to the time a CT scan or other type of axial imaging was ordered (an average of 1.1 months vs. 0.1 month, P <.001).
There was also a statistically significant association between a more advanced stage and initial misdiagnosis. Patients who were initially misdiagnosed had a 1.4-fold greater risk of having stage III or IV disease at the time of the pancreatic cancer diagnosis, Dr. Swords said.
Almost 40% (39) of those who were initially misdiagnosed were diagnosed with stage IV disease when they were correctly diagnosed, compared with 23.7% (51 patients) of those who were correctly diagnosed. The proportion diagnosed with stage III disease was similar, 21.4% among those initially misdiagnosed and 20% of those correctly diagnosed. Almost 51% of those correctly diagnosed were diagnosed with stage II disease, vs. 33.7% of those who were initially misdiagnosed. Of those initially misdiagnosed, 5.1% were diagnosed with stage I disease, compared with 5.6% of those correctly diagnosed.
However, the earlier stage at diagnosis for those with an initial correct diagnosis “did not translate into a survival difference,” Dr. Swords said, noting that there was a trend toward shorter survival among those who were initially misdiagnosed (median overall survival of 9.6 vs. 10.3 months).
Based on these results, Dr. Swords said, “surgeons should consider the diagnosis of pancreatic cancer when a patient referred for cholecystectomy has vague or atypical symptoms.”
He said he had no relevant financial disclosures.
AT DDW® 2015
Key clinical point: Pancreatic cancer is often misdiagnosed, and should be considered in patients with vague or atypical symptoms who are referred for a cholecystectomy.
Major finding: About 31% of patients with pancreatic cancer were initially misdiagnosed, most often with a gallbladder disease–related diagnosis.
Data source: A study of 313 patients diagnosed with pancreatic cancer comparing presenting symptoms, the time it took to reach the correct diagnosis, and other features in patients initially misdiagnosed and those who were not misdiagnosed.
Disclosures: Dr. Swords said he had no relevant financial disclosures.
FDA approves Orkambi for cystic fibrosis
The fixed-dose combination of ivacaftor and lumacaftor has been approved by the Food and Drug Administration for the treatment of cystic fibrosis in people aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. This is the first drug treatment approved for people who have two copies of this mutation, the most common type of cystic fibrosis.
“Today’s approval significantly broadens the availability of targeted treatments for the specific defects that cause cystic fibrosis,” Dr. John Jenkins, director of the Office of New Drugs in the FDA Center for Drug Evaluation and Research, said in a statement. About half of the approximately 30,000 people in the United States who have cystic fibrosis are homozygous for the F508del, the most common CF mutation, according to the FDA.
The combination contains 200 mg of lumacaftor and 125 mg of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator; it is taken twice a day. It will be marketed as Orkambi by Vertex Pharmaceuticals. Ivacaftor, marketed as Kalydeco by Vertex, was approved in January 2012 for treating patients with the G551D mutation (about 4% of patients with CF), and its indications have been expanded since that time to include other CFTR gene mutations.
Dr. Robert Giusti, director of the pediatric cystic fibrosis center at New York University Langone Medical Center, said in an interview that although new treatments have improved survival and patients with CF are now living longer, “we haven’t been able to reverse the downward trend in pulmonary function,” which is about 1%-2% a year in patients with CF. For a significant number of patients with CF, treatment with Orkambi “will reverse that trend and will allow them to maintain their lung function,” he added. Referring to the discovery of the CF gene in 1989, he pointed out that the availability of this treatment for half of all patients with CF is the culmination of more than 25 years of research,.
The approval is “very, very exciting,” said Dr. Susan Millard, director for clinical research for the pediatric cystic fibrosis care center at Helen DeVos Children’s Hospital, Grand Rapids, Mich. Ivacaftor alone was not effective in patients with two copies of the F08del mutation, and both drugs are needed for the beneficial effects, she said in an interview.
Lumacaftor “is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein, and ivacaftor... is designed to enhance the function of the CFTR protein once it reaches the cell surface,” according to a statement from Vertex.
According to the prescribing information for ivacaftor/lumacaftor, “if the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.” The indications and usage section also states that efficacy and safety “have not been established in patients with CF other than those homozygous for the F508del mutation.”
Approval was based on two double-blind, placebo-controlled studies of 1,108 patients with CF with the F508del mutation aged 12 years and older. In the studies, improvements in lung function among those treated with the combination drug were greater than those on placebo.
At 24 weeks, the absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) over placebo, the primary efficacy endpoint, was a mean of 2.6% and 3.0% among those treated with the 400 mg/250 mg fixed dose (two pills) every 12 hours, which were statistically significant changes. In an extension study, the effect was sustained through 48 weeks. There also were reductions in pulmonary exacerbations, improvements in body mass index, and Cystic Fibrosis Questionnaire-Revised improvements – secondary endpoints that favored the treatment arms, according to company presentations at the FDA panel meeting where the drug was reviewed in May.
One of the issues raised by FDA advisers then was that there was no substantial evidence that the efficacy of the combination was greater than with ivacaftor alone. But despite the lack of monotherapy arms and the inability to determine the contribution of the individual components to the treatment effects, the panel agreed that the drug combination had been shown to be efficacious and voted 12-1 that the available safety and efficacy data supported approval for the proposed indication.
Dr. Millard said that one theory that may explain why BMI improves with treatment is that reduced bicarbonate production in CF patients increases the degradation of the pancreatic enzymes they take, and that the drug may result in more appropriate bicarbonate secretion. This possibility is being evaluated in studies comparing bicarbonate secretion in patients on and off the drug, she said.
The drug was reviewed under the FDA’s priority review program, which evaluates a drug “that may offer significant improvement in safety or effectiveness in treatment over available therapy in a serious disease or condition” in 6 months, instead of the usual 10 months, the FDA statement said. Orkambi has also been designated as an orphan drug, because it is used to treat a rare disease.
The wholesale acquisition cost of Orkambi is $259,000 per year. Vertex will offer a co-pay assistance program for patients with commercial insurance, and a free medicine program for uninsured patients who qualify, the company announced during a telephone briefing after the approval announcement. There are an estimated 8,500 patients aged 12 and older with CF with 2 copies of the F508del mutation in the United States; about 35%-40% are on Medicaid, and the majority of the remainder have commercial insurance, according to the company.
Dr. Giusti had no disclosures. Dr. Millard, an investigator in past and current trials of Orkambi, said she had no other disclosures.
emechcatie@frontlinemedcom.com
This article was updated on 7/6/2015.
The fixed-dose combination of ivacaftor and lumacaftor has been approved by the Food and Drug Administration for the treatment of cystic fibrosis in people aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. This is the first drug treatment approved for people who have two copies of this mutation, the most common type of cystic fibrosis.
“Today’s approval significantly broadens the availability of targeted treatments for the specific defects that cause cystic fibrosis,” Dr. John Jenkins, director of the Office of New Drugs in the FDA Center for Drug Evaluation and Research, said in a statement. About half of the approximately 30,000 people in the United States who have cystic fibrosis are homozygous for the F508del, the most common CF mutation, according to the FDA.
The combination contains 200 mg of lumacaftor and 125 mg of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator; it is taken twice a day. It will be marketed as Orkambi by Vertex Pharmaceuticals. Ivacaftor, marketed as Kalydeco by Vertex, was approved in January 2012 for treating patients with the G551D mutation (about 4% of patients with CF), and its indications have been expanded since that time to include other CFTR gene mutations.
Dr. Robert Giusti, director of the pediatric cystic fibrosis center at New York University Langone Medical Center, said in an interview that although new treatments have improved survival and patients with CF are now living longer, “we haven’t been able to reverse the downward trend in pulmonary function,” which is about 1%-2% a year in patients with CF. For a significant number of patients with CF, treatment with Orkambi “will reverse that trend and will allow them to maintain their lung function,” he added. Referring to the discovery of the CF gene in 1989, he pointed out that the availability of this treatment for half of all patients with CF is the culmination of more than 25 years of research,.
The approval is “very, very exciting,” said Dr. Susan Millard, director for clinical research for the pediatric cystic fibrosis care center at Helen DeVos Children’s Hospital, Grand Rapids, Mich. Ivacaftor alone was not effective in patients with two copies of the F08del mutation, and both drugs are needed for the beneficial effects, she said in an interview.
Lumacaftor “is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein, and ivacaftor... is designed to enhance the function of the CFTR protein once it reaches the cell surface,” according to a statement from Vertex.
According to the prescribing information for ivacaftor/lumacaftor, “if the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.” The indications and usage section also states that efficacy and safety “have not been established in patients with CF other than those homozygous for the F508del mutation.”
Approval was based on two double-blind, placebo-controlled studies of 1,108 patients with CF with the F508del mutation aged 12 years and older. In the studies, improvements in lung function among those treated with the combination drug were greater than those on placebo.
At 24 weeks, the absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) over placebo, the primary efficacy endpoint, was a mean of 2.6% and 3.0% among those treated with the 400 mg/250 mg fixed dose (two pills) every 12 hours, which were statistically significant changes. In an extension study, the effect was sustained through 48 weeks. There also were reductions in pulmonary exacerbations, improvements in body mass index, and Cystic Fibrosis Questionnaire-Revised improvements – secondary endpoints that favored the treatment arms, according to company presentations at the FDA panel meeting where the drug was reviewed in May.
One of the issues raised by FDA advisers then was that there was no substantial evidence that the efficacy of the combination was greater than with ivacaftor alone. But despite the lack of monotherapy arms and the inability to determine the contribution of the individual components to the treatment effects, the panel agreed that the drug combination had been shown to be efficacious and voted 12-1 that the available safety and efficacy data supported approval for the proposed indication.
Dr. Millard said that one theory that may explain why BMI improves with treatment is that reduced bicarbonate production in CF patients increases the degradation of the pancreatic enzymes they take, and that the drug may result in more appropriate bicarbonate secretion. This possibility is being evaluated in studies comparing bicarbonate secretion in patients on and off the drug, she said.
The drug was reviewed under the FDA’s priority review program, which evaluates a drug “that may offer significant improvement in safety or effectiveness in treatment over available therapy in a serious disease or condition” in 6 months, instead of the usual 10 months, the FDA statement said. Orkambi has also been designated as an orphan drug, because it is used to treat a rare disease.
The wholesale acquisition cost of Orkambi is $259,000 per year. Vertex will offer a co-pay assistance program for patients with commercial insurance, and a free medicine program for uninsured patients who qualify, the company announced during a telephone briefing after the approval announcement. There are an estimated 8,500 patients aged 12 and older with CF with 2 copies of the F508del mutation in the United States; about 35%-40% are on Medicaid, and the majority of the remainder have commercial insurance, according to the company.
Dr. Giusti had no disclosures. Dr. Millard, an investigator in past and current trials of Orkambi, said she had no other disclosures.
emechcatie@frontlinemedcom.com
This article was updated on 7/6/2015.
The fixed-dose combination of ivacaftor and lumacaftor has been approved by the Food and Drug Administration for the treatment of cystic fibrosis in people aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. This is the first drug treatment approved for people who have two copies of this mutation, the most common type of cystic fibrosis.
“Today’s approval significantly broadens the availability of targeted treatments for the specific defects that cause cystic fibrosis,” Dr. John Jenkins, director of the Office of New Drugs in the FDA Center for Drug Evaluation and Research, said in a statement. About half of the approximately 30,000 people in the United States who have cystic fibrosis are homozygous for the F508del, the most common CF mutation, according to the FDA.
The combination contains 200 mg of lumacaftor and 125 mg of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator; it is taken twice a day. It will be marketed as Orkambi by Vertex Pharmaceuticals. Ivacaftor, marketed as Kalydeco by Vertex, was approved in January 2012 for treating patients with the G551D mutation (about 4% of patients with CF), and its indications have been expanded since that time to include other CFTR gene mutations.
Dr. Robert Giusti, director of the pediatric cystic fibrosis center at New York University Langone Medical Center, said in an interview that although new treatments have improved survival and patients with CF are now living longer, “we haven’t been able to reverse the downward trend in pulmonary function,” which is about 1%-2% a year in patients with CF. For a significant number of patients with CF, treatment with Orkambi “will reverse that trend and will allow them to maintain their lung function,” he added. Referring to the discovery of the CF gene in 1989, he pointed out that the availability of this treatment for half of all patients with CF is the culmination of more than 25 years of research,.
The approval is “very, very exciting,” said Dr. Susan Millard, director for clinical research for the pediatric cystic fibrosis care center at Helen DeVos Children’s Hospital, Grand Rapids, Mich. Ivacaftor alone was not effective in patients with two copies of the F08del mutation, and both drugs are needed for the beneficial effects, she said in an interview.
Lumacaftor “is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein, and ivacaftor... is designed to enhance the function of the CFTR protein once it reaches the cell surface,” according to a statement from Vertex.
According to the prescribing information for ivacaftor/lumacaftor, “if the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.” The indications and usage section also states that efficacy and safety “have not been established in patients with CF other than those homozygous for the F508del mutation.”
Approval was based on two double-blind, placebo-controlled studies of 1,108 patients with CF with the F508del mutation aged 12 years and older. In the studies, improvements in lung function among those treated with the combination drug were greater than those on placebo.
At 24 weeks, the absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) over placebo, the primary efficacy endpoint, was a mean of 2.6% and 3.0% among those treated with the 400 mg/250 mg fixed dose (two pills) every 12 hours, which were statistically significant changes. In an extension study, the effect was sustained through 48 weeks. There also were reductions in pulmonary exacerbations, improvements in body mass index, and Cystic Fibrosis Questionnaire-Revised improvements – secondary endpoints that favored the treatment arms, according to company presentations at the FDA panel meeting where the drug was reviewed in May.
One of the issues raised by FDA advisers then was that there was no substantial evidence that the efficacy of the combination was greater than with ivacaftor alone. But despite the lack of monotherapy arms and the inability to determine the contribution of the individual components to the treatment effects, the panel agreed that the drug combination had been shown to be efficacious and voted 12-1 that the available safety and efficacy data supported approval for the proposed indication.
Dr. Millard said that one theory that may explain why BMI improves with treatment is that reduced bicarbonate production in CF patients increases the degradation of the pancreatic enzymes they take, and that the drug may result in more appropriate bicarbonate secretion. This possibility is being evaluated in studies comparing bicarbonate secretion in patients on and off the drug, she said.
The drug was reviewed under the FDA’s priority review program, which evaluates a drug “that may offer significant improvement in safety or effectiveness in treatment over available therapy in a serious disease or condition” in 6 months, instead of the usual 10 months, the FDA statement said. Orkambi has also been designated as an orphan drug, because it is used to treat a rare disease.
The wholesale acquisition cost of Orkambi is $259,000 per year. Vertex will offer a co-pay assistance program for patients with commercial insurance, and a free medicine program for uninsured patients who qualify, the company announced during a telephone briefing after the approval announcement. There are an estimated 8,500 patients aged 12 and older with CF with 2 copies of the F508del mutation in the United States; about 35%-40% are on Medicaid, and the majority of the remainder have commercial insurance, according to the company.
Dr. Giusti had no disclosures. Dr. Millard, an investigator in past and current trials of Orkambi, said she had no other disclosures.
emechcatie@frontlinemedcom.com
This article was updated on 7/6/2015.
Restylane Lyft approved for cheeks, midface concerns
Restylane Lyft has been approved for cheek augmentation and correction of age-related midface contour deficiencies in people more than 21 years of age, the manufacturer, Galderma announced on July 2.
Restylane Lyft, an injectable hyaluronic acid gel, contains lidocaine. It is already approved for mid- to deep-dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds, and for submucosal implantation for lip augmentation in patients 21 years and older, according to the prescribing information.
Approval of Restylane Lyft was based on a study of 200 patients; results included improvements “in the fullness in the right and left midface areas (combined) at 2 months” in almost 90% of the patients, according to a statement from the manufacturer.
The most common adverse events included tenderness, redness, bruising, swelling, and itching, most of which resolved within 2 weeks, the release said.
Contraindications to Restylane Lyft included severe allergies (a history of anaphylaxis or the history or presence of multiple severe allergies) and bleeding disorders.
Restylane Lyft was previously marketed as Perlane-L, according to Galderma.
Restylane Lyft has been approved for cheek augmentation and correction of age-related midface contour deficiencies in people more than 21 years of age, the manufacturer, Galderma announced on July 2.
Restylane Lyft, an injectable hyaluronic acid gel, contains lidocaine. It is already approved for mid- to deep-dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds, and for submucosal implantation for lip augmentation in patients 21 years and older, according to the prescribing information.
Approval of Restylane Lyft was based on a study of 200 patients; results included improvements “in the fullness in the right and left midface areas (combined) at 2 months” in almost 90% of the patients, according to a statement from the manufacturer.
The most common adverse events included tenderness, redness, bruising, swelling, and itching, most of which resolved within 2 weeks, the release said.
Contraindications to Restylane Lyft included severe allergies (a history of anaphylaxis or the history or presence of multiple severe allergies) and bleeding disorders.
Restylane Lyft was previously marketed as Perlane-L, according to Galderma.
Restylane Lyft has been approved for cheek augmentation and correction of age-related midface contour deficiencies in people more than 21 years of age, the manufacturer, Galderma announced on July 2.
Restylane Lyft, an injectable hyaluronic acid gel, contains lidocaine. It is already approved for mid- to deep-dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds, and for submucosal implantation for lip augmentation in patients 21 years and older, according to the prescribing information.
Approval of Restylane Lyft was based on a study of 200 patients; results included improvements “in the fullness in the right and left midface areas (combined) at 2 months” in almost 90% of the patients, according to a statement from the manufacturer.
The most common adverse events included tenderness, redness, bruising, swelling, and itching, most of which resolved within 2 weeks, the release said.
Contraindications to Restylane Lyft included severe allergies (a history of anaphylaxis or the history or presence of multiple severe allergies) and bleeding disorders.
Restylane Lyft was previously marketed as Perlane-L, according to Galderma.
DDW: LINX device beneficial, safe for GERD
WASHINGTON – Five-year follow-up data on the magnetic device approved for treating gastroesophageal reflux disease confirm its long-term safety and efficacy, Dr. Robert A. Ganz reported at the annual Digestive Disease Week.
Five years after device implantation, the proportion of patients experiencing moderate to severe regurgitation had dropped to about 1%, from almost 60% at baseline, and two-thirds of patients were not taking any proton pump inhibitors (PPIs), said Dr. Ganz, chief of gastroenterology at Abbott Northwestern Hospital, Minneapolis, and one of the study investigators. These were among the results of the study that evaluated the device, the LINX Reflux Management System. The device was approved by the Food and Drug Administration FDA) in 2012 and is for the treatment of people with GERD as defined by abnormal pH testing, who continue to have chronic GERD symptoms that persist despite maximum medical therapy for the treatment of reflux.
“Magnetic sphincter augmentation should be considered first-line surgical therapy for those with gastroesophageal reflux disease, based on the results of this study,” he said.
The 2-year results of the prospective, multicenter study were the basis of the FDA approval of the device, described by the manufacturer, Torax Medical, as a “small implant [composed] of interlinked titanium beads with magnetic cores,” implanted during standard laparoscopy. The magnetic attraction between the beads augments the existing esophageal sphincter’s barrier function to prevent reflux,” according to the company.
The study enrolled 100 patients with reflux disease with a median age of 53 years, who had experienced typical heartburn for at least 6 months with or without regurgitation and were taking PPIs daily for at least 3 months (median use 5 years). Patients had GERD for a median of 10 years (range: 1-40 years). People who had any type of previous gastric or esophageal surgery, Barrett’s esophagus, a hiatal hernia greater than 3 cm, a body mass index over 35 kg/m2, or grade C or D esophagitis were excluded.
The device was implanted in all patients, who served as their own controls; 85 patients were followed through 5 years (6 were lost to follow-up, the device was explanted in 6 patients, 2 patients did not consent to extended follow-up, and 1 patient died of an unrelated cancer). The median procedure time was 36 minutes with a range of 7-125 minutes); all procedures were successfully completed with no intraoperative complications and all patients were discharged within 24 hours on an unrestricted diet.
The median total Gastroesophageal Reflux Disease–Health-Related Quality of Life (GERD-HRQL) score at baseline was 27 points among those not on PPIs and 11 points on PPIs, dropping to 4 points at 5 years off PPIs. At baseline, 95% of patients expressed dissatisfaction related to reflux, which dropped to 7% at year 5. Moderate to severe heartburn was reported by 89% at baseline, dropping to about 12% at year 5. The proportion of patients experiencing moderate to severe regurgitation dropped from 57% at baseline to about 1% at 5 years, Dr. Ganz said.
At baseline, 100% were taking PPIs every day, compared with 15% at 5 years. (At 5 years, 75% had discontinued PPIs, and about 9% reported PRN use only). Grade A and B esophagitis decreased from 40% at baseline to 16% at 5 years, at which point most cases were grade A, and there were no patients with grade C or D esophagitis, he said. In addition, at 5 years, 100% of patients “reported the ability to belch, and those needing to vomit – about 16% – reported the ability to vomit,” demonstrating that normal physiology was preserved with the device.
At 5 years, there were no device erosions or migrations, or any significant adverse events other than dysphagia, which “was typically mild and not associated with weight loss and tended to resolve over time,” from about 70% in the first few weeks after surgery to 11% at 1 year and 7% at 5 years, Dr. Ganz said.
In seven cases, the device was removed laparoscopically, with no complications and gastric anatomy was preserved for future treatments. All removals were elective. The device was removed in four patients because of dysphagia, which completely resolved in those patients. One patient had the device removed because of vomiting of unknown cause that persisted after removal. Another two patients who “had the device removed for disease management” continued to experience reflux and had “uneventful” Nissen fundoplication,” he said.
“Five years after magnetic augmentation, we have demonstrated objective evidence of reduction in acid exposure and in the majority of patients, normalized pH [and] we demonstrated significant and durable improvement in all group parameters measured, with preservation of fundic anatomy and normal physiology, with the ability to belch and vomit,” Dr. Ganz concluded. The results also show that the “procedure is reproducible, safe and reversible if necessary,” he added, noting that one of the limitations of the study was that subjects served as their own controls. During the discussion period, he was asked about hiatal hernia repairs, an apparent trend to “decay” from years 1 to 5 in some parameters measured, and dysphagia after the procedure.
About 40% of the patients in the study had a hiatal hernia, and about one-third of these patients had a hernia repair. A subgroup analysis of the data is being performed to evaluate the impact of hernia repair, Dr. Ganz said.
PPI use increased from 8% in year 4, to 15% in year 5. The reason for this s difficult to determine but “even though there is a bit of a decay, patients are still quite satisfied at 5 years,” Dr. Ganz remarked, also referring to the marked impact on regurgitation. Many U.S. patients use PPIs for reasons other than reflux, and studies show that many patients are on PPIs after the Nissen procedure in the absence of pathologic pH scores, he pointed out.
Compared with the type of dysphagia patients experience after the Nissen procedure, which is immediate and improves with time, Dr. Ganz said that the dysphagia associated with the device “seemed to peak around 2 weeks and then it slowly improved with time, so this may be more of a scar tissue–associated dysphagia than an edema dysphagia, but … it does improve with time.
Three-year results of the study were published in 2013 (N. Engl. J. Med. 2013;368:719-72), Dr. Ganz was the lead author.
The study was funded by Torax Medical. Dr. Ganz had no disclosures related to the topic of this presentation.
*This story was updated 7/9/2015.
At DDW this year, Dr. Ganz reported on the 5-year follow-up of the original LINX data that was published in the New England Journal of Medicine in 2013 (368:2039-40). The original study enrolled and followed 100 reflux patients for 3 years after implantation of the magnetic sphincter augmentation device, and it appears that the successful outcomes are sustained over the 5-year period. Most notable are the lasting improvement in regurgitation and the dramatic reduction in requirement for maintenance PPI therapy. These findings led the investigators to suggest that this should be considered a first-line surgical therapy for GERD. Overall, this is not an unreasonable statement when one considers the current model wherein antireflux surgery fits in the treatment of GERD. Medical therapy with proton pump inhibitors is extremely safe and effective for a substantial number of patients with GERD and based on this risk/benefit profile should be the first line therapy (Am. J. Gastroenterol. 2013;108:308-28; quiz 329). However, this treatment is not perfect and there are many patients who continue to have persistent symptoms despite PPI therapy (Clin. Gastroenterol. Hepatol. 2012;10:612-9). Although the majority of PPI nonresponders have a functional etiology, there is a distinct population that continue to have refractory reflux-related symptoms, such as regurgitation, that escape the therapeutic target of PPIs. These patients will require an augmentation of the antireflux barrier and the LINX approach appears to be as effective as fundoplication in this regard (J. Am. Coll. Surg. 2015;221:123-8). The question is whether the side effect profile and durability of LINX is better than fundoplication. The answer here is not clear and I would carefully state that LINX and fundoplication can be considered first-line surgical therapies for GERD patients who have documented pathologic acid gastroesophageal reflux and are intolerant to PPIs or not responding to PPIs.
Dr. John E. Pandolfino is professor of medicine and chief of the division of gastroenterology and hepatology at Northwestern University, Chicago. He is a speaker for Astra Zeneca/Takeda and a consultant for EndoGastric Solutions.
At DDW this year, Dr. Ganz reported on the 5-year follow-up of the original LINX data that was published in the New England Journal of Medicine in 2013 (368:2039-40). The original study enrolled and followed 100 reflux patients for 3 years after implantation of the magnetic sphincter augmentation device, and it appears that the successful outcomes are sustained over the 5-year period. Most notable are the lasting improvement in regurgitation and the dramatic reduction in requirement for maintenance PPI therapy. These findings led the investigators to suggest that this should be considered a first-line surgical therapy for GERD. Overall, this is not an unreasonable statement when one considers the current model wherein antireflux surgery fits in the treatment of GERD. Medical therapy with proton pump inhibitors is extremely safe and effective for a substantial number of patients with GERD and based on this risk/benefit profile should be the first line therapy (Am. J. Gastroenterol. 2013;108:308-28; quiz 329). However, this treatment is not perfect and there are many patients who continue to have persistent symptoms despite PPI therapy (Clin. Gastroenterol. Hepatol. 2012;10:612-9). Although the majority of PPI nonresponders have a functional etiology, there is a distinct population that continue to have refractory reflux-related symptoms, such as regurgitation, that escape the therapeutic target of PPIs. These patients will require an augmentation of the antireflux barrier and the LINX approach appears to be as effective as fundoplication in this regard (J. Am. Coll. Surg. 2015;221:123-8). The question is whether the side effect profile and durability of LINX is better than fundoplication. The answer here is not clear and I would carefully state that LINX and fundoplication can be considered first-line surgical therapies for GERD patients who have documented pathologic acid gastroesophageal reflux and are intolerant to PPIs or not responding to PPIs.
Dr. John E. Pandolfino is professor of medicine and chief of the division of gastroenterology and hepatology at Northwestern University, Chicago. He is a speaker for Astra Zeneca/Takeda and a consultant for EndoGastric Solutions.
At DDW this year, Dr. Ganz reported on the 5-year follow-up of the original LINX data that was published in the New England Journal of Medicine in 2013 (368:2039-40). The original study enrolled and followed 100 reflux patients for 3 years after implantation of the magnetic sphincter augmentation device, and it appears that the successful outcomes are sustained over the 5-year period. Most notable are the lasting improvement in regurgitation and the dramatic reduction in requirement for maintenance PPI therapy. These findings led the investigators to suggest that this should be considered a first-line surgical therapy for GERD. Overall, this is not an unreasonable statement when one considers the current model wherein antireflux surgery fits in the treatment of GERD. Medical therapy with proton pump inhibitors is extremely safe and effective for a substantial number of patients with GERD and based on this risk/benefit profile should be the first line therapy (Am. J. Gastroenterol. 2013;108:308-28; quiz 329). However, this treatment is not perfect and there are many patients who continue to have persistent symptoms despite PPI therapy (Clin. Gastroenterol. Hepatol. 2012;10:612-9). Although the majority of PPI nonresponders have a functional etiology, there is a distinct population that continue to have refractory reflux-related symptoms, such as regurgitation, that escape the therapeutic target of PPIs. These patients will require an augmentation of the antireflux barrier and the LINX approach appears to be as effective as fundoplication in this regard (J. Am. Coll. Surg. 2015;221:123-8). The question is whether the side effect profile and durability of LINX is better than fundoplication. The answer here is not clear and I would carefully state that LINX and fundoplication can be considered first-line surgical therapies for GERD patients who have documented pathologic acid gastroesophageal reflux and are intolerant to PPIs or not responding to PPIs.
Dr. John E. Pandolfino is professor of medicine and chief of the division of gastroenterology and hepatology at Northwestern University, Chicago. He is a speaker for Astra Zeneca/Takeda and a consultant for EndoGastric Solutions.
WASHINGTON – Five-year follow-up data on the magnetic device approved for treating gastroesophageal reflux disease confirm its long-term safety and efficacy, Dr. Robert A. Ganz reported at the annual Digestive Disease Week.
Five years after device implantation, the proportion of patients experiencing moderate to severe regurgitation had dropped to about 1%, from almost 60% at baseline, and two-thirds of patients were not taking any proton pump inhibitors (PPIs), said Dr. Ganz, chief of gastroenterology at Abbott Northwestern Hospital, Minneapolis, and one of the study investigators. These were among the results of the study that evaluated the device, the LINX Reflux Management System. The device was approved by the Food and Drug Administration FDA) in 2012 and is for the treatment of people with GERD as defined by abnormal pH testing, who continue to have chronic GERD symptoms that persist despite maximum medical therapy for the treatment of reflux.
“Magnetic sphincter augmentation should be considered first-line surgical therapy for those with gastroesophageal reflux disease, based on the results of this study,” he said.
The 2-year results of the prospective, multicenter study were the basis of the FDA approval of the device, described by the manufacturer, Torax Medical, as a “small implant [composed] of interlinked titanium beads with magnetic cores,” implanted during standard laparoscopy. The magnetic attraction between the beads augments the existing esophageal sphincter’s barrier function to prevent reflux,” according to the company.
The study enrolled 100 patients with reflux disease with a median age of 53 years, who had experienced typical heartburn for at least 6 months with or without regurgitation and were taking PPIs daily for at least 3 months (median use 5 years). Patients had GERD for a median of 10 years (range: 1-40 years). People who had any type of previous gastric or esophageal surgery, Barrett’s esophagus, a hiatal hernia greater than 3 cm, a body mass index over 35 kg/m2, or grade C or D esophagitis were excluded.
The device was implanted in all patients, who served as their own controls; 85 patients were followed through 5 years (6 were lost to follow-up, the device was explanted in 6 patients, 2 patients did not consent to extended follow-up, and 1 patient died of an unrelated cancer). The median procedure time was 36 minutes with a range of 7-125 minutes); all procedures were successfully completed with no intraoperative complications and all patients were discharged within 24 hours on an unrestricted diet.
The median total Gastroesophageal Reflux Disease–Health-Related Quality of Life (GERD-HRQL) score at baseline was 27 points among those not on PPIs and 11 points on PPIs, dropping to 4 points at 5 years off PPIs. At baseline, 95% of patients expressed dissatisfaction related to reflux, which dropped to 7% at year 5. Moderate to severe heartburn was reported by 89% at baseline, dropping to about 12% at year 5. The proportion of patients experiencing moderate to severe regurgitation dropped from 57% at baseline to about 1% at 5 years, Dr. Ganz said.
At baseline, 100% were taking PPIs every day, compared with 15% at 5 years. (At 5 years, 75% had discontinued PPIs, and about 9% reported PRN use only). Grade A and B esophagitis decreased from 40% at baseline to 16% at 5 years, at which point most cases were grade A, and there were no patients with grade C or D esophagitis, he said. In addition, at 5 years, 100% of patients “reported the ability to belch, and those needing to vomit – about 16% – reported the ability to vomit,” demonstrating that normal physiology was preserved with the device.
At 5 years, there were no device erosions or migrations, or any significant adverse events other than dysphagia, which “was typically mild and not associated with weight loss and tended to resolve over time,” from about 70% in the first few weeks after surgery to 11% at 1 year and 7% at 5 years, Dr. Ganz said.
In seven cases, the device was removed laparoscopically, with no complications and gastric anatomy was preserved for future treatments. All removals were elective. The device was removed in four patients because of dysphagia, which completely resolved in those patients. One patient had the device removed because of vomiting of unknown cause that persisted after removal. Another two patients who “had the device removed for disease management” continued to experience reflux and had “uneventful” Nissen fundoplication,” he said.
“Five years after magnetic augmentation, we have demonstrated objective evidence of reduction in acid exposure and in the majority of patients, normalized pH [and] we demonstrated significant and durable improvement in all group parameters measured, with preservation of fundic anatomy and normal physiology, with the ability to belch and vomit,” Dr. Ganz concluded. The results also show that the “procedure is reproducible, safe and reversible if necessary,” he added, noting that one of the limitations of the study was that subjects served as their own controls. During the discussion period, he was asked about hiatal hernia repairs, an apparent trend to “decay” from years 1 to 5 in some parameters measured, and dysphagia after the procedure.
About 40% of the patients in the study had a hiatal hernia, and about one-third of these patients had a hernia repair. A subgroup analysis of the data is being performed to evaluate the impact of hernia repair, Dr. Ganz said.
PPI use increased from 8% in year 4, to 15% in year 5. The reason for this s difficult to determine but “even though there is a bit of a decay, patients are still quite satisfied at 5 years,” Dr. Ganz remarked, also referring to the marked impact on regurgitation. Many U.S. patients use PPIs for reasons other than reflux, and studies show that many patients are on PPIs after the Nissen procedure in the absence of pathologic pH scores, he pointed out.
Compared with the type of dysphagia patients experience after the Nissen procedure, which is immediate and improves with time, Dr. Ganz said that the dysphagia associated with the device “seemed to peak around 2 weeks and then it slowly improved with time, so this may be more of a scar tissue–associated dysphagia than an edema dysphagia, but … it does improve with time.
Three-year results of the study were published in 2013 (N. Engl. J. Med. 2013;368:719-72), Dr. Ganz was the lead author.
The study was funded by Torax Medical. Dr. Ganz had no disclosures related to the topic of this presentation.
*This story was updated 7/9/2015.
WASHINGTON – Five-year follow-up data on the magnetic device approved for treating gastroesophageal reflux disease confirm its long-term safety and efficacy, Dr. Robert A. Ganz reported at the annual Digestive Disease Week.
Five years after device implantation, the proportion of patients experiencing moderate to severe regurgitation had dropped to about 1%, from almost 60% at baseline, and two-thirds of patients were not taking any proton pump inhibitors (PPIs), said Dr. Ganz, chief of gastroenterology at Abbott Northwestern Hospital, Minneapolis, and one of the study investigators. These were among the results of the study that evaluated the device, the LINX Reflux Management System. The device was approved by the Food and Drug Administration FDA) in 2012 and is for the treatment of people with GERD as defined by abnormal pH testing, who continue to have chronic GERD symptoms that persist despite maximum medical therapy for the treatment of reflux.
“Magnetic sphincter augmentation should be considered first-line surgical therapy for those with gastroesophageal reflux disease, based on the results of this study,” he said.
The 2-year results of the prospective, multicenter study were the basis of the FDA approval of the device, described by the manufacturer, Torax Medical, as a “small implant [composed] of interlinked titanium beads with magnetic cores,” implanted during standard laparoscopy. The magnetic attraction between the beads augments the existing esophageal sphincter’s barrier function to prevent reflux,” according to the company.
The study enrolled 100 patients with reflux disease with a median age of 53 years, who had experienced typical heartburn for at least 6 months with or without regurgitation and were taking PPIs daily for at least 3 months (median use 5 years). Patients had GERD for a median of 10 years (range: 1-40 years). People who had any type of previous gastric or esophageal surgery, Barrett’s esophagus, a hiatal hernia greater than 3 cm, a body mass index over 35 kg/m2, or grade C or D esophagitis were excluded.
The device was implanted in all patients, who served as their own controls; 85 patients were followed through 5 years (6 were lost to follow-up, the device was explanted in 6 patients, 2 patients did not consent to extended follow-up, and 1 patient died of an unrelated cancer). The median procedure time was 36 minutes with a range of 7-125 minutes); all procedures were successfully completed with no intraoperative complications and all patients were discharged within 24 hours on an unrestricted diet.
The median total Gastroesophageal Reflux Disease–Health-Related Quality of Life (GERD-HRQL) score at baseline was 27 points among those not on PPIs and 11 points on PPIs, dropping to 4 points at 5 years off PPIs. At baseline, 95% of patients expressed dissatisfaction related to reflux, which dropped to 7% at year 5. Moderate to severe heartburn was reported by 89% at baseline, dropping to about 12% at year 5. The proportion of patients experiencing moderate to severe regurgitation dropped from 57% at baseline to about 1% at 5 years, Dr. Ganz said.
At baseline, 100% were taking PPIs every day, compared with 15% at 5 years. (At 5 years, 75% had discontinued PPIs, and about 9% reported PRN use only). Grade A and B esophagitis decreased from 40% at baseline to 16% at 5 years, at which point most cases were grade A, and there were no patients with grade C or D esophagitis, he said. In addition, at 5 years, 100% of patients “reported the ability to belch, and those needing to vomit – about 16% – reported the ability to vomit,” demonstrating that normal physiology was preserved with the device.
At 5 years, there were no device erosions or migrations, or any significant adverse events other than dysphagia, which “was typically mild and not associated with weight loss and tended to resolve over time,” from about 70% in the first few weeks after surgery to 11% at 1 year and 7% at 5 years, Dr. Ganz said.
In seven cases, the device was removed laparoscopically, with no complications and gastric anatomy was preserved for future treatments. All removals were elective. The device was removed in four patients because of dysphagia, which completely resolved in those patients. One patient had the device removed because of vomiting of unknown cause that persisted after removal. Another two patients who “had the device removed for disease management” continued to experience reflux and had “uneventful” Nissen fundoplication,” he said.
“Five years after magnetic augmentation, we have demonstrated objective evidence of reduction in acid exposure and in the majority of patients, normalized pH [and] we demonstrated significant and durable improvement in all group parameters measured, with preservation of fundic anatomy and normal physiology, with the ability to belch and vomit,” Dr. Ganz concluded. The results also show that the “procedure is reproducible, safe and reversible if necessary,” he added, noting that one of the limitations of the study was that subjects served as their own controls. During the discussion period, he was asked about hiatal hernia repairs, an apparent trend to “decay” from years 1 to 5 in some parameters measured, and dysphagia after the procedure.
About 40% of the patients in the study had a hiatal hernia, and about one-third of these patients had a hernia repair. A subgroup analysis of the data is being performed to evaluate the impact of hernia repair, Dr. Ganz said.
PPI use increased from 8% in year 4, to 15% in year 5. The reason for this s difficult to determine but “even though there is a bit of a decay, patients are still quite satisfied at 5 years,” Dr. Ganz remarked, also referring to the marked impact on regurgitation. Many U.S. patients use PPIs for reasons other than reflux, and studies show that many patients are on PPIs after the Nissen procedure in the absence of pathologic pH scores, he pointed out.
Compared with the type of dysphagia patients experience after the Nissen procedure, which is immediate and improves with time, Dr. Ganz said that the dysphagia associated with the device “seemed to peak around 2 weeks and then it slowly improved with time, so this may be more of a scar tissue–associated dysphagia than an edema dysphagia, but … it does improve with time.
Three-year results of the study were published in 2013 (N. Engl. J. Med. 2013;368:719-72), Dr. Ganz was the lead author.
The study was funded by Torax Medical. Dr. Ganz had no disclosures related to the topic of this presentation.
*This story was updated 7/9/2015.
AT DDW 2015
Key clinical point: A magnetic device designed to augment the lower esophageal sphincter is a surgical option that can be expected to provide long-term control of reflux symptoms in patients with GERD.
Major finding: Improvements 5 years after treatment with the Linx Reflux Management System include a drop from 60% experiencing regurgitation to 1%, and two-third of patients no longer taking PPIs.
Data source: The multicenter, prospective study evaluated the long-term safety and efficacy of the device over 5 years in 100 patients with GERD, who served as their own controls; 85 were included in the 5-year follow-up.
Disclosures: The study was funded by the device manufacturer, Torax Medical. Dr. Ganz had no disclosures related to the topic of this presentation.
HBV, tuberculosis reactivations after anti-TNFs rare in IBD patients on biologic therapy
WASHINGTON – Reactivation of tuberculosis and hepatitis B virus infections after starting treatment with anti–tumor necrosis factor (TNF) therapy was “rare” in a large national cohort study of veterans with inflammatory bowel disease (IBD), Dr. Jason Hou reported at the annual Digestive Disease Week.
The estimated rate of tuberculosis reactivations was 2.8 per 10,000 patient-years of exposure to anti-TNF therapy “in a fairly well-screened cohort of IBD patients,” said Dr. Hou, codirector of the Inflammatory Bowel Disease Center at Baylor College of Medicine, Houston. The estimate for HBV reactivation or acute liver failure in this cohort was less than 1.4 per 10,000 patient-years of exposure, he noted.
Practice guidelines recommend that patients with IBD should be screened for latent tuberculosis and HBV before starting treatment with an anti-TNF drug, but how often reactivation actually occurs in this population is not known, he pointed out. Moreover, recent studies have questioned the cost-effectiveness of universal screening for HBV before starting treatment, and TB reactivation rates in patients with IBD treated with anti-TNF drugs “have not been assessed on a national population level.”
Dr. Hou and his associates used a national Veterans Affairs database to identify patients who had been diagnosed between 2003 and 2011 with Crohn’s disease or ulcerative colitis, based on ICD-9 codes, and had filled at least one prescription for infliximab, adalimumab, or certolizumab pegol; they also looked for codes related to possible tuberculosis reactivation or acute liver failure related to HBV reactivation at the time of or after anti-TNF therapy was started. Cases were then verified by reviewing electronic medical records of patients to confirm the diagnosis of tuberculosis or HBV, exposure to an anti-TNF drug, and completion of pretreatment screening.
They identified 3,357 patients with IBD who had received a prescription for an anti-TNF treatment, representing 7,210 patient-years of anti-TNF treatment; most were men and were white. The mean time on treatment was about 2 years, and they had started treatment at a mean age of 57 years.
Screening rates for tuberculosis were relatively high and remained stable throughout the study period, at 72% overall, but HBV screening rates were low, at 24% overall. HBV screening was not included in practice guidelines until 2006, and the rate significantly increased from under 10% at the beginning of the period studied to 42% at the end, Dr. Hou noted.
They identified 23 patients with ICD-9 codes related to tuberculosis occurring after they started anti-TNF therapy, but “on chart review, only two patients were confirmed to have tuberculosis reactivation” related to anti-TNF therapy, which occurred at 8 and 18 months of treatment, he said. “Very interestingly, both of these patients had latent tuberculosis and documented completed courses of INH [isonicotinylhydrazine] and a negative chest x-ray prior to [anti-]TNF initiation.” Because the only cases of tuberculosis reactivation occurred in patients with a prior history of latent tuberculosis, “we should maintain extra diligence in those patients even if appropriate screening has been performed,” he advised.
They identified 12 patients with codes related to hepatitis B after the treatment started; 2 had clinically relevant outcomes, but the chart review indicated that neither case was HPV reactivation.
There were two cases of patients with positive HBV tests. One of these patients, who developed acute jaundice with serologies consistent with acute HBV infection, reported a possible exposure to HBV and was newly diagnosed with HIV, associated with the same encounter. This patient was on infliximab and continued treatment, and HBV viremia spontaneously cleared without antiviral treatment, Dr. Hou said.
The second “clinically relevant” case was a patient with chronic HBV infection, identified in a presurgical screen, who was asymptomatic and had normal liver function tests. Infliximab was discontinued, and the patient started antiviral therapy; viremia resolved and the patient resumed treatment with infliximab “without complications,” Dr. Hou said.
Another four patients were identified related to codes for acute liver failure, but on chart review, none had liver failure related to hepatitis B.
The study’s limitations include the possibility that patients may receive medical care outside the VA system, which would not be picked up in the analysis, he said, but added, “when we look at our estimate of tuberculosis reactivation, they mirror almost exactly those reported in the rheumatology literature in screened populations.”
Another limitation is that the study depended on the accuracy of ICD-9 codes for the diagnoses, but all outcomes were verified in the chart review, he said. Dr. Hou is also director of Inflammatory Bowel Diseases and an investigator in the clinical epidemiology and outcomes program in the Center for Innovations in Quality Effectiveness and Safety at the Michael E. DeBakey VA Medical Center, Houston.
WASHINGTON – Reactivation of tuberculosis and hepatitis B virus infections after starting treatment with anti–tumor necrosis factor (TNF) therapy was “rare” in a large national cohort study of veterans with inflammatory bowel disease (IBD), Dr. Jason Hou reported at the annual Digestive Disease Week.
The estimated rate of tuberculosis reactivations was 2.8 per 10,000 patient-years of exposure to anti-TNF therapy “in a fairly well-screened cohort of IBD patients,” said Dr. Hou, codirector of the Inflammatory Bowel Disease Center at Baylor College of Medicine, Houston. The estimate for HBV reactivation or acute liver failure in this cohort was less than 1.4 per 10,000 patient-years of exposure, he noted.
Practice guidelines recommend that patients with IBD should be screened for latent tuberculosis and HBV before starting treatment with an anti-TNF drug, but how often reactivation actually occurs in this population is not known, he pointed out. Moreover, recent studies have questioned the cost-effectiveness of universal screening for HBV before starting treatment, and TB reactivation rates in patients with IBD treated with anti-TNF drugs “have not been assessed on a national population level.”
Dr. Hou and his associates used a national Veterans Affairs database to identify patients who had been diagnosed between 2003 and 2011 with Crohn’s disease or ulcerative colitis, based on ICD-9 codes, and had filled at least one prescription for infliximab, adalimumab, or certolizumab pegol; they also looked for codes related to possible tuberculosis reactivation or acute liver failure related to HBV reactivation at the time of or after anti-TNF therapy was started. Cases were then verified by reviewing electronic medical records of patients to confirm the diagnosis of tuberculosis or HBV, exposure to an anti-TNF drug, and completion of pretreatment screening.
They identified 3,357 patients with IBD who had received a prescription for an anti-TNF treatment, representing 7,210 patient-years of anti-TNF treatment; most were men and were white. The mean time on treatment was about 2 years, and they had started treatment at a mean age of 57 years.
Screening rates for tuberculosis were relatively high and remained stable throughout the study period, at 72% overall, but HBV screening rates were low, at 24% overall. HBV screening was not included in practice guidelines until 2006, and the rate significantly increased from under 10% at the beginning of the period studied to 42% at the end, Dr. Hou noted.
They identified 23 patients with ICD-9 codes related to tuberculosis occurring after they started anti-TNF therapy, but “on chart review, only two patients were confirmed to have tuberculosis reactivation” related to anti-TNF therapy, which occurred at 8 and 18 months of treatment, he said. “Very interestingly, both of these patients had latent tuberculosis and documented completed courses of INH [isonicotinylhydrazine] and a negative chest x-ray prior to [anti-]TNF initiation.” Because the only cases of tuberculosis reactivation occurred in patients with a prior history of latent tuberculosis, “we should maintain extra diligence in those patients even if appropriate screening has been performed,” he advised.
They identified 12 patients with codes related to hepatitis B after the treatment started; 2 had clinically relevant outcomes, but the chart review indicated that neither case was HPV reactivation.
There were two cases of patients with positive HBV tests. One of these patients, who developed acute jaundice with serologies consistent with acute HBV infection, reported a possible exposure to HBV and was newly diagnosed with HIV, associated with the same encounter. This patient was on infliximab and continued treatment, and HBV viremia spontaneously cleared without antiviral treatment, Dr. Hou said.
The second “clinically relevant” case was a patient with chronic HBV infection, identified in a presurgical screen, who was asymptomatic and had normal liver function tests. Infliximab was discontinued, and the patient started antiviral therapy; viremia resolved and the patient resumed treatment with infliximab “without complications,” Dr. Hou said.
Another four patients were identified related to codes for acute liver failure, but on chart review, none had liver failure related to hepatitis B.
The study’s limitations include the possibility that patients may receive medical care outside the VA system, which would not be picked up in the analysis, he said, but added, “when we look at our estimate of tuberculosis reactivation, they mirror almost exactly those reported in the rheumatology literature in screened populations.”
Another limitation is that the study depended on the accuracy of ICD-9 codes for the diagnoses, but all outcomes were verified in the chart review, he said. Dr. Hou is also director of Inflammatory Bowel Diseases and an investigator in the clinical epidemiology and outcomes program in the Center for Innovations in Quality Effectiveness and Safety at the Michael E. DeBakey VA Medical Center, Houston.
WASHINGTON – Reactivation of tuberculosis and hepatitis B virus infections after starting treatment with anti–tumor necrosis factor (TNF) therapy was “rare” in a large national cohort study of veterans with inflammatory bowel disease (IBD), Dr. Jason Hou reported at the annual Digestive Disease Week.
The estimated rate of tuberculosis reactivations was 2.8 per 10,000 patient-years of exposure to anti-TNF therapy “in a fairly well-screened cohort of IBD patients,” said Dr. Hou, codirector of the Inflammatory Bowel Disease Center at Baylor College of Medicine, Houston. The estimate for HBV reactivation or acute liver failure in this cohort was less than 1.4 per 10,000 patient-years of exposure, he noted.
Practice guidelines recommend that patients with IBD should be screened for latent tuberculosis and HBV before starting treatment with an anti-TNF drug, but how often reactivation actually occurs in this population is not known, he pointed out. Moreover, recent studies have questioned the cost-effectiveness of universal screening for HBV before starting treatment, and TB reactivation rates in patients with IBD treated with anti-TNF drugs “have not been assessed on a national population level.”
Dr. Hou and his associates used a national Veterans Affairs database to identify patients who had been diagnosed between 2003 and 2011 with Crohn’s disease or ulcerative colitis, based on ICD-9 codes, and had filled at least one prescription for infliximab, adalimumab, or certolizumab pegol; they also looked for codes related to possible tuberculosis reactivation or acute liver failure related to HBV reactivation at the time of or after anti-TNF therapy was started. Cases were then verified by reviewing electronic medical records of patients to confirm the diagnosis of tuberculosis or HBV, exposure to an anti-TNF drug, and completion of pretreatment screening.
They identified 3,357 patients with IBD who had received a prescription for an anti-TNF treatment, representing 7,210 patient-years of anti-TNF treatment; most were men and were white. The mean time on treatment was about 2 years, and they had started treatment at a mean age of 57 years.
Screening rates for tuberculosis were relatively high and remained stable throughout the study period, at 72% overall, but HBV screening rates were low, at 24% overall. HBV screening was not included in practice guidelines until 2006, and the rate significantly increased from under 10% at the beginning of the period studied to 42% at the end, Dr. Hou noted.
They identified 23 patients with ICD-9 codes related to tuberculosis occurring after they started anti-TNF therapy, but “on chart review, only two patients were confirmed to have tuberculosis reactivation” related to anti-TNF therapy, which occurred at 8 and 18 months of treatment, he said. “Very interestingly, both of these patients had latent tuberculosis and documented completed courses of INH [isonicotinylhydrazine] and a negative chest x-ray prior to [anti-]TNF initiation.” Because the only cases of tuberculosis reactivation occurred in patients with a prior history of latent tuberculosis, “we should maintain extra diligence in those patients even if appropriate screening has been performed,” he advised.
They identified 12 patients with codes related to hepatitis B after the treatment started; 2 had clinically relevant outcomes, but the chart review indicated that neither case was HPV reactivation.
There were two cases of patients with positive HBV tests. One of these patients, who developed acute jaundice with serologies consistent with acute HBV infection, reported a possible exposure to HBV and was newly diagnosed with HIV, associated with the same encounter. This patient was on infliximab and continued treatment, and HBV viremia spontaneously cleared without antiviral treatment, Dr. Hou said.
The second “clinically relevant” case was a patient with chronic HBV infection, identified in a presurgical screen, who was asymptomatic and had normal liver function tests. Infliximab was discontinued, and the patient started antiviral therapy; viremia resolved and the patient resumed treatment with infliximab “without complications,” Dr. Hou said.
Another four patients were identified related to codes for acute liver failure, but on chart review, none had liver failure related to hepatitis B.
The study’s limitations include the possibility that patients may receive medical care outside the VA system, which would not be picked up in the analysis, he said, but added, “when we look at our estimate of tuberculosis reactivation, they mirror almost exactly those reported in the rheumatology literature in screened populations.”
Another limitation is that the study depended on the accuracy of ICD-9 codes for the diagnoses, but all outcomes were verified in the chart review, he said. Dr. Hou is also director of Inflammatory Bowel Diseases and an investigator in the clinical epidemiology and outcomes program in the Center for Innovations in Quality Effectiveness and Safety at the Michael E. DeBakey VA Medical Center, Houston.
AT DDW® 2015
Key clinical point: Significant clinical events related to tuberculosis and hepatitis B virus reactivation after initiating anti–tumor necrosis factor therapy in a screened population are rare.
Major finding: Rates of tuberculosis and HBV were estimated at 2.8 and less than 1.4 cases per 10,000 patient-years of exposure to treatment, respectively, in a large, fairly well screened national cohort of veterans with IBD treated with an anti-TNF drug.
Data source: A retrospective cohort study evaluated the rates of tuberculosis and HBV reactivation, identifying cases of IBD treated with anti-TNF therapy in a Veterans Health Administration database during 2003-2011, confirming cases, treatment, and HBV and TB screening status with electronic medical record review.
Disclosures: Dr. Hou’s financial disclosure includes receiving consulting, speaking, teaching, and/or advisory fees from Janssen, Aptalis, and Abbvie.
ACIP: Tdap during pregnancy optimal strategy for protecting infants
Based on the available evidence of the impact “cocooning” has on transmission of pertussis to infants, no changes are currently recommended in the use of Tdap vaccine for close contacts of infants, Jennifer Liang, D.V.M., said at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
Presenting the conclusions of ACIP’s pertussis vaccines work group review on the impact of cocooning strategies, Dr. Liang, the CDC’s lead member of the work group, said that pertussis vaccination programs should be focused on vaccinating women during every pregnancy, maintaining high levels of DTap coverage, sustaining Tdap coverage in adolescents, and improving Tdap coverage in adults.
In 2005, ACIP recommended the “cocooning” strategy: vaccinating with Tdap for all close contacts of infants under age 12 months to reduce the risk of transmitting pertussis, including parents, siblings, grandparents, child care providers, and health care personnel, in addition to vaccinating pregnant women immediately post partum. In 2011, ACIP recommended Tdap during pregnancy for women who had not previously received the vaccine, or a postpartum dose for women who did not receive the vaccine during pregnancy and had not previously received the vaccine. In 2012, the recommendation was expanded to every pregnancy, whether or not the woman had received the vaccine before.
The optimal strategy to prevent the transmission of pertussis is vaccinating women during pregnancy, which has been shown to be highly effective in reducing transmission to infants, but rates of vaccination in pregnant women have not been high, said Dr. Liang, an epidemiologist in the CDC’s National Center for Immunization and Respiratory Diseases.
Rates of Tdap coverage, however, among pregnant women in the United States have ranged from 14% to 23% in studies using different sources, including a Michigan Medicaid study, she said.
Implementing and sustaining cocooning programs remain a challenge. Although uptake of Tdap has been highest in postpartum women, there has been limited success in vaccinating fathers or other family members, she said, noting that, in 2012, the rate of Tdap coverage among adults aged 19-64 years who reported living with an infant under age 1 year was 26%.
The effect of cocooning in preventing infant pertussis also is “unclear and inconclusive,” and evidence of the effectiveness of the postpartum dose in preventing infant pertussis is limited and the data are conflicting, Dr. Liang said. Another issue is that, over the past decade, the source of transmission to infants has shifted from parents (usually mothers) as the most common source to siblings, who have more recently been identified as the most common source, she said. A CDC study determined that, between 2006 and 2013, family members were the source of the infection in 66%-85% of infant pertussis cases in which the source of infection was known. Siblings were the most common source, linked to almost 40% of cases.
“Even if additional Tdap doses are recommended, this would not address the observed shift to siblings as the source of pertussis to infants and puts greater emphasis on the importance of providing newborns with antipertussis antibodies, and there is an optimal strategy in place – vaccinating women during pregnancy,” she said.
This message is emphasized in a recently launched CDC campaign to improve Tdap vaccination rates during pregnancy, which includes fact sheets for health care professionals that point out that Tdap during pregnancy provides the best protection for infants, postpartum Tdap administration is not optimal, and “cocooning alone may not be effective and is hard to implement.”
Several meeting participants pointed out that vaccine uptake during pregnancy is higher in settings where the vaccine is available on site, as high as 80%-90% of pregnancies, and that having to get the vaccine outside of the office, such as at a pharmacy, can markedly reduce the likelihood of vaccination. The CDC’s updated materials, including fact sheets and posters, are available for health care professionals at http://www.cdc.gov/pertussis/materials/hcp.html.
A single dose of Tdap is recommended for people aged 11-64 years: one dose is routinely administered at age 11 or 12 years and one dose of Tdap is recommended for pregnant women during every pregnancy. DTaP vaccine is used to vaccinate younger children starting at age 2 months and is not licensed for adolescents, adults, or children 7 years of age and older.
Based on the available evidence of the impact “cocooning” has on transmission of pertussis to infants, no changes are currently recommended in the use of Tdap vaccine for close contacts of infants, Jennifer Liang, D.V.M., said at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
Presenting the conclusions of ACIP’s pertussis vaccines work group review on the impact of cocooning strategies, Dr. Liang, the CDC’s lead member of the work group, said that pertussis vaccination programs should be focused on vaccinating women during every pregnancy, maintaining high levels of DTap coverage, sustaining Tdap coverage in adolescents, and improving Tdap coverage in adults.
In 2005, ACIP recommended the “cocooning” strategy: vaccinating with Tdap for all close contacts of infants under age 12 months to reduce the risk of transmitting pertussis, including parents, siblings, grandparents, child care providers, and health care personnel, in addition to vaccinating pregnant women immediately post partum. In 2011, ACIP recommended Tdap during pregnancy for women who had not previously received the vaccine, or a postpartum dose for women who did not receive the vaccine during pregnancy and had not previously received the vaccine. In 2012, the recommendation was expanded to every pregnancy, whether or not the woman had received the vaccine before.
The optimal strategy to prevent the transmission of pertussis is vaccinating women during pregnancy, which has been shown to be highly effective in reducing transmission to infants, but rates of vaccination in pregnant women have not been high, said Dr. Liang, an epidemiologist in the CDC’s National Center for Immunization and Respiratory Diseases.
Rates of Tdap coverage, however, among pregnant women in the United States have ranged from 14% to 23% in studies using different sources, including a Michigan Medicaid study, she said.
Implementing and sustaining cocooning programs remain a challenge. Although uptake of Tdap has been highest in postpartum women, there has been limited success in vaccinating fathers or other family members, she said, noting that, in 2012, the rate of Tdap coverage among adults aged 19-64 years who reported living with an infant under age 1 year was 26%.
The effect of cocooning in preventing infant pertussis also is “unclear and inconclusive,” and evidence of the effectiveness of the postpartum dose in preventing infant pertussis is limited and the data are conflicting, Dr. Liang said. Another issue is that, over the past decade, the source of transmission to infants has shifted from parents (usually mothers) as the most common source to siblings, who have more recently been identified as the most common source, she said. A CDC study determined that, between 2006 and 2013, family members were the source of the infection in 66%-85% of infant pertussis cases in which the source of infection was known. Siblings were the most common source, linked to almost 40% of cases.
“Even if additional Tdap doses are recommended, this would not address the observed shift to siblings as the source of pertussis to infants and puts greater emphasis on the importance of providing newborns with antipertussis antibodies, and there is an optimal strategy in place – vaccinating women during pregnancy,” she said.
This message is emphasized in a recently launched CDC campaign to improve Tdap vaccination rates during pregnancy, which includes fact sheets for health care professionals that point out that Tdap during pregnancy provides the best protection for infants, postpartum Tdap administration is not optimal, and “cocooning alone may not be effective and is hard to implement.”
Several meeting participants pointed out that vaccine uptake during pregnancy is higher in settings where the vaccine is available on site, as high as 80%-90% of pregnancies, and that having to get the vaccine outside of the office, such as at a pharmacy, can markedly reduce the likelihood of vaccination. The CDC’s updated materials, including fact sheets and posters, are available for health care professionals at http://www.cdc.gov/pertussis/materials/hcp.html.
A single dose of Tdap is recommended for people aged 11-64 years: one dose is routinely administered at age 11 or 12 years and one dose of Tdap is recommended for pregnant women during every pregnancy. DTaP vaccine is used to vaccinate younger children starting at age 2 months and is not licensed for adolescents, adults, or children 7 years of age and older.
Based on the available evidence of the impact “cocooning” has on transmission of pertussis to infants, no changes are currently recommended in the use of Tdap vaccine for close contacts of infants, Jennifer Liang, D.V.M., said at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
Presenting the conclusions of ACIP’s pertussis vaccines work group review on the impact of cocooning strategies, Dr. Liang, the CDC’s lead member of the work group, said that pertussis vaccination programs should be focused on vaccinating women during every pregnancy, maintaining high levels of DTap coverage, sustaining Tdap coverage in adolescents, and improving Tdap coverage in adults.
In 2005, ACIP recommended the “cocooning” strategy: vaccinating with Tdap for all close contacts of infants under age 12 months to reduce the risk of transmitting pertussis, including parents, siblings, grandparents, child care providers, and health care personnel, in addition to vaccinating pregnant women immediately post partum. In 2011, ACIP recommended Tdap during pregnancy for women who had not previously received the vaccine, or a postpartum dose for women who did not receive the vaccine during pregnancy and had not previously received the vaccine. In 2012, the recommendation was expanded to every pregnancy, whether or not the woman had received the vaccine before.
The optimal strategy to prevent the transmission of pertussis is vaccinating women during pregnancy, which has been shown to be highly effective in reducing transmission to infants, but rates of vaccination in pregnant women have not been high, said Dr. Liang, an epidemiologist in the CDC’s National Center for Immunization and Respiratory Diseases.
Rates of Tdap coverage, however, among pregnant women in the United States have ranged from 14% to 23% in studies using different sources, including a Michigan Medicaid study, she said.
Implementing and sustaining cocooning programs remain a challenge. Although uptake of Tdap has been highest in postpartum women, there has been limited success in vaccinating fathers or other family members, she said, noting that, in 2012, the rate of Tdap coverage among adults aged 19-64 years who reported living with an infant under age 1 year was 26%.
The effect of cocooning in preventing infant pertussis also is “unclear and inconclusive,” and evidence of the effectiveness of the postpartum dose in preventing infant pertussis is limited and the data are conflicting, Dr. Liang said. Another issue is that, over the past decade, the source of transmission to infants has shifted from parents (usually mothers) as the most common source to siblings, who have more recently been identified as the most common source, she said. A CDC study determined that, between 2006 and 2013, family members were the source of the infection in 66%-85% of infant pertussis cases in which the source of infection was known. Siblings were the most common source, linked to almost 40% of cases.
“Even if additional Tdap doses are recommended, this would not address the observed shift to siblings as the source of pertussis to infants and puts greater emphasis on the importance of providing newborns with antipertussis antibodies, and there is an optimal strategy in place – vaccinating women during pregnancy,” she said.
This message is emphasized in a recently launched CDC campaign to improve Tdap vaccination rates during pregnancy, which includes fact sheets for health care professionals that point out that Tdap during pregnancy provides the best protection for infants, postpartum Tdap administration is not optimal, and “cocooning alone may not be effective and is hard to implement.”
Several meeting participants pointed out that vaccine uptake during pregnancy is higher in settings where the vaccine is available on site, as high as 80%-90% of pregnancies, and that having to get the vaccine outside of the office, such as at a pharmacy, can markedly reduce the likelihood of vaccination. The CDC’s updated materials, including fact sheets and posters, are available for health care professionals at http://www.cdc.gov/pertussis/materials/hcp.html.
A single dose of Tdap is recommended for people aged 11-64 years: one dose is routinely administered at age 11 or 12 years and one dose of Tdap is recommended for pregnant women during every pregnancy. DTaP vaccine is used to vaccinate younger children starting at age 2 months and is not licensed for adolescents, adults, or children 7 years of age and older.
FROM AN ACIP MEETING