User login
Investigating the etiology of recurrent pregnancy loss
With attention to the timing of loss
Introduction: Reassurance through pregnancy loss and workups
Pregnancy loss is not an uncommon complication but it can be associated with significant stress among parents and loved ones when it occurs. Especially when recurrent, it also becomes a medical dilemma for physicians and nurses because the cause is not always obvious immediately, and even with exploration, the cause may not always be found.
First and foremost, it is important that physicians provide counseling and reassurance to families experiencing loss, and that they encourage a level of patience while the investigation for loss is done. Investigations tend not to be linear. One must look at a number of diagnostic areas including genetics, anatomy, immunology, and infections.
Even with an extensive workup, what often is found are potential associations rather than precise causes. For instance, one may find that certain antibodies or certain conditions are present, or that certain anatomic structures are abnormal. While such findings are not necessarily causative, there are therapeutic interventions that we can offer to address many of the conditions (e.g., surgical correction of the septate uterus, and low-dose aspirin and heparin for antiphospholipid syndrome).
Less than 1% of couples experience recurrent pregnancy loss (traditionally defined as three or more losses), so parents who experience one loss should be given reassurance that their loss was likely a sporadic miscarriage and that chances of recurrence will be low. Even as workups proceed, reassurance is important.
For this month’s Master Class in Obstetrics we’ve invited Wendy L. Kinzler, MD, and Anthony Vintzileos, MD, both of whom have expertise in the area of recurrent pregnancy loss, to review the potential causes and the management approach. They focus on the first trimester, when genetic causes predominate, and the early second trimester, when undetected uterine factors can be at play. They explain that the gestational age at which recurrent losses occur is an important factor in decoding etiology and management.
Dr. Kinzler is associate dean, graduate medical education, and professor of obstetrics and gynecology at NYU Long Island School of Medicine, Mineola, N.Y., and Dr. Vintzileos is chief patient safety officer for obstetrics, Northwell Health–Western Region, and professor in the department of obstetrics and gynecology in the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. Dr. Kinzler and Dr. Vintzileos reported no relevant disclosures.
E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at obnews@mdedge.com.
Investigating the etiology of recurrent pregnancy loss
Pregnancy loss is defined as a loss occurring at < 20 weeks’ gestation.
Consideration of the timing of the pregnancy loss can provide a useful guide to this evaluation, as etiologies vary depending on when in gestation losses occur. In this Master Class, we will address the evaluation of pregnancy loss at < 20 weeks’ gestation, with particular attention to first trimester and early second trimester causes. Literature on the role of the cervix and intra-amniotic infection in midtrimester loss is extensive and will not be covered here.
Although early first trimester miscarriage is common, occurring in approximately 15% of clinically recognized pregnancies, only 2%-3% of couples experience two or more miscarriages and 0.5%-1% experience three or more.
When to begin a diagnostic workup should be part of a shared decision-making process, taking into consideration future family planning, parity, number of previous losses, and notably, the gestational age at which loss(es) occurred. Recurrence rates for first trimester miscarriage are similar after two versus three consecutive losses and either situation usually prompts an evaluation, whereas any second-trimester loss should be evaluated.
Increasingly, we are appreciating the value of a more targeted, gestational age–driven approach to the evaluation of pregnancy loss in an attempt to provide grieving parents with useful information without subjecting them to a wide array of expensive and unnecessary tests.
Genetic causes
The earlier the pregnancy loss, the more likely it is the result of abnormal fetal genetics. Genetic factors should be considered as the most likely cause for first trimester pregnancy losses (especially those occurring at < 10 weeks’ gestation), the most frequent being autosomal trisomies or monosomy X. The vast majority of trisomy conceptuses are sporadic in nature and are related to the natural aging process of the ovary (increasing the rate of meiotic nondisjunction).
If fetal aneuploidy is identified in a pregnancy loss, couples can be counseled about the definitive cause of the loss and can be counseled about recurrence based on age-related risks and/or tests of ovarian reserve. Recurrent pregnancy loss (RPL) is only rarely associated with a parental translocation (< 5%). Testing parental karyotypes should be reserved for cases in which the fetal karyotypes are unknown or in which an unbalanced translocation was identified in the fetus.
When a first trimester pregnancy loss is diagnosed, chorionic villus sampling (CVS) with microarray testing is the most reliable and comprehensive method for evaluating potential genetic causes. It provides valuable information even when cells are not viable and reduces the risk of maternal cell contamination – two significant limitations to standard karyotype analysis performed on tissue passed spontaneously or at the time of D&C. Studies of products of conception (POC) testing with microarray have documented the detection of abnormalities in an additional 10%-15% of cases compared with traditional karyotype analysis.
When CVS is not feasible, testing maternal serum for cell-free DNA is a reasonable alternative. In a prospective cohort study of 50 maternal blood samples taken after fetal demise, 76% of samples yielded cell-free DNA results, meaning fetal fractions were within the detectable range. The higher the gestational age at the time of loss, the higher the chance of obtaining a result: Findings in the study were possible in 88% of samples when the gestational age was 8 weeks or greater, and in 53% of cases involving a lower gestational age. The time from demise to blood draw did not affect the likelihood of obtaining a result (Obstet Gynecol. 2015 Jun;125[6]:1321-29).
When neither CVS nor cell-free DNA analysis is feasible, analysis of either spontaneously passed tissue or tissue obtained at the time of a D&C may still be worthwhile. Maternal cell contamination, of course, is the main downside.
A paper published in 2020 documented the value of refocusing the initial workup. Researchers reported that 57% of 1,400 cases of recurrent pregnancy loss went unexplained using the 2012 ASRM guidelines, which included parental karyotyping but not POC cytogenetic analysis. When parental karyotypes were omitted from the initial workup and POC analysis with 24-chromosome microarray was added, at least one potential explanation for loss could be identified in 92% of cases. Only 8% were left “unexplained” (Curr Opin Obstet Gynecol. 2020 Oct;32[5]:371-9).
When genetics are ruled out
Issues that are top of mind when we lack genetic information or when genetic causes are ruled out include maternal metabolic disorders (uncontrolled diabetes, obesity, uncontrolled thyroid disease), environmental exposures (smoking), uterine abnormalities, and antiphospholipid syndrome.
Thorough evaluation of the uterine cavity after recurrent first trimester miscarriage – or after any second trimester loss – is too often a missing element of investigation. It is a vital component of the evaluation, and information about uterine structure is easily obtained.
A saline infusion sonogram (SIS) allows us to look at the external contour of the uterus, assess the myometrium for muscular abnormalities, visualize the uterine lining, and assess uterine orientation. Performed in the nonpregnant state, and ideally coupled with 3D technology, this relatively simple test can identify congenital uterine anomalies, intracavitary abnormalities (such as fibroids, polyps, or synechiae) which can surgically be removed prior to another pregnancy, a retroverted uterus that may be predisposed to incarceration during pregnancy, and other potentially impactful conditions, such as adenomyosis.
Structural anomalies
Congenital uterine anomalies are associated with first trimester miscarriage, second trimester pregnancy loss, and preterm birth. A uterine septum is of particular concern for early miscarriage, as the early embryo can implant on the relatively avascular septum.
Other congenital uterine anomalies (bicornuate, didelphys, unicornuate) can be associated with concomitant cervical structural abnormalities leading to cervical insufficiency and/or result in pathologic uterine stretch of a space-limited cavity, leading to midtrimester loss or preterm birth. The diagnosis of these anomalies is an important part of the evaluation of pregnancy loss, as it can guide monitoring in future pregnancies, or can be surgically corrected, as in the case of a uterine septum, significantly improving pregnancy outcomes.
A short cervix can result either congenitally or from injury or trauma and may also be associated with cervical insufficiency and miscarriage. It can be evaluated and monitored by ultrasound and, in some cases, treated by surgical cerclage. Pregnancy losses due to cervical insufficiency usually occur after 16 weeks of gestation and frequently are associated with intra-amniotic infections.
Incarcerated uterus and adenomyosis
Other uterine factors that can contribute to pregnancy loss and that are largely underdiagnosed or undiagnosed are an incarcerated retroverted uterus and adenomyosis.
Most of the time, a retroverted uterus naturally assumes an anteverted position by the late first trimester or early second trimester, allowing for continued growth of the uterus and developing fetus. In approximately 10% of cases, however, the retroverted uterus becomes “stuck” or incarcerated in the posterior pelvis. This is more likely if there are large uterine fibroids or in the presence of pelvic adhesions due to endometriosis or previous pelvic surgery.
When this occurs, the fundus is wedged on the sacral promontory (may cause pelvic discomfort and constipation) and the cervix is markedly displaced anteriorly under the pubic symphysis (causing bladder outlet obstruction and urinary retention).
It is critical that ob.gyns. and emergency medicine providers are aware of this condition, which typically presents between 12 and 16 weeks’ gestation. The most frequent complaint is lower abdominal discomfort due to distended bladder and inability to void, which usually leads to bladder catheterization with drainage of large amounts of urine. An incarcerated uterus can predispose to pregnancy loss during this time (few other conditions cause loss during this time window), presumably due to impaired uterine artery blood flow.
Once the diagnosis is made, uterine incarceration may be corrected by elevating the gravid uterus out of the pelvis either manually, or by using a transvaginal ultrasound probe. (The latter minimally invasive approach was described in March at the American Institute of Ultrasound in Medicine’s annual conference by Martin Chavez, MD, and coinvestigators. More invasive approaches are rarely required but include CO2 intraperitoneal insufflation, as used prior to laparoscopy, or laparotomy.
The later in gestation the condition is allowed to persist, the less likely correction will be possible due to the enlarging fundus. Correction between 14 and 16 weeks, or earlier if symptoms develop, is recommended.
Adenomyosis, another poorly understood condition impacting pregnancy outcomes, has been associated with increased rates of miscarriage after in vitro fertilization (in addition to lower implantation rates); a meta-analysis published almost a decade ago found a risk ratio of miscarriage of 2.12 (95% confidence interval, 1.2-3.75) in women with adenomyosis versus those without (Hum Reprod. 2014 May;29[5]:964-77). However, outside of reproductive endocrinology, its impact on pregnancy outcomes in the obstetrical literature is not well recognized.
Although more research is necessary, we believe that adenomyosis should be considered a risk factor for pregnancy loss in the second trimester. The presence of endometrial glands within the myometrium, predisposing for an inflammatory environment, can lead to abnormal implantation, poor uterine distensibility, sterile inflammation, and early cervical insufficiency. As the prevalence of adenomyosis increases with age and maternal ages are increasing, this is an important condition to consider.
Diagnosis is typically made with MRI (although pathology of a hysterectomy specimen is the gold standard). Ultrasound findings consistent with adenomyosis are not routinely assessed and have not been studied in a gravid uterus. Nonetheless, a heightened sense of awareness about this possible contributor to pregnancy loss is very important.
A word about antiphospholipid syndrome
Antiphospholipid syndrome can cause a variety of adverse pregnancy outcomes, including first and second trimester pregnancy loss, fetal demise, fetal growth restriction, preeclampsia, preterm birth, and maternal thromboembolism. The classical presentation of miscarriage due to untreated antiphospholipid antibody syndrome is early severe fetal growth restriction, oligohydramnios, and IUFD in the second trimester.
The diagnosis requires at least one clinical criterion and one laboratory criterion. The mere presence of low level antibodies does not make the diagnosis of antiphospholipid antibody syndrome, and care should be taken to consider both the clinical and laboratory diagnostic criteria to make an accurate diagnosis.
When present, close maternal and fetal surveillance and a combination of low-dose aspirin and heparin are mainstays of treatment. The majority of studies suggest that low-molecular weight heparin (LMWH) and unfractionated heparin have comparable clinical efficacy. However, if a recurrent loss is experienced despite treatment with LMWH, the use of unfractionated heparin in a subsequent pregnancy should be considered.
With attention to the timing of loss
With attention to the timing of loss
Introduction: Reassurance through pregnancy loss and workups
Pregnancy loss is not an uncommon complication but it can be associated with significant stress among parents and loved ones when it occurs. Especially when recurrent, it also becomes a medical dilemma for physicians and nurses because the cause is not always obvious immediately, and even with exploration, the cause may not always be found.
First and foremost, it is important that physicians provide counseling and reassurance to families experiencing loss, and that they encourage a level of patience while the investigation for loss is done. Investigations tend not to be linear. One must look at a number of diagnostic areas including genetics, anatomy, immunology, and infections.
Even with an extensive workup, what often is found are potential associations rather than precise causes. For instance, one may find that certain antibodies or certain conditions are present, or that certain anatomic structures are abnormal. While such findings are not necessarily causative, there are therapeutic interventions that we can offer to address many of the conditions (e.g., surgical correction of the septate uterus, and low-dose aspirin and heparin for antiphospholipid syndrome).
Less than 1% of couples experience recurrent pregnancy loss (traditionally defined as three or more losses), so parents who experience one loss should be given reassurance that their loss was likely a sporadic miscarriage and that chances of recurrence will be low. Even as workups proceed, reassurance is important.
For this month’s Master Class in Obstetrics we’ve invited Wendy L. Kinzler, MD, and Anthony Vintzileos, MD, both of whom have expertise in the area of recurrent pregnancy loss, to review the potential causes and the management approach. They focus on the first trimester, when genetic causes predominate, and the early second trimester, when undetected uterine factors can be at play. They explain that the gestational age at which recurrent losses occur is an important factor in decoding etiology and management.
Dr. Kinzler is associate dean, graduate medical education, and professor of obstetrics and gynecology at NYU Long Island School of Medicine, Mineola, N.Y., and Dr. Vintzileos is chief patient safety officer for obstetrics, Northwell Health–Western Region, and professor in the department of obstetrics and gynecology in the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. Dr. Kinzler and Dr. Vintzileos reported no relevant disclosures.
E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at obnews@mdedge.com.
Investigating the etiology of recurrent pregnancy loss
Pregnancy loss is defined as a loss occurring at < 20 weeks’ gestation.
Consideration of the timing of the pregnancy loss can provide a useful guide to this evaluation, as etiologies vary depending on when in gestation losses occur. In this Master Class, we will address the evaluation of pregnancy loss at < 20 weeks’ gestation, with particular attention to first trimester and early second trimester causes. Literature on the role of the cervix and intra-amniotic infection in midtrimester loss is extensive and will not be covered here.
Although early first trimester miscarriage is common, occurring in approximately 15% of clinically recognized pregnancies, only 2%-3% of couples experience two or more miscarriages and 0.5%-1% experience three or more.
When to begin a diagnostic workup should be part of a shared decision-making process, taking into consideration future family planning, parity, number of previous losses, and notably, the gestational age at which loss(es) occurred. Recurrence rates for first trimester miscarriage are similar after two versus three consecutive losses and either situation usually prompts an evaluation, whereas any second-trimester loss should be evaluated.
Increasingly, we are appreciating the value of a more targeted, gestational age–driven approach to the evaluation of pregnancy loss in an attempt to provide grieving parents with useful information without subjecting them to a wide array of expensive and unnecessary tests.
Genetic causes
The earlier the pregnancy loss, the more likely it is the result of abnormal fetal genetics. Genetic factors should be considered as the most likely cause for first trimester pregnancy losses (especially those occurring at < 10 weeks’ gestation), the most frequent being autosomal trisomies or monosomy X. The vast majority of trisomy conceptuses are sporadic in nature and are related to the natural aging process of the ovary (increasing the rate of meiotic nondisjunction).
If fetal aneuploidy is identified in a pregnancy loss, couples can be counseled about the definitive cause of the loss and can be counseled about recurrence based on age-related risks and/or tests of ovarian reserve. Recurrent pregnancy loss (RPL) is only rarely associated with a parental translocation (< 5%). Testing parental karyotypes should be reserved for cases in which the fetal karyotypes are unknown or in which an unbalanced translocation was identified in the fetus.
When a first trimester pregnancy loss is diagnosed, chorionic villus sampling (CVS) with microarray testing is the most reliable and comprehensive method for evaluating potential genetic causes. It provides valuable information even when cells are not viable and reduces the risk of maternal cell contamination – two significant limitations to standard karyotype analysis performed on tissue passed spontaneously or at the time of D&C. Studies of products of conception (POC) testing with microarray have documented the detection of abnormalities in an additional 10%-15% of cases compared with traditional karyotype analysis.
When CVS is not feasible, testing maternal serum for cell-free DNA is a reasonable alternative. In a prospective cohort study of 50 maternal blood samples taken after fetal demise, 76% of samples yielded cell-free DNA results, meaning fetal fractions were within the detectable range. The higher the gestational age at the time of loss, the higher the chance of obtaining a result: Findings in the study were possible in 88% of samples when the gestational age was 8 weeks or greater, and in 53% of cases involving a lower gestational age. The time from demise to blood draw did not affect the likelihood of obtaining a result (Obstet Gynecol. 2015 Jun;125[6]:1321-29).
When neither CVS nor cell-free DNA analysis is feasible, analysis of either spontaneously passed tissue or tissue obtained at the time of a D&C may still be worthwhile. Maternal cell contamination, of course, is the main downside.
A paper published in 2020 documented the value of refocusing the initial workup. Researchers reported that 57% of 1,400 cases of recurrent pregnancy loss went unexplained using the 2012 ASRM guidelines, which included parental karyotyping but not POC cytogenetic analysis. When parental karyotypes were omitted from the initial workup and POC analysis with 24-chromosome microarray was added, at least one potential explanation for loss could be identified in 92% of cases. Only 8% were left “unexplained” (Curr Opin Obstet Gynecol. 2020 Oct;32[5]:371-9).
When genetics are ruled out
Issues that are top of mind when we lack genetic information or when genetic causes are ruled out include maternal metabolic disorders (uncontrolled diabetes, obesity, uncontrolled thyroid disease), environmental exposures (smoking), uterine abnormalities, and antiphospholipid syndrome.
Thorough evaluation of the uterine cavity after recurrent first trimester miscarriage – or after any second trimester loss – is too often a missing element of investigation. It is a vital component of the evaluation, and information about uterine structure is easily obtained.
A saline infusion sonogram (SIS) allows us to look at the external contour of the uterus, assess the myometrium for muscular abnormalities, visualize the uterine lining, and assess uterine orientation. Performed in the nonpregnant state, and ideally coupled with 3D technology, this relatively simple test can identify congenital uterine anomalies, intracavitary abnormalities (such as fibroids, polyps, or synechiae) which can surgically be removed prior to another pregnancy, a retroverted uterus that may be predisposed to incarceration during pregnancy, and other potentially impactful conditions, such as adenomyosis.
Structural anomalies
Congenital uterine anomalies are associated with first trimester miscarriage, second trimester pregnancy loss, and preterm birth. A uterine septum is of particular concern for early miscarriage, as the early embryo can implant on the relatively avascular septum.
Other congenital uterine anomalies (bicornuate, didelphys, unicornuate) can be associated with concomitant cervical structural abnormalities leading to cervical insufficiency and/or result in pathologic uterine stretch of a space-limited cavity, leading to midtrimester loss or preterm birth. The diagnosis of these anomalies is an important part of the evaluation of pregnancy loss, as it can guide monitoring in future pregnancies, or can be surgically corrected, as in the case of a uterine septum, significantly improving pregnancy outcomes.
A short cervix can result either congenitally or from injury or trauma and may also be associated with cervical insufficiency and miscarriage. It can be evaluated and monitored by ultrasound and, in some cases, treated by surgical cerclage. Pregnancy losses due to cervical insufficiency usually occur after 16 weeks of gestation and frequently are associated with intra-amniotic infections.
Incarcerated uterus and adenomyosis
Other uterine factors that can contribute to pregnancy loss and that are largely underdiagnosed or undiagnosed are an incarcerated retroverted uterus and adenomyosis.
Most of the time, a retroverted uterus naturally assumes an anteverted position by the late first trimester or early second trimester, allowing for continued growth of the uterus and developing fetus. In approximately 10% of cases, however, the retroverted uterus becomes “stuck” or incarcerated in the posterior pelvis. This is more likely if there are large uterine fibroids or in the presence of pelvic adhesions due to endometriosis or previous pelvic surgery.
When this occurs, the fundus is wedged on the sacral promontory (may cause pelvic discomfort and constipation) and the cervix is markedly displaced anteriorly under the pubic symphysis (causing bladder outlet obstruction and urinary retention).
It is critical that ob.gyns. and emergency medicine providers are aware of this condition, which typically presents between 12 and 16 weeks’ gestation. The most frequent complaint is lower abdominal discomfort due to distended bladder and inability to void, which usually leads to bladder catheterization with drainage of large amounts of urine. An incarcerated uterus can predispose to pregnancy loss during this time (few other conditions cause loss during this time window), presumably due to impaired uterine artery blood flow.
Once the diagnosis is made, uterine incarceration may be corrected by elevating the gravid uterus out of the pelvis either manually, or by using a transvaginal ultrasound probe. (The latter minimally invasive approach was described in March at the American Institute of Ultrasound in Medicine’s annual conference by Martin Chavez, MD, and coinvestigators. More invasive approaches are rarely required but include CO2 intraperitoneal insufflation, as used prior to laparoscopy, or laparotomy.
The later in gestation the condition is allowed to persist, the less likely correction will be possible due to the enlarging fundus. Correction between 14 and 16 weeks, or earlier if symptoms develop, is recommended.
Adenomyosis, another poorly understood condition impacting pregnancy outcomes, has been associated with increased rates of miscarriage after in vitro fertilization (in addition to lower implantation rates); a meta-analysis published almost a decade ago found a risk ratio of miscarriage of 2.12 (95% confidence interval, 1.2-3.75) in women with adenomyosis versus those without (Hum Reprod. 2014 May;29[5]:964-77). However, outside of reproductive endocrinology, its impact on pregnancy outcomes in the obstetrical literature is not well recognized.
Although more research is necessary, we believe that adenomyosis should be considered a risk factor for pregnancy loss in the second trimester. The presence of endometrial glands within the myometrium, predisposing for an inflammatory environment, can lead to abnormal implantation, poor uterine distensibility, sterile inflammation, and early cervical insufficiency. As the prevalence of adenomyosis increases with age and maternal ages are increasing, this is an important condition to consider.
Diagnosis is typically made with MRI (although pathology of a hysterectomy specimen is the gold standard). Ultrasound findings consistent with adenomyosis are not routinely assessed and have not been studied in a gravid uterus. Nonetheless, a heightened sense of awareness about this possible contributor to pregnancy loss is very important.
A word about antiphospholipid syndrome
Antiphospholipid syndrome can cause a variety of adverse pregnancy outcomes, including first and second trimester pregnancy loss, fetal demise, fetal growth restriction, preeclampsia, preterm birth, and maternal thromboembolism. The classical presentation of miscarriage due to untreated antiphospholipid antibody syndrome is early severe fetal growth restriction, oligohydramnios, and IUFD in the second trimester.
The diagnosis requires at least one clinical criterion and one laboratory criterion. The mere presence of low level antibodies does not make the diagnosis of antiphospholipid antibody syndrome, and care should be taken to consider both the clinical and laboratory diagnostic criteria to make an accurate diagnosis.
When present, close maternal and fetal surveillance and a combination of low-dose aspirin and heparin are mainstays of treatment. The majority of studies suggest that low-molecular weight heparin (LMWH) and unfractionated heparin have comparable clinical efficacy. However, if a recurrent loss is experienced despite treatment with LMWH, the use of unfractionated heparin in a subsequent pregnancy should be considered.
Introduction: Reassurance through pregnancy loss and workups
Pregnancy loss is not an uncommon complication but it can be associated with significant stress among parents and loved ones when it occurs. Especially when recurrent, it also becomes a medical dilemma for physicians and nurses because the cause is not always obvious immediately, and even with exploration, the cause may not always be found.
First and foremost, it is important that physicians provide counseling and reassurance to families experiencing loss, and that they encourage a level of patience while the investigation for loss is done. Investigations tend not to be linear. One must look at a number of diagnostic areas including genetics, anatomy, immunology, and infections.
Even with an extensive workup, what often is found are potential associations rather than precise causes. For instance, one may find that certain antibodies or certain conditions are present, or that certain anatomic structures are abnormal. While such findings are not necessarily causative, there are therapeutic interventions that we can offer to address many of the conditions (e.g., surgical correction of the septate uterus, and low-dose aspirin and heparin for antiphospholipid syndrome).
Less than 1% of couples experience recurrent pregnancy loss (traditionally defined as three or more losses), so parents who experience one loss should be given reassurance that their loss was likely a sporadic miscarriage and that chances of recurrence will be low. Even as workups proceed, reassurance is important.
For this month’s Master Class in Obstetrics we’ve invited Wendy L. Kinzler, MD, and Anthony Vintzileos, MD, both of whom have expertise in the area of recurrent pregnancy loss, to review the potential causes and the management approach. They focus on the first trimester, when genetic causes predominate, and the early second trimester, when undetected uterine factors can be at play. They explain that the gestational age at which recurrent losses occur is an important factor in decoding etiology and management.
Dr. Kinzler is associate dean, graduate medical education, and professor of obstetrics and gynecology at NYU Long Island School of Medicine, Mineola, N.Y., and Dr. Vintzileos is chief patient safety officer for obstetrics, Northwell Health–Western Region, and professor in the department of obstetrics and gynecology in the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. Dr. Kinzler and Dr. Vintzileos reported no relevant disclosures.
E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at obnews@mdedge.com.
Investigating the etiology of recurrent pregnancy loss
Pregnancy loss is defined as a loss occurring at < 20 weeks’ gestation.
Consideration of the timing of the pregnancy loss can provide a useful guide to this evaluation, as etiologies vary depending on when in gestation losses occur. In this Master Class, we will address the evaluation of pregnancy loss at < 20 weeks’ gestation, with particular attention to first trimester and early second trimester causes. Literature on the role of the cervix and intra-amniotic infection in midtrimester loss is extensive and will not be covered here.
Although early first trimester miscarriage is common, occurring in approximately 15% of clinically recognized pregnancies, only 2%-3% of couples experience two or more miscarriages and 0.5%-1% experience three or more.
When to begin a diagnostic workup should be part of a shared decision-making process, taking into consideration future family planning, parity, number of previous losses, and notably, the gestational age at which loss(es) occurred. Recurrence rates for first trimester miscarriage are similar after two versus three consecutive losses and either situation usually prompts an evaluation, whereas any second-trimester loss should be evaluated.
Increasingly, we are appreciating the value of a more targeted, gestational age–driven approach to the evaluation of pregnancy loss in an attempt to provide grieving parents with useful information without subjecting them to a wide array of expensive and unnecessary tests.
Genetic causes
The earlier the pregnancy loss, the more likely it is the result of abnormal fetal genetics. Genetic factors should be considered as the most likely cause for first trimester pregnancy losses (especially those occurring at < 10 weeks’ gestation), the most frequent being autosomal trisomies or monosomy X. The vast majority of trisomy conceptuses are sporadic in nature and are related to the natural aging process of the ovary (increasing the rate of meiotic nondisjunction).
If fetal aneuploidy is identified in a pregnancy loss, couples can be counseled about the definitive cause of the loss and can be counseled about recurrence based on age-related risks and/or tests of ovarian reserve. Recurrent pregnancy loss (RPL) is only rarely associated with a parental translocation (< 5%). Testing parental karyotypes should be reserved for cases in which the fetal karyotypes are unknown or in which an unbalanced translocation was identified in the fetus.
When a first trimester pregnancy loss is diagnosed, chorionic villus sampling (CVS) with microarray testing is the most reliable and comprehensive method for evaluating potential genetic causes. It provides valuable information even when cells are not viable and reduces the risk of maternal cell contamination – two significant limitations to standard karyotype analysis performed on tissue passed spontaneously or at the time of D&C. Studies of products of conception (POC) testing with microarray have documented the detection of abnormalities in an additional 10%-15% of cases compared with traditional karyotype analysis.
When CVS is not feasible, testing maternal serum for cell-free DNA is a reasonable alternative. In a prospective cohort study of 50 maternal blood samples taken after fetal demise, 76% of samples yielded cell-free DNA results, meaning fetal fractions were within the detectable range. The higher the gestational age at the time of loss, the higher the chance of obtaining a result: Findings in the study were possible in 88% of samples when the gestational age was 8 weeks or greater, and in 53% of cases involving a lower gestational age. The time from demise to blood draw did not affect the likelihood of obtaining a result (Obstet Gynecol. 2015 Jun;125[6]:1321-29).
When neither CVS nor cell-free DNA analysis is feasible, analysis of either spontaneously passed tissue or tissue obtained at the time of a D&C may still be worthwhile. Maternal cell contamination, of course, is the main downside.
A paper published in 2020 documented the value of refocusing the initial workup. Researchers reported that 57% of 1,400 cases of recurrent pregnancy loss went unexplained using the 2012 ASRM guidelines, which included parental karyotyping but not POC cytogenetic analysis. When parental karyotypes were omitted from the initial workup and POC analysis with 24-chromosome microarray was added, at least one potential explanation for loss could be identified in 92% of cases. Only 8% were left “unexplained” (Curr Opin Obstet Gynecol. 2020 Oct;32[5]:371-9).
When genetics are ruled out
Issues that are top of mind when we lack genetic information or when genetic causes are ruled out include maternal metabolic disorders (uncontrolled diabetes, obesity, uncontrolled thyroid disease), environmental exposures (smoking), uterine abnormalities, and antiphospholipid syndrome.
Thorough evaluation of the uterine cavity after recurrent first trimester miscarriage – or after any second trimester loss – is too often a missing element of investigation. It is a vital component of the evaluation, and information about uterine structure is easily obtained.
A saline infusion sonogram (SIS) allows us to look at the external contour of the uterus, assess the myometrium for muscular abnormalities, visualize the uterine lining, and assess uterine orientation. Performed in the nonpregnant state, and ideally coupled with 3D technology, this relatively simple test can identify congenital uterine anomalies, intracavitary abnormalities (such as fibroids, polyps, or synechiae) which can surgically be removed prior to another pregnancy, a retroverted uterus that may be predisposed to incarceration during pregnancy, and other potentially impactful conditions, such as adenomyosis.
Structural anomalies
Congenital uterine anomalies are associated with first trimester miscarriage, second trimester pregnancy loss, and preterm birth. A uterine septum is of particular concern for early miscarriage, as the early embryo can implant on the relatively avascular septum.
Other congenital uterine anomalies (bicornuate, didelphys, unicornuate) can be associated with concomitant cervical structural abnormalities leading to cervical insufficiency and/or result in pathologic uterine stretch of a space-limited cavity, leading to midtrimester loss or preterm birth. The diagnosis of these anomalies is an important part of the evaluation of pregnancy loss, as it can guide monitoring in future pregnancies, or can be surgically corrected, as in the case of a uterine septum, significantly improving pregnancy outcomes.
A short cervix can result either congenitally or from injury or trauma and may also be associated with cervical insufficiency and miscarriage. It can be evaluated and monitored by ultrasound and, in some cases, treated by surgical cerclage. Pregnancy losses due to cervical insufficiency usually occur after 16 weeks of gestation and frequently are associated with intra-amniotic infections.
Incarcerated uterus and adenomyosis
Other uterine factors that can contribute to pregnancy loss and that are largely underdiagnosed or undiagnosed are an incarcerated retroverted uterus and adenomyosis.
Most of the time, a retroverted uterus naturally assumes an anteverted position by the late first trimester or early second trimester, allowing for continued growth of the uterus and developing fetus. In approximately 10% of cases, however, the retroverted uterus becomes “stuck” or incarcerated in the posterior pelvis. This is more likely if there are large uterine fibroids or in the presence of pelvic adhesions due to endometriosis or previous pelvic surgery.
When this occurs, the fundus is wedged on the sacral promontory (may cause pelvic discomfort and constipation) and the cervix is markedly displaced anteriorly under the pubic symphysis (causing bladder outlet obstruction and urinary retention).
It is critical that ob.gyns. and emergency medicine providers are aware of this condition, which typically presents between 12 and 16 weeks’ gestation. The most frequent complaint is lower abdominal discomfort due to distended bladder and inability to void, which usually leads to bladder catheterization with drainage of large amounts of urine. An incarcerated uterus can predispose to pregnancy loss during this time (few other conditions cause loss during this time window), presumably due to impaired uterine artery blood flow.
Once the diagnosis is made, uterine incarceration may be corrected by elevating the gravid uterus out of the pelvis either manually, or by using a transvaginal ultrasound probe. (The latter minimally invasive approach was described in March at the American Institute of Ultrasound in Medicine’s annual conference by Martin Chavez, MD, and coinvestigators. More invasive approaches are rarely required but include CO2 intraperitoneal insufflation, as used prior to laparoscopy, or laparotomy.
The later in gestation the condition is allowed to persist, the less likely correction will be possible due to the enlarging fundus. Correction between 14 and 16 weeks, or earlier if symptoms develop, is recommended.
Adenomyosis, another poorly understood condition impacting pregnancy outcomes, has been associated with increased rates of miscarriage after in vitro fertilization (in addition to lower implantation rates); a meta-analysis published almost a decade ago found a risk ratio of miscarriage of 2.12 (95% confidence interval, 1.2-3.75) in women with adenomyosis versus those without (Hum Reprod. 2014 May;29[5]:964-77). However, outside of reproductive endocrinology, its impact on pregnancy outcomes in the obstetrical literature is not well recognized.
Although more research is necessary, we believe that adenomyosis should be considered a risk factor for pregnancy loss in the second trimester. The presence of endometrial glands within the myometrium, predisposing for an inflammatory environment, can lead to abnormal implantation, poor uterine distensibility, sterile inflammation, and early cervical insufficiency. As the prevalence of adenomyosis increases with age and maternal ages are increasing, this is an important condition to consider.
Diagnosis is typically made with MRI (although pathology of a hysterectomy specimen is the gold standard). Ultrasound findings consistent with adenomyosis are not routinely assessed and have not been studied in a gravid uterus. Nonetheless, a heightened sense of awareness about this possible contributor to pregnancy loss is very important.
A word about antiphospholipid syndrome
Antiphospholipid syndrome can cause a variety of adverse pregnancy outcomes, including first and second trimester pregnancy loss, fetal demise, fetal growth restriction, preeclampsia, preterm birth, and maternal thromboembolism. The classical presentation of miscarriage due to untreated antiphospholipid antibody syndrome is early severe fetal growth restriction, oligohydramnios, and IUFD in the second trimester.
The diagnosis requires at least one clinical criterion and one laboratory criterion. The mere presence of low level antibodies does not make the diagnosis of antiphospholipid antibody syndrome, and care should be taken to consider both the clinical and laboratory diagnostic criteria to make an accurate diagnosis.
When present, close maternal and fetal surveillance and a combination of low-dose aspirin and heparin are mainstays of treatment. The majority of studies suggest that low-molecular weight heparin (LMWH) and unfractionated heparin have comparable clinical efficacy. However, if a recurrent loss is experienced despite treatment with LMWH, the use of unfractionated heparin in a subsequent pregnancy should be considered.
Younger age of type 2 diabetes onset linked to dementia risk
, new findings suggest.
Moreover, the new data from the prospective Atherosclerosis Risk in Communities (ARIC) cohort also suggest that the previously identified increased risk for dementia among people with prediabetes appears to be entirely explained by the subset who go on to develop type 2 diabetes.
“Our findings suggest that preventing prediabetes progression, especially in younger individuals, may be an important way to reduce the dementia burden,” wrote PhD student Jiaqi Hu of Johns Hopkins University, Baltimore, and colleagues. Their article was published online in Diabetologia.
The result builds on previous findings linking dysglycemia and cognitive decline, the study’s lead author, Elizabeth Selvin, PhD, of the Bloomberg School of Public Health at Johns Hopkins, said in an interview.
“Our prior work in the ARIC study suggests that improving glucose control could help prevent dementia in later life,” she said. 
Other studies have also linked higher A1c levels and diabetes in midlife to increased rates of cognitive decline. In addition, Dr. Selvin noted, “There is growing evidence that focusing on vascular health, especially focusing on diabetes and blood pressure, in midlife can stave off dementia in later life.”
This new study is the first to examine the effect of diabetes in the relationship between prediabetes and dementia, as well as the age of diabetes onset on subsequent dementia.
Prediabetes linked to dementia via diabetes development
Of the 11,656 ARIC participants without diabetes at baseline during 1990-1992 (age 46-70 years), 20.0% had prediabetes (defined as A1c 5.7%-6.4% or 39-46 mmol/mol). During a median follow-up of 15.9 years, 3,143 participants developed diabetes. The proportions of patients who developed diabetes were 44.6% among those with prediabetes at baseline versus 22.5% of those without.
Dementia developed in 2,247 participants over a median follow-up of 24.7 years. The cumulative incidence of dementia was 23.9% among those who developed diabetes versus 20.5% among those who did not.
After adjustment for demographics and for the Alzheimer’s disease–linked apolipoprotein E (APOE) gene, prediabetes was significantly associated with incident dementia (hazard ratio [HR], 1.19). However, significance disappeared after adjustment for incident diabetes (HR, 1.09), the researchers reported.
Younger age at diabetes diagnosis raises dementia risk
Age at diabetes diagnosis made a difference in dementia risk. With adjustments for lifestyle, demographic, and clinical factors, those diagnosed with diabetes before age 60 years had a nearly threefold increased risk for dementia compared with those who never developed diabetes (HR, 2.92; P < .001).
The dementia risk was also significantly increased, although to a lesser degree, among those aged 60-69 years at diabetes diagnosis (HR, 1.73; P < .001) and age 70-79 years at diabetes diagnosis (HR, 1.23; P < .001). The relationship was not significant for those aged 80 years and older (HR, 1.13).
“Prevention efforts in people with diabetes diagnosed younger than 65 years should be a high priority,” the authors urged.
Taken together, the data suggest that prolonged exposure to hyperglycemia plays a major role in dementia development.
“Putative mechanisms include acute and chronic hyperglycemia, glucose toxicity, insulin resistance, and microvascular dysfunction of the central nervous system. ... Glucose toxicity and microvascular dysfunction are associated with increased inflammatory and oxidative stress, leading to increased blood–brain permeability,” the researchers wrote.
Dr. Selvin said that her group is pursuing further work in this area using continuous glucose monitoring. “We plan to look at ... how glycemic control and different patterns of glucose in older adults may be linked to cognitive decline and other neurocognitive outcomes.”
The researchers reported no relevant financial relationships. Dr. Selvin has reported being on the advisory board for Diabetologia; she had no role in peer review of the manuscript.
A version of this article first appeared on Medscape.com.
, new findings suggest.
Moreover, the new data from the prospective Atherosclerosis Risk in Communities (ARIC) cohort also suggest that the previously identified increased risk for dementia among people with prediabetes appears to be entirely explained by the subset who go on to develop type 2 diabetes.
“Our findings suggest that preventing prediabetes progression, especially in younger individuals, may be an important way to reduce the dementia burden,” wrote PhD student Jiaqi Hu of Johns Hopkins University, Baltimore, and colleagues. Their article was published online in Diabetologia.
The result builds on previous findings linking dysglycemia and cognitive decline, the study’s lead author, Elizabeth Selvin, PhD, of the Bloomberg School of Public Health at Johns Hopkins, said in an interview.
“Our prior work in the ARIC study suggests that improving glucose control could help prevent dementia in later life,” she said.
Other studies have also linked higher A1c levels and diabetes in midlife to increased rates of cognitive decline. In addition, Dr. Selvin noted, “There is growing evidence that focusing on vascular health, especially focusing on diabetes and blood pressure, in midlife can stave off dementia in later life.”
This new study is the first to examine the effect of diabetes in the relationship between prediabetes and dementia, as well as the age of diabetes onset on subsequent dementia.
Prediabetes linked to dementia via diabetes development
Of the 11,656 ARIC participants without diabetes at baseline during 1990-1992 (age 46-70 years), 20.0% had prediabetes (defined as A1c 5.7%-6.4% or 39-46 mmol/mol). During a median follow-up of 15.9 years, 3,143 participants developed diabetes. The proportions of patients who developed diabetes were 44.6% among those with prediabetes at baseline versus 22.5% of those without.
Dementia developed in 2,247 participants over a median follow-up of 24.7 years. The cumulative incidence of dementia was 23.9% among those who developed diabetes versus 20.5% among those who did not.
After adjustment for demographics and for the Alzheimer’s disease–linked apolipoprotein E (APOE) gene, prediabetes was significantly associated with incident dementia (hazard ratio [HR], 1.19). However, significance disappeared after adjustment for incident diabetes (HR, 1.09), the researchers reported.
Younger age at diabetes diagnosis raises dementia risk
Age at diabetes diagnosis made a difference in dementia risk. With adjustments for lifestyle, demographic, and clinical factors, those diagnosed with diabetes before age 60 years had a nearly threefold increased risk for dementia compared with those who never developed diabetes (HR, 2.92; P < .001).
The dementia risk was also significantly increased, although to a lesser degree, among those aged 60-69 years at diabetes diagnosis (HR, 1.73; P < .001) and age 70-79 years at diabetes diagnosis (HR, 1.23; P < .001). The relationship was not significant for those aged 80 years and older (HR, 1.13).
“Prevention efforts in people with diabetes diagnosed younger than 65 years should be a high priority,” the authors urged.
Taken together, the data suggest that prolonged exposure to hyperglycemia plays a major role in dementia development.
“Putative mechanisms include acute and chronic hyperglycemia, glucose toxicity, insulin resistance, and microvascular dysfunction of the central nervous system. ... Glucose toxicity and microvascular dysfunction are associated with increased inflammatory and oxidative stress, leading to increased blood–brain permeability,” the researchers wrote.
Dr. Selvin said that her group is pursuing further work in this area using continuous glucose monitoring. “We plan to look at ... how glycemic control and different patterns of glucose in older adults may be linked to cognitive decline and other neurocognitive outcomes.”
The researchers reported no relevant financial relationships. Dr. Selvin has reported being on the advisory board for Diabetologia; she had no role in peer review of the manuscript.
A version of this article first appeared on Medscape.com.
, new findings suggest.
Moreover, the new data from the prospective Atherosclerosis Risk in Communities (ARIC) cohort also suggest that the previously identified increased risk for dementia among people with prediabetes appears to be entirely explained by the subset who go on to develop type 2 diabetes.
“Our findings suggest that preventing prediabetes progression, especially in younger individuals, may be an important way to reduce the dementia burden,” wrote PhD student Jiaqi Hu of Johns Hopkins University, Baltimore, and colleagues. Their article was published online in Diabetologia.
The result builds on previous findings linking dysglycemia and cognitive decline, the study’s lead author, Elizabeth Selvin, PhD, of the Bloomberg School of Public Health at Johns Hopkins, said in an interview.
“Our prior work in the ARIC study suggests that improving glucose control could help prevent dementia in later life,” she said.
Other studies have also linked higher A1c levels and diabetes in midlife to increased rates of cognitive decline. In addition, Dr. Selvin noted, “There is growing evidence that focusing on vascular health, especially focusing on diabetes and blood pressure, in midlife can stave off dementia in later life.”
This new study is the first to examine the effect of diabetes in the relationship between prediabetes and dementia, as well as the age of diabetes onset on subsequent dementia.
Prediabetes linked to dementia via diabetes development
Of the 11,656 ARIC participants without diabetes at baseline during 1990-1992 (age 46-70 years), 20.0% had prediabetes (defined as A1c 5.7%-6.4% or 39-46 mmol/mol). During a median follow-up of 15.9 years, 3,143 participants developed diabetes. The proportions of patients who developed diabetes were 44.6% among those with prediabetes at baseline versus 22.5% of those without.
Dementia developed in 2,247 participants over a median follow-up of 24.7 years. The cumulative incidence of dementia was 23.9% among those who developed diabetes versus 20.5% among those who did not.
After adjustment for demographics and for the Alzheimer’s disease–linked apolipoprotein E (APOE) gene, prediabetes was significantly associated with incident dementia (hazard ratio [HR], 1.19). However, significance disappeared after adjustment for incident diabetes (HR, 1.09), the researchers reported.
Younger age at diabetes diagnosis raises dementia risk
Age at diabetes diagnosis made a difference in dementia risk. With adjustments for lifestyle, demographic, and clinical factors, those diagnosed with diabetes before age 60 years had a nearly threefold increased risk for dementia compared with those who never developed diabetes (HR, 2.92; P < .001).
The dementia risk was also significantly increased, although to a lesser degree, among those aged 60-69 years at diabetes diagnosis (HR, 1.73; P < .001) and age 70-79 years at diabetes diagnosis (HR, 1.23; P < .001). The relationship was not significant for those aged 80 years and older (HR, 1.13).
“Prevention efforts in people with diabetes diagnosed younger than 65 years should be a high priority,” the authors urged.
Taken together, the data suggest that prolonged exposure to hyperglycemia plays a major role in dementia development.
“Putative mechanisms include acute and chronic hyperglycemia, glucose toxicity, insulin resistance, and microvascular dysfunction of the central nervous system. ... Glucose toxicity and microvascular dysfunction are associated with increased inflammatory and oxidative stress, leading to increased blood–brain permeability,” the researchers wrote.
Dr. Selvin said that her group is pursuing further work in this area using continuous glucose monitoring. “We plan to look at ... how glycemic control and different patterns of glucose in older adults may be linked to cognitive decline and other neurocognitive outcomes.”
The researchers reported no relevant financial relationships. Dr. Selvin has reported being on the advisory board for Diabetologia; she had no role in peer review of the manuscript.
A version of this article first appeared on Medscape.com.
FROM DIABETOLOGIA
Real-world data validate ESC risk model in NSTE-ACS
ESC model appropriately identifies risk
A real-world study of more than 12,000 cases over 7 years has validated the predictive ability of the proposed guidelines for stratifying thrombotic risks at 1 year for patients with non–ST-elevated acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).
In research presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions, George Dangas, MD, PhD, current SCAI president and professor of cardiology and vascular surgery at the Icahn School of Medicine at Mount Sinai, New York, reported that the European Society of Cardiology risk stratification criteria appropriately predicted risk in 12,538 patients treated from 2012 to 2019.
Despite these proposed guidelines put forward by the ESC in 2020, no consensus exists on criteria for ischemic or thrombotic risk in NSTE-ACS patients, Dr. Dangas noted.
The new study shows that the 1-year major adverse cardiovascular events (MACE) risk was four times greater in patients classified as medium risk (hazard ratio, 4.31; 95% confidence interval, 2.47-7.52) and six times greater in high-risk patients (HR, 6.16; 95% CI, 3.52-10.8), compared with the low-risk group, mostly because of higher rates of all-cause death and myocardial infarction, Dr. Dangas said in an interview.
“Indeed, we found some good correlation between the three risk categories and gradation of risk that validates essentially, but with the statistical testing that we need, that this classification is meaningful if not perfect,” Dr. Dangas said. “In the future we may perform calibrations to enhance its performance.”
The study used data on consecutive patients from the Angioplasty and Stent Procedures Database of Mount Sinai, grouping them into low, medium, and high thrombotic risk based on the proposed ESC guidelines for the management of NSTE-ACS.
The guidelines included a subset of criteria to identify patients with increased thrombotic risk who may benefit from extended treatment with a second antithrombotic agent.
This study aimed to evaluate the value of the criteria to identify patients at higher risk of ischemic events. “That’s why we went to our database to see how this might work,” Dr. Dangas said.
The researchers also found that high-risk patients had about a 40% greater risk of major bleeding (HR, 1.39; 95% CI, 1.06-1.84). Bleeding risks were similar between the low- and moderate-risk groups.
The risk categories reflected the rates of all-cause death, myocardial infarction, or stroke: 5.4%, 4.1%, and 1.6% in the high-, moderate-, and low-risks groups, respectively (P < .001).
“This identification of ischemic risks worked very well for all-cause mortality,” Dr. Dangas said. “I feel this is a strength because mortality is a leader of outcomes. And of course, we’ve had some associations with all events like mortality, myocardial infarction, repeat revascularization, which are interesting and valid, but I think a study result that indicates the mortality itself is known to be unidirectional and a very good correlation makes the result more robust.”
Critical role
Risk prediction models such as the proposed ESC guidelines will play a critical role as individualized medicine continues to evolve, Somjot Brar, MD, MPH, director of the regional department of cardiac catheterization at Kaiser Permanente, Los Angeles Medical Center, and associate clinical professor at the University of California, Los Angeles, said in an interview.
“This study highlights again the importance of the value for predictive and precision medicine,” Dr. Brar said. “Everything is moving in this direction where we make decisions that are more appropriate for a given patient as opposed to a population of patients.”
Study strengths are the large sample size in a real-world setting and thorough 1-year follow-up, Dr. Brar said.
A limitation is the three risk categories the guidelines proposed. “These are still pretty big boxes,” he said. “The low-, moderate- and high-risk categorization is still very, very broad and can be very vague.”
The relatively low percentage of low-risk patients – 12% versus 56% and 32% for the moderate- and high-risk groups – in this data set may also skew results, Dr. Brar said.
“As we move toward predictive analytics and medicine, we want to make these boxes smaller and smaller and smaller to be able to better understand which treatments should be administered to which patients to maximize the benefit against the risk,” he said. That would be a focus for future analyses, Dr. Brar said.
Dr. Dangas and Dr. Brar have no relevant financial disclosures.
ESC model appropriately identifies risk
ESC model appropriately identifies risk
A real-world study of more than 12,000 cases over 7 years has validated the predictive ability of the proposed guidelines for stratifying thrombotic risks at 1 year for patients with non–ST-elevated acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).
In research presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions, George Dangas, MD, PhD, current SCAI president and professor of cardiology and vascular surgery at the Icahn School of Medicine at Mount Sinai, New York, reported that the European Society of Cardiology risk stratification criteria appropriately predicted risk in 12,538 patients treated from 2012 to 2019.
Despite these proposed guidelines put forward by the ESC in 2020, no consensus exists on criteria for ischemic or thrombotic risk in NSTE-ACS patients, Dr. Dangas noted.
The new study shows that the 1-year major adverse cardiovascular events (MACE) risk was four times greater in patients classified as medium risk (hazard ratio, 4.31; 95% confidence interval, 2.47-7.52) and six times greater in high-risk patients (HR, 6.16; 95% CI, 3.52-10.8), compared with the low-risk group, mostly because of higher rates of all-cause death and myocardial infarction, Dr. Dangas said in an interview.
“Indeed, we found some good correlation between the three risk categories and gradation of risk that validates essentially, but with the statistical testing that we need, that this classification is meaningful if not perfect,” Dr. Dangas said. “In the future we may perform calibrations to enhance its performance.”
The study used data on consecutive patients from the Angioplasty and Stent Procedures Database of Mount Sinai, grouping them into low, medium, and high thrombotic risk based on the proposed ESC guidelines for the management of NSTE-ACS.
The guidelines included a subset of criteria to identify patients with increased thrombotic risk who may benefit from extended treatment with a second antithrombotic agent.
This study aimed to evaluate the value of the criteria to identify patients at higher risk of ischemic events. “That’s why we went to our database to see how this might work,” Dr. Dangas said.
The researchers also found that high-risk patients had about a 40% greater risk of major bleeding (HR, 1.39; 95% CI, 1.06-1.84). Bleeding risks were similar between the low- and moderate-risk groups.
The risk categories reflected the rates of all-cause death, myocardial infarction, or stroke: 5.4%, 4.1%, and 1.6% in the high-, moderate-, and low-risks groups, respectively (P < .001).
“This identification of ischemic risks worked very well for all-cause mortality,” Dr. Dangas said. “I feel this is a strength because mortality is a leader of outcomes. And of course, we’ve had some associations with all events like mortality, myocardial infarction, repeat revascularization, which are interesting and valid, but I think a study result that indicates the mortality itself is known to be unidirectional and a very good correlation makes the result more robust.”
Critical role
Risk prediction models such as the proposed ESC guidelines will play a critical role as individualized medicine continues to evolve, Somjot Brar, MD, MPH, director of the regional department of cardiac catheterization at Kaiser Permanente, Los Angeles Medical Center, and associate clinical professor at the University of California, Los Angeles, said in an interview.
“This study highlights again the importance of the value for predictive and precision medicine,” Dr. Brar said. “Everything is moving in this direction where we make decisions that are more appropriate for a given patient as opposed to a population of patients.”
Study strengths are the large sample size in a real-world setting and thorough 1-year follow-up, Dr. Brar said.
A limitation is the three risk categories the guidelines proposed. “These are still pretty big boxes,” he said. “The low-, moderate- and high-risk categorization is still very, very broad and can be very vague.”
The relatively low percentage of low-risk patients – 12% versus 56% and 32% for the moderate- and high-risk groups – in this data set may also skew results, Dr. Brar said.
“As we move toward predictive analytics and medicine, we want to make these boxes smaller and smaller and smaller to be able to better understand which treatments should be administered to which patients to maximize the benefit against the risk,” he said. That would be a focus for future analyses, Dr. Brar said.
Dr. Dangas and Dr. Brar have no relevant financial disclosures.
A real-world study of more than 12,000 cases over 7 years has validated the predictive ability of the proposed guidelines for stratifying thrombotic risks at 1 year for patients with non–ST-elevated acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).
In research presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions, George Dangas, MD, PhD, current SCAI president and professor of cardiology and vascular surgery at the Icahn School of Medicine at Mount Sinai, New York, reported that the European Society of Cardiology risk stratification criteria appropriately predicted risk in 12,538 patients treated from 2012 to 2019.
Despite these proposed guidelines put forward by the ESC in 2020, no consensus exists on criteria for ischemic or thrombotic risk in NSTE-ACS patients, Dr. Dangas noted.
The new study shows that the 1-year major adverse cardiovascular events (MACE) risk was four times greater in patients classified as medium risk (hazard ratio, 4.31; 95% confidence interval, 2.47-7.52) and six times greater in high-risk patients (HR, 6.16; 95% CI, 3.52-10.8), compared with the low-risk group, mostly because of higher rates of all-cause death and myocardial infarction, Dr. Dangas said in an interview.
“Indeed, we found some good correlation between the three risk categories and gradation of risk that validates essentially, but with the statistical testing that we need, that this classification is meaningful if not perfect,” Dr. Dangas said. “In the future we may perform calibrations to enhance its performance.”
The study used data on consecutive patients from the Angioplasty and Stent Procedures Database of Mount Sinai, grouping them into low, medium, and high thrombotic risk based on the proposed ESC guidelines for the management of NSTE-ACS.
The guidelines included a subset of criteria to identify patients with increased thrombotic risk who may benefit from extended treatment with a second antithrombotic agent.
This study aimed to evaluate the value of the criteria to identify patients at higher risk of ischemic events. “That’s why we went to our database to see how this might work,” Dr. Dangas said.
The researchers also found that high-risk patients had about a 40% greater risk of major bleeding (HR, 1.39; 95% CI, 1.06-1.84). Bleeding risks were similar between the low- and moderate-risk groups.
The risk categories reflected the rates of all-cause death, myocardial infarction, or stroke: 5.4%, 4.1%, and 1.6% in the high-, moderate-, and low-risks groups, respectively (P < .001).
“This identification of ischemic risks worked very well for all-cause mortality,” Dr. Dangas said. “I feel this is a strength because mortality is a leader of outcomes. And of course, we’ve had some associations with all events like mortality, myocardial infarction, repeat revascularization, which are interesting and valid, but I think a study result that indicates the mortality itself is known to be unidirectional and a very good correlation makes the result more robust.”
Critical role
Risk prediction models such as the proposed ESC guidelines will play a critical role as individualized medicine continues to evolve, Somjot Brar, MD, MPH, director of the regional department of cardiac catheterization at Kaiser Permanente, Los Angeles Medical Center, and associate clinical professor at the University of California, Los Angeles, said in an interview.
“This study highlights again the importance of the value for predictive and precision medicine,” Dr. Brar said. “Everything is moving in this direction where we make decisions that are more appropriate for a given patient as opposed to a population of patients.”
Study strengths are the large sample size in a real-world setting and thorough 1-year follow-up, Dr. Brar said.
A limitation is the three risk categories the guidelines proposed. “These are still pretty big boxes,” he said. “The low-, moderate- and high-risk categorization is still very, very broad and can be very vague.”
The relatively low percentage of low-risk patients – 12% versus 56% and 32% for the moderate- and high-risk groups – in this data set may also skew results, Dr. Brar said.
“As we move toward predictive analytics and medicine, we want to make these boxes smaller and smaller and smaller to be able to better understand which treatments should be administered to which patients to maximize the benefit against the risk,” he said. That would be a focus for future analyses, Dr. Brar said.
Dr. Dangas and Dr. Brar have no relevant financial disclosures.
FROM SCAI 2023
FDA approves buprenorphine injection for opioid use disorder
The medication comes in two formulations: a weekly and a monthly version. The weekly treatment is indicated in patients who have initiated treatment with a single dose of transmucosal buprenorphine or who are already being treated with the drug. The monthly version is for patients already receiving buprenorphine.
“Buprenorphine is an important treatment option for opioid use disorder. Today’s approval expands dosing options and provides people with opioid use disorder a greater opportunity to sustain long-term recovery,” said FDA Commissioner Robert M. Califf, MD, in a release. “The FDA will continue to take the critical steps necessary to pursue efforts that advance evidence-based treatments for substance use disorders, which is a strategic priority under the FDA’s Overdose Prevention Framework,” Dr. Califf added.
The Substance Abuse and Mental Health Services Administration reports that patients receiving medication for OUD have their risk for all-cause mortality cut by 50%.
In its release, the FDA said that it remains committed to increasing treatment options for OUD. Earlier this month, the agency issued a joint letter with SAMHSA to underscore the importance of counseling and other services as part of a comprehensive treatment plan the disorder. It also emphasized that receiving buprenorphine should not be contingent on participating in such services.
Brixadi is approved in both weekly and monthly subcutaneous injectable formulations at varying doses, including lower doses that may be appropriate for patients who do not tolerate higher doses of extended-release buprenorphine that are currently available.
The drug will be available through a Risk Evaluation and Mitigation Strategy program and administered only by health care providers in a health care setting.
The most common adverse reactions associated with the drug include injection-site pain, headache, constipation, nausea, injection-site erythema, injection-site pruritus, insomnia, and urinary tract infections. The FDA reports that such side effects occur in at least 5% of patients.
A version of this article originally appeared on Medscape.com.
The medication comes in two formulations: a weekly and a monthly version. The weekly treatment is indicated in patients who have initiated treatment with a single dose of transmucosal buprenorphine or who are already being treated with the drug. The monthly version is for patients already receiving buprenorphine.
“Buprenorphine is an important treatment option for opioid use disorder. Today’s approval expands dosing options and provides people with opioid use disorder a greater opportunity to sustain long-term recovery,” said FDA Commissioner Robert M. Califf, MD, in a release. “The FDA will continue to take the critical steps necessary to pursue efforts that advance evidence-based treatments for substance use disorders, which is a strategic priority under the FDA’s Overdose Prevention Framework,” Dr. Califf added.
The Substance Abuse and Mental Health Services Administration reports that patients receiving medication for OUD have their risk for all-cause mortality cut by 50%.
In its release, the FDA said that it remains committed to increasing treatment options for OUD. Earlier this month, the agency issued a joint letter with SAMHSA to underscore the importance of counseling and other services as part of a comprehensive treatment plan the disorder. It also emphasized that receiving buprenorphine should not be contingent on participating in such services.
Brixadi is approved in both weekly and monthly subcutaneous injectable formulations at varying doses, including lower doses that may be appropriate for patients who do not tolerate higher doses of extended-release buprenorphine that are currently available.
The drug will be available through a Risk Evaluation and Mitigation Strategy program and administered only by health care providers in a health care setting.
The most common adverse reactions associated with the drug include injection-site pain, headache, constipation, nausea, injection-site erythema, injection-site pruritus, insomnia, and urinary tract infections. The FDA reports that such side effects occur in at least 5% of patients.
A version of this article originally appeared on Medscape.com.
The medication comes in two formulations: a weekly and a monthly version. The weekly treatment is indicated in patients who have initiated treatment with a single dose of transmucosal buprenorphine or who are already being treated with the drug. The monthly version is for patients already receiving buprenorphine.
“Buprenorphine is an important treatment option for opioid use disorder. Today’s approval expands dosing options and provides people with opioid use disorder a greater opportunity to sustain long-term recovery,” said FDA Commissioner Robert M. Califf, MD, in a release. “The FDA will continue to take the critical steps necessary to pursue efforts that advance evidence-based treatments for substance use disorders, which is a strategic priority under the FDA’s Overdose Prevention Framework,” Dr. Califf added.
The Substance Abuse and Mental Health Services Administration reports that patients receiving medication for OUD have their risk for all-cause mortality cut by 50%.
In its release, the FDA said that it remains committed to increasing treatment options for OUD. Earlier this month, the agency issued a joint letter with SAMHSA to underscore the importance of counseling and other services as part of a comprehensive treatment plan the disorder. It also emphasized that receiving buprenorphine should not be contingent on participating in such services.
Brixadi is approved in both weekly and monthly subcutaneous injectable formulations at varying doses, including lower doses that may be appropriate for patients who do not tolerate higher doses of extended-release buprenorphine that are currently available.
The drug will be available through a Risk Evaluation and Mitigation Strategy program and administered only by health care providers in a health care setting.
The most common adverse reactions associated with the drug include injection-site pain, headache, constipation, nausea, injection-site erythema, injection-site pruritus, insomnia, and urinary tract infections. The FDA reports that such side effects occur in at least 5% of patients.
A version of this article originally appeared on Medscape.com.
Female sexual pleasure: Is it in the water?
BALTIMORE – , according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. In a secondary analysis also presented at the meeting, the lubricants were found not to alter the vaginal microbiome.
Using these types of lubricants during vaginal intercourse at least once a week over a 4-week period resulted in a statistically significant increase of over four points in the 36-point Female Sexual Function Index (FSFI), a self-reported measure of sexual functioning, for participants, said Michael Krychman, MD, executive director of the Southern California Center for Sexual Health and Survivorship Medicine, Newport Beach, the senior author of the study. Statistically significant improvements also were observed in individual areas such as sexual desire and arousal, orgasm, and satisfaction. Results of the study have been published in the Journal of Sexual Medicine.
In the open-label, five-arm, parallel study conducted in Germany, 174 women aged 18-65 years were randomly assigned to use one of five lubricants from three popular brands. After a 4-week run-in period with no use of lubricants, participants were shown how to apply the products and instructed to use the substances during vaginal intercourse at least once a week over a 4-week period.
Participants reported experiencing mild to moderate vaginal dryness and dyspareunia during vaginal intercourse within the previous 3 months.
Statistically significant improvements were seen across all six individual domain scores of the FSFI (desire, arousal, lubrication, orgasm, satisfaction, and pain reduction) from baseline to week 4 with all five lubricants (P < .0001 for lubrication and pain reduction; P < .05 for desire, arousal, orgasm, and satisfaction), according to the researchers.
After 4 weeks, a clinically meaningful improvement in the total FSFI score was observed for four lubricants among premenopausal women and for all lubricants among postmenopausal women. The percentage of participants with sexual function as defined as a score of at least 26.55 on the FSFI was significantly greater after treatment (76.9%) than before treatment (20.8%; P < .0001).
“You would assume if you’re using lubricant it would improve the dryness, but what was very exciting for us is that it improved desire, it improved orgasm, it improved arousal,” Dr. Krychman said in an interview. Like concentric overlapping circles of female sexual function, he said, “if you improve one aspect, you improve the other.”
Nearly 80 nonserious adverse effects occurred in 43 participants, five of which were thought to be possibly attributed to the products, such as vulvovaginal burning, itching, or discomfort. In questionnaires, most women agreed that using the lubricants made sex more enjoyable and provided an overall pleasant experience.
One limitation of the study is that because most participants were Caucasian, the results may not be generalizable to all populations, according to the researchers. Further research is required to fully determine safety and efficacy in patients of all races and ethnicities, they reported, especially given that vaginal dryness has been reported more frequently in non-White ethnic groups.
In a companion presentation, Dr. Krychman discussed another aspect of the study looking at the lubricants’ effects on the vaginal microbiome. Repeated application of the products did not significantly alter the vaginal microbiome for up to 4 weeks, and vaginal pH slightly increased in all treatment groups shortly after use but was restored in most cases after a day.
Water-based lubricants are recommended by the WHO for use with condoms because they do not erode latex, said Karen Adams, MD, professor emeritus of obstetrics and gynecology and founding director of the Menopause and Sexual Medicine Program at Oregon Health & Science University, Portland. Guidelines from the group recommend lubricants should have an osmolality that is as close to normal vaginal secretions as possible to decrease the likelihood of irritation or other side effects, she said. Some available lubricants have four to six times that osmolality, which potentially could dehydrate cells, achieving the opposite of the desired effect.
“The reason this is important is they’re trying to develop lubricants that are more ‘vaginal friendly’ and more in line with the WHO guidelines,” said Dr. Adams, who is joining Stanford (Calif.) University in July to create and lead a new program in menopause and healthy aging. “They came up with four formulas consistent with WHO guidelines to see if these new ones worked at least as well [as commercially available products with higher osmolality], and it turns out they did,” she said. “They worked just fine.”
The study was funded by Reckitt Healthcare. Dr. Krychman is a paid medical consultant for the company. Dr. Adams disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BALTIMORE – , according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. In a secondary analysis also presented at the meeting, the lubricants were found not to alter the vaginal microbiome.
Using these types of lubricants during vaginal intercourse at least once a week over a 4-week period resulted in a statistically significant increase of over four points in the 36-point Female Sexual Function Index (FSFI), a self-reported measure of sexual functioning, for participants, said Michael Krychman, MD, executive director of the Southern California Center for Sexual Health and Survivorship Medicine, Newport Beach, the senior author of the study. Statistically significant improvements also were observed in individual areas such as sexual desire and arousal, orgasm, and satisfaction. Results of the study have been published in the Journal of Sexual Medicine.
In the open-label, five-arm, parallel study conducted in Germany, 174 women aged 18-65 years were randomly assigned to use one of five lubricants from three popular brands. After a 4-week run-in period with no use of lubricants, participants were shown how to apply the products and instructed to use the substances during vaginal intercourse at least once a week over a 4-week period.
Participants reported experiencing mild to moderate vaginal dryness and dyspareunia during vaginal intercourse within the previous 3 months.
Statistically significant improvements were seen across all six individual domain scores of the FSFI (desire, arousal, lubrication, orgasm, satisfaction, and pain reduction) from baseline to week 4 with all five lubricants (P < .0001 for lubrication and pain reduction; P < .05 for desire, arousal, orgasm, and satisfaction), according to the researchers.
After 4 weeks, a clinically meaningful improvement in the total FSFI score was observed for four lubricants among premenopausal women and for all lubricants among postmenopausal women. The percentage of participants with sexual function as defined as a score of at least 26.55 on the FSFI was significantly greater after treatment (76.9%) than before treatment (20.8%; P < .0001).
“You would assume if you’re using lubricant it would improve the dryness, but what was very exciting for us is that it improved desire, it improved orgasm, it improved arousal,” Dr. Krychman said in an interview. Like concentric overlapping circles of female sexual function, he said, “if you improve one aspect, you improve the other.”
Nearly 80 nonserious adverse effects occurred in 43 participants, five of which were thought to be possibly attributed to the products, such as vulvovaginal burning, itching, or discomfort. In questionnaires, most women agreed that using the lubricants made sex more enjoyable and provided an overall pleasant experience.
One limitation of the study is that because most participants were Caucasian, the results may not be generalizable to all populations, according to the researchers. Further research is required to fully determine safety and efficacy in patients of all races and ethnicities, they reported, especially given that vaginal dryness has been reported more frequently in non-White ethnic groups.
In a companion presentation, Dr. Krychman discussed another aspect of the study looking at the lubricants’ effects on the vaginal microbiome. Repeated application of the products did not significantly alter the vaginal microbiome for up to 4 weeks, and vaginal pH slightly increased in all treatment groups shortly after use but was restored in most cases after a day.
Water-based lubricants are recommended by the WHO for use with condoms because they do not erode latex, said Karen Adams, MD, professor emeritus of obstetrics and gynecology and founding director of the Menopause and Sexual Medicine Program at Oregon Health & Science University, Portland. Guidelines from the group recommend lubricants should have an osmolality that is as close to normal vaginal secretions as possible to decrease the likelihood of irritation or other side effects, she said. Some available lubricants have four to six times that osmolality, which potentially could dehydrate cells, achieving the opposite of the desired effect.
“The reason this is important is they’re trying to develop lubricants that are more ‘vaginal friendly’ and more in line with the WHO guidelines,” said Dr. Adams, who is joining Stanford (Calif.) University in July to create and lead a new program in menopause and healthy aging. “They came up with four formulas consistent with WHO guidelines to see if these new ones worked at least as well [as commercially available products with higher osmolality], and it turns out they did,” she said. “They worked just fine.”
The study was funded by Reckitt Healthcare. Dr. Krychman is a paid medical consultant for the company. Dr. Adams disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BALTIMORE – , according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. In a secondary analysis also presented at the meeting, the lubricants were found not to alter the vaginal microbiome.
Using these types of lubricants during vaginal intercourse at least once a week over a 4-week period resulted in a statistically significant increase of over four points in the 36-point Female Sexual Function Index (FSFI), a self-reported measure of sexual functioning, for participants, said Michael Krychman, MD, executive director of the Southern California Center for Sexual Health and Survivorship Medicine, Newport Beach, the senior author of the study. Statistically significant improvements also were observed in individual areas such as sexual desire and arousal, orgasm, and satisfaction. Results of the study have been published in the Journal of Sexual Medicine.
In the open-label, five-arm, parallel study conducted in Germany, 174 women aged 18-65 years were randomly assigned to use one of five lubricants from three popular brands. After a 4-week run-in period with no use of lubricants, participants were shown how to apply the products and instructed to use the substances during vaginal intercourse at least once a week over a 4-week period.
Participants reported experiencing mild to moderate vaginal dryness and dyspareunia during vaginal intercourse within the previous 3 months.
Statistically significant improvements were seen across all six individual domain scores of the FSFI (desire, arousal, lubrication, orgasm, satisfaction, and pain reduction) from baseline to week 4 with all five lubricants (P < .0001 for lubrication and pain reduction; P < .05 for desire, arousal, orgasm, and satisfaction), according to the researchers.
After 4 weeks, a clinically meaningful improvement in the total FSFI score was observed for four lubricants among premenopausal women and for all lubricants among postmenopausal women. The percentage of participants with sexual function as defined as a score of at least 26.55 on the FSFI was significantly greater after treatment (76.9%) than before treatment (20.8%; P < .0001).
“You would assume if you’re using lubricant it would improve the dryness, but what was very exciting for us is that it improved desire, it improved orgasm, it improved arousal,” Dr. Krychman said in an interview. Like concentric overlapping circles of female sexual function, he said, “if you improve one aspect, you improve the other.”
Nearly 80 nonserious adverse effects occurred in 43 participants, five of which were thought to be possibly attributed to the products, such as vulvovaginal burning, itching, or discomfort. In questionnaires, most women agreed that using the lubricants made sex more enjoyable and provided an overall pleasant experience.
One limitation of the study is that because most participants were Caucasian, the results may not be generalizable to all populations, according to the researchers. Further research is required to fully determine safety and efficacy in patients of all races and ethnicities, they reported, especially given that vaginal dryness has been reported more frequently in non-White ethnic groups.
In a companion presentation, Dr. Krychman discussed another aspect of the study looking at the lubricants’ effects on the vaginal microbiome. Repeated application of the products did not significantly alter the vaginal microbiome for up to 4 weeks, and vaginal pH slightly increased in all treatment groups shortly after use but was restored in most cases after a day.
Water-based lubricants are recommended by the WHO for use with condoms because they do not erode latex, said Karen Adams, MD, professor emeritus of obstetrics and gynecology and founding director of the Menopause and Sexual Medicine Program at Oregon Health & Science University, Portland. Guidelines from the group recommend lubricants should have an osmolality that is as close to normal vaginal secretions as possible to decrease the likelihood of irritation or other side effects, she said. Some available lubricants have four to six times that osmolality, which potentially could dehydrate cells, achieving the opposite of the desired effect.
“The reason this is important is they’re trying to develop lubricants that are more ‘vaginal friendly’ and more in line with the WHO guidelines,” said Dr. Adams, who is joining Stanford (Calif.) University in July to create and lead a new program in menopause and healthy aging. “They came up with four formulas consistent with WHO guidelines to see if these new ones worked at least as well [as commercially available products with higher osmolality], and it turns out they did,” she said. “They worked just fine.”
The study was funded by Reckitt Healthcare. Dr. Krychman is a paid medical consultant for the company. Dr. Adams disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
AT ACOG 2023
Can online mindfulness and self-compassion training improve quality of life for patients with atopic dermatitis?
, according to results of a small randomized controlled trial in Japan.
“We found that skin disease–specific QOL improved over time with a large effect size,” lead study author Sanae Kishimoto, MHS, MPH, of the School of Public Health, Graduate School of Medicine at Kyoto University and colleagues write in JAMA Dermatology. “These findings suggest that mindfulness and self-compassion training is an effective treatment option for adults with AD.”
A bothersome disease that worsens quality of life
AD, a chronic, relapsing, inflammatory, multifactorial skin disease involving intense itching, affects an estimated 15%-30% of children and 2%-10% of adults, with the incidence increasing in industrialized countries, the authors state.
Measured by disability-adjusted life years, AD has the highest disease burden among skin diseases, and people with AD commonly have anxiety, depression, and sleep problems. Treatments include medications, other skin care, and lifestyle changes. New biologics appear to be effective but are expensive and need to be studied for their long-term safety, the authors add.
“Stress can make the skin worse, but at the same time the skin disease and symptoms cause stress,” Peter A. Lio, MD, who was not involved in the study, told this news organization by email. “This vicious cycle contributes greatly to impairing quality of life.”
A program focused on wise, kind self-care
In the SMiLE study, the authors recruited adults with moderate to severe AD and Dermatology Life Quality Index (DLQI) score above 6 from dermatology clinics and through online announcements over 1 year beginning in July 2019.
Participants averaged 36.3 years of age, 80% were women, and their mean AD duration was 26.6 years. Everyone was allowed to receive usual care during the study, except for dupilumab (a newly marketed drug when the study started), psychotherapy, or other mindfulness training.
The researchers randomly assigned 56 adults to receive mindfulness training in addition to their usual care and 51 to the wait list plus usual care. Those in the training group received eight weekly 90-minute online mindfulness and self-compassion sessions. Each group-based session was conducted at the same time and day of the week and included meditation, informal psychoeducation, inquiry, and a short lecture, along with an optional 1-day silent meditation retreat at week 7 and an optional 2-hour videoconferencing booster session at week 13.
The intervention encouraged a nonjudgmental relationship with stress using mindfulness-based stress reduction (MBSR) and emphasized a compassionate relationship with oneself during suffering using mindful self-compassion (MSC). The program was developed and taught by lead author Dr. Kishimoto, a Japanese licensed clinical psychologist who has a history of AD, the paper notes.
At 13 weeks, after completing electronic assessments, patients in the training group showed greater improvement in the DLQI score than those on the wait list (between-group difference estimate, –6.34; 95% confidence interval, –8.27 to –4.41; P < .001). The standardized effect size (Cohen’s d) at 13 weeks was –1.06 (95% CI, –1.39 to –0.74).
Patients in the training group also improved more in all secondary outcomes: severity, itch- and scratch-related visual analog scales, self-compassion, mindfulness, psychological symptoms, and adherence to dermatologist-advised treatments.
They were also more likely to follow their dermatologist’s medical treatment plans, including moisturizer and topical steroid use.
One serious adverse event, endometrial cancer in one patient, was judged to be unrelated to the intervention.
Online format may give more patients access to treatment
“With relatively limited data in the literature, this particularly well-done, important study is likely to positively shape thinking around this topic,” said Dr. Lio, of the departments of dermatology and pediatrics at Northwestern University, Chicago. “This study nicely demonstrates that an online approach can be effective.
“In theory, these methods or techniques could democratize treatments like this, and open them up to many more patients,” he added. He would like to see partially or entirely automated apps (free of cost), similar to meditation “apps,” to treat patients more cost-effectively.
Dr. Lio explained that excluding participants on dupilumab (Dupixent) makes the results slightly less generalizable to patients with moderate to severe AD, who may have the most serious QOL challenges and who are often candidates for dupilumab.
“However, given that we almost never have all the known variables for a study, we are generally comfortable extrapolating that the intervention would likely be helpful for patients taking dupilumab as well, despite it not being specifically evaluated in that group,” he said.
Susan Massick, MD, of the department of dermatology at the Ohio State University Wexner Medical Center in Columbus, advises clinicians to take a multipronged approach to treating the physical and behavioral components of AD and to embrace therapies beyond prescription medications.
“Self-compassion training is another tool in our toolbox toward finding the right fix for our patients,” Dr. Massick said by email. She was not involved with this research.
“I applaud the focus of this study on behavioral health training as a means toward wellness and improved mindfulness,” she added. “I was impressed by the extent to which these simple measures helped improve the quality of life for patients who used the training.”
U.S. patients can benefit from these findings
“My sense is that AD patients the world over have many similar characteristics and concerns, so I would anticipate that the results would be comparable in a U.S. population,” Dr. Lio said. “Other studies performed in the U.S. also support this line of thinking.”
Although the study involved highly motivated patients in Japan, the suffering that patients with AD experience is universal regardless of race or ethnicity, Dr. Massick said. “Americans may be even more willing to embrace mindfulness and self-compassion training as a path toward better health and wellness.”
The study was funded by the Japan Agency for Medical Research and Development and the Mental Health Okamoto Memorial Foundation, the KDDI Foundation, the Pfizer Health Research Foundation, and the Japan Society for the Promotion of Science.
Dr. Kishimoto and several coauthors report relevant financial relationships with pharmaceutical companies. Dr. Lio reports financial relationships with Sanofi and Regeneron, the joint developers of dupilumab. Dr. Massick reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to results of a small randomized controlled trial in Japan.
“We found that skin disease–specific QOL improved over time with a large effect size,” lead study author Sanae Kishimoto, MHS, MPH, of the School of Public Health, Graduate School of Medicine at Kyoto University and colleagues write in JAMA Dermatology. “These findings suggest that mindfulness and self-compassion training is an effective treatment option for adults with AD.”
A bothersome disease that worsens quality of life
AD, a chronic, relapsing, inflammatory, multifactorial skin disease involving intense itching, affects an estimated 15%-30% of children and 2%-10% of adults, with the incidence increasing in industrialized countries, the authors state.
Measured by disability-adjusted life years, AD has the highest disease burden among skin diseases, and people with AD commonly have anxiety, depression, and sleep problems. Treatments include medications, other skin care, and lifestyle changes. New biologics appear to be effective but are expensive and need to be studied for their long-term safety, the authors add.
“Stress can make the skin worse, but at the same time the skin disease and symptoms cause stress,” Peter A. Lio, MD, who was not involved in the study, told this news organization by email. “This vicious cycle contributes greatly to impairing quality of life.”
A program focused on wise, kind self-care
In the SMiLE study, the authors recruited adults with moderate to severe AD and Dermatology Life Quality Index (DLQI) score above 6 from dermatology clinics and through online announcements over 1 year beginning in July 2019.
Participants averaged 36.3 years of age, 80% were women, and their mean AD duration was 26.6 years. Everyone was allowed to receive usual care during the study, except for dupilumab (a newly marketed drug when the study started), psychotherapy, or other mindfulness training.
The researchers randomly assigned 56 adults to receive mindfulness training in addition to their usual care and 51 to the wait list plus usual care. Those in the training group received eight weekly 90-minute online mindfulness and self-compassion sessions. Each group-based session was conducted at the same time and day of the week and included meditation, informal psychoeducation, inquiry, and a short lecture, along with an optional 1-day silent meditation retreat at week 7 and an optional 2-hour videoconferencing booster session at week 13.
The intervention encouraged a nonjudgmental relationship with stress using mindfulness-based stress reduction (MBSR) and emphasized a compassionate relationship with oneself during suffering using mindful self-compassion (MSC). The program was developed and taught by lead author Dr. Kishimoto, a Japanese licensed clinical psychologist who has a history of AD, the paper notes.
At 13 weeks, after completing electronic assessments, patients in the training group showed greater improvement in the DLQI score than those on the wait list (between-group difference estimate, –6.34; 95% confidence interval, –8.27 to –4.41; P < .001). The standardized effect size (Cohen’s d) at 13 weeks was –1.06 (95% CI, –1.39 to –0.74).
Patients in the training group also improved more in all secondary outcomes: severity, itch- and scratch-related visual analog scales, self-compassion, mindfulness, psychological symptoms, and adherence to dermatologist-advised treatments.
They were also more likely to follow their dermatologist’s medical treatment plans, including moisturizer and topical steroid use.
One serious adverse event, endometrial cancer in one patient, was judged to be unrelated to the intervention.
Online format may give more patients access to treatment
“With relatively limited data in the literature, this particularly well-done, important study is likely to positively shape thinking around this topic,” said Dr. Lio, of the departments of dermatology and pediatrics at Northwestern University, Chicago. “This study nicely demonstrates that an online approach can be effective.
“In theory, these methods or techniques could democratize treatments like this, and open them up to many more patients,” he added. He would like to see partially or entirely automated apps (free of cost), similar to meditation “apps,” to treat patients more cost-effectively.
Dr. Lio explained that excluding participants on dupilumab (Dupixent) makes the results slightly less generalizable to patients with moderate to severe AD, who may have the most serious QOL challenges and who are often candidates for dupilumab.
“However, given that we almost never have all the known variables for a study, we are generally comfortable extrapolating that the intervention would likely be helpful for patients taking dupilumab as well, despite it not being specifically evaluated in that group,” he said.
Susan Massick, MD, of the department of dermatology at the Ohio State University Wexner Medical Center in Columbus, advises clinicians to take a multipronged approach to treating the physical and behavioral components of AD and to embrace therapies beyond prescription medications.
“Self-compassion training is another tool in our toolbox toward finding the right fix for our patients,” Dr. Massick said by email. She was not involved with this research.
“I applaud the focus of this study on behavioral health training as a means toward wellness and improved mindfulness,” she added. “I was impressed by the extent to which these simple measures helped improve the quality of life for patients who used the training.”
U.S. patients can benefit from these findings
“My sense is that AD patients the world over have many similar characteristics and concerns, so I would anticipate that the results would be comparable in a U.S. population,” Dr. Lio said. “Other studies performed in the U.S. also support this line of thinking.”
Although the study involved highly motivated patients in Japan, the suffering that patients with AD experience is universal regardless of race or ethnicity, Dr. Massick said. “Americans may be even more willing to embrace mindfulness and self-compassion training as a path toward better health and wellness.”
The study was funded by the Japan Agency for Medical Research and Development and the Mental Health Okamoto Memorial Foundation, the KDDI Foundation, the Pfizer Health Research Foundation, and the Japan Society for the Promotion of Science.
Dr. Kishimoto and several coauthors report relevant financial relationships with pharmaceutical companies. Dr. Lio reports financial relationships with Sanofi and Regeneron, the joint developers of dupilumab. Dr. Massick reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to results of a small randomized controlled trial in Japan.
“We found that skin disease–specific QOL improved over time with a large effect size,” lead study author Sanae Kishimoto, MHS, MPH, of the School of Public Health, Graduate School of Medicine at Kyoto University and colleagues write in JAMA Dermatology. “These findings suggest that mindfulness and self-compassion training is an effective treatment option for adults with AD.”
A bothersome disease that worsens quality of life
AD, a chronic, relapsing, inflammatory, multifactorial skin disease involving intense itching, affects an estimated 15%-30% of children and 2%-10% of adults, with the incidence increasing in industrialized countries, the authors state.
Measured by disability-adjusted life years, AD has the highest disease burden among skin diseases, and people with AD commonly have anxiety, depression, and sleep problems. Treatments include medications, other skin care, and lifestyle changes. New biologics appear to be effective but are expensive and need to be studied for their long-term safety, the authors add.
“Stress can make the skin worse, but at the same time the skin disease and symptoms cause stress,” Peter A. Lio, MD, who was not involved in the study, told this news organization by email. “This vicious cycle contributes greatly to impairing quality of life.”
A program focused on wise, kind self-care
In the SMiLE study, the authors recruited adults with moderate to severe AD and Dermatology Life Quality Index (DLQI) score above 6 from dermatology clinics and through online announcements over 1 year beginning in July 2019.
Participants averaged 36.3 years of age, 80% were women, and their mean AD duration was 26.6 years. Everyone was allowed to receive usual care during the study, except for dupilumab (a newly marketed drug when the study started), psychotherapy, or other mindfulness training.
The researchers randomly assigned 56 adults to receive mindfulness training in addition to their usual care and 51 to the wait list plus usual care. Those in the training group received eight weekly 90-minute online mindfulness and self-compassion sessions. Each group-based session was conducted at the same time and day of the week and included meditation, informal psychoeducation, inquiry, and a short lecture, along with an optional 1-day silent meditation retreat at week 7 and an optional 2-hour videoconferencing booster session at week 13.
The intervention encouraged a nonjudgmental relationship with stress using mindfulness-based stress reduction (MBSR) and emphasized a compassionate relationship with oneself during suffering using mindful self-compassion (MSC). The program was developed and taught by lead author Dr. Kishimoto, a Japanese licensed clinical psychologist who has a history of AD, the paper notes.
At 13 weeks, after completing electronic assessments, patients in the training group showed greater improvement in the DLQI score than those on the wait list (between-group difference estimate, –6.34; 95% confidence interval, –8.27 to –4.41; P < .001). The standardized effect size (Cohen’s d) at 13 weeks was –1.06 (95% CI, –1.39 to –0.74).
Patients in the training group also improved more in all secondary outcomes: severity, itch- and scratch-related visual analog scales, self-compassion, mindfulness, psychological symptoms, and adherence to dermatologist-advised treatments.
They were also more likely to follow their dermatologist’s medical treatment plans, including moisturizer and topical steroid use.
One serious adverse event, endometrial cancer in one patient, was judged to be unrelated to the intervention.
Online format may give more patients access to treatment
“With relatively limited data in the literature, this particularly well-done, important study is likely to positively shape thinking around this topic,” said Dr. Lio, of the departments of dermatology and pediatrics at Northwestern University, Chicago. “This study nicely demonstrates that an online approach can be effective.
“In theory, these methods or techniques could democratize treatments like this, and open them up to many more patients,” he added. He would like to see partially or entirely automated apps (free of cost), similar to meditation “apps,” to treat patients more cost-effectively.
Dr. Lio explained that excluding participants on dupilumab (Dupixent) makes the results slightly less generalizable to patients with moderate to severe AD, who may have the most serious QOL challenges and who are often candidates for dupilumab.
“However, given that we almost never have all the known variables for a study, we are generally comfortable extrapolating that the intervention would likely be helpful for patients taking dupilumab as well, despite it not being specifically evaluated in that group,” he said.
Susan Massick, MD, of the department of dermatology at the Ohio State University Wexner Medical Center in Columbus, advises clinicians to take a multipronged approach to treating the physical and behavioral components of AD and to embrace therapies beyond prescription medications.
“Self-compassion training is another tool in our toolbox toward finding the right fix for our patients,” Dr. Massick said by email. She was not involved with this research.
“I applaud the focus of this study on behavioral health training as a means toward wellness and improved mindfulness,” she added. “I was impressed by the extent to which these simple measures helped improve the quality of life for patients who used the training.”
U.S. patients can benefit from these findings
“My sense is that AD patients the world over have many similar characteristics and concerns, so I would anticipate that the results would be comparable in a U.S. population,” Dr. Lio said. “Other studies performed in the U.S. also support this line of thinking.”
Although the study involved highly motivated patients in Japan, the suffering that patients with AD experience is universal regardless of race or ethnicity, Dr. Massick said. “Americans may be even more willing to embrace mindfulness and self-compassion training as a path toward better health and wellness.”
The study was funded by the Japan Agency for Medical Research and Development and the Mental Health Okamoto Memorial Foundation, the KDDI Foundation, the Pfizer Health Research Foundation, and the Japan Society for the Promotion of Science.
Dr. Kishimoto and several coauthors report relevant financial relationships with pharmaceutical companies. Dr. Lio reports financial relationships with Sanofi and Regeneron, the joint developers of dupilumab. Dr. Massick reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA DERMATOLOGY
Cut in AFib burden gains traction as gauge of ablation success: PULSED-AF
suggests a new analysis.
It’s the first study tying those outcomes to residual AFib burden after ablation achieved using the emerging pulsed-field ablation (PFA) technology, say researchers. These associations are already established for cath ablation using traditional radiofrequency energy or cryoablation.
The new findings come from a secondary analysis of the recently published PULSED-AF study, which highlighted the ablation efficacy of Medtronic’s investigational PulseSelect PFA system in patients with either paroxysmal AFib (PAF) or persistent AFib.
The trial had entered 300 adult candidates for catheter ablation of recurrent, symptomatic PAF or persistent AFib at 41 centers in Australia, Canada, Europe, Japan, and the United States.
After ablation, 69% of PAF patients and 62% of those who had persistent AFib showed no sign of atrial arrhythmia (AA) over 12 months, based on the trial’s method for estimating AA burden.
Residual AA burden less than 10% was seen in 87% and 82% of those initially with PAF and persistent AFib, respectively. Burdens in that lowest range, compared with greater AA burden, predicted a “clinically meaningful” improvement in QoL scores in PAF patients.
Those who entered the study with persistent AFib showed such improvement – defined as a more than 19-point gain on the Atrial Fibrillation Effect on Quality-of-Life Questionnaire – regardless of postablation AA burden.
Moreover, patients initially with either type of AFib and residual burdens in the lowest range went on to have fewer cardioversions and repeat ablations (P < .01), Atul Verma, MD, McGill University Health Centre, Montreal, reported at the annual scientific sessions of the Heart Rhythm Society.
Dr. Verma, the trial’s principal investigator, is also lead author on the same-day publication of the secondary analysis in Heart Rhythm.
Binary endpoint lacks relevance
The PULSED-AF primary analysis defined ablation efficacy partly as freedom from AA recurrence lasting at least 30 seconds, with or without symptoms, a traditional AFib-ablation trial endpoint that is nonetheless considered clinically unhelpful.
The secondary analysis recasts that binary endpoint as degree of reduction in AFib burden, a continuous variable. That potentially allows AFib ablation efficacy to be assessed in a more nuanced way likely to be more meaningful to patients and the health care system, observed Dr. Verma and colleagues.
The “30-second endpoint” is limited in clinical usefulness and “doesn’t mean much to the patient,” he said at a press conference on the analysis before formally presenting it at the HRS sessions.
Recent AFib ablation trials have explored AA burden as possibly a superior way to assess the procedure’s success “but also to see if it’s better correlated with quality of life and health care outcomes,” Dr. Verma said. “So that’s exactly what we’ve tried to do here using the PULSED-AF data.”
In the secondary analysis, he said, patients’ rate of freedom from the 30-second endpoint was about 70%, but “more than 85% of them had an AFib burden of less than 10%.”
“This efficacy endpoint of 30 seconds of atrial arrhythmia has been challenged and has been seen clinically as insignificant,” agreed Rajeev Pathak, MBBS, PhD, of Australian National University and director of cardiac electrophysiology at Canberra (Australia) Hospital.
In AFib radiofrequency ablation and cryoablation studies “there is clear disconnect between these 30-second episodes of atrial arrhythmias we see and the clinical relevance of health care utilization and quality of life,” said Dr. Pathak, invited discussant for Dr. Verma’s presentation at the sessions.
Now an AFib ablation trial using PFA catheters has yielded similar results, finding AA burden to be “a more objective and relevant measure of success,” he said. “A 30-second endpoint is arbitrary, lacks significance, and is highly dependent on the monitoring strategy.”
The more you look, the more you see
The new secondary analysis included a demonstration that success rates based on the 30-second endpoint indeed vary depending on how subsequent arrhythmias are monitored.
As described by Dr. Verma, PULSED-AF data were assessed for the 30-second endpoint captured using three separate intermittent monitoring strategies that it and other recent ablation trials have used:
- Strategy A: Transtelephonic monitoring weekly and in the event of symptoms, plus 24-hour Holter monitoring at 6 and 12 months and 12-lead ECG at 3, 6, and 12 months
- Strategy B: Transtelephonic monitoring weekly and at symptoms for 3-6 months followed by monthly and at symptoms from 6 to 12 months, plus 24-hour Holter monitoring at 6 and 12 months, plus 12-lead ECG at 3, 6, and 12 months
- Strategy C: The median of two 24-hour Holter monitoring sessions per patient over 12 months
As Dr. Verma reported, rates of freedom from the 30-second endpoint climbed with successive monitoring strategies. The rates for PAF and persistent AFib patients, respectively, were: Strategy A – 70% and 62%, Strategy B – 71% and 68%, Strategy C – 91% and 86%.
“If you’re using the ‘freedom-from-30-seconds’ endpoint, the results that you are going to get are highly dependent on the monitoring strategy,” Dr. Verma said. “The more you look, the more you see.”
Valid estimation of burden
For the main PULSED-AF secondary analysis, the investigators defined AA burden according to findings on either Holter monitoring or the 12-lead ECG. “So as not to bias these results,” Dr. Verma said, “for every patient, we picked the method that gave us the highest atrial arrhythmia burden.”
Ideally, Dr. Verma said in an interview, arrhythmia burden would be determined using devices such as implantable loop recorders. “The problem is, this is expensive and not practical” in both clinical practice and many trials, so PULSED-AF investigators went with the intermittent monitoring strategy to estimate burdens.
Their method appears valid, he said, given that the study identified a statistically relevant 10% AA burden cut off for predicting quality of life improvement or less health care resource use.
“If their residual atrial arrhythmia burden was greater than 10%, they did not have a statistically significant improvement in quality of life,” Dr. Verma observed. And “very few” of them had cardioversions or repeat ablation.
“I couldn’t agree more” that residual AA burden is preferable to the 30-second endpoint for gauging AFib ablation success, Kenneth Ellenbogen, MD, Virginia Commonwealth University Medical Center, Richmond, said in an interview. Dr. Ellenbogen is also director of clinical cardiac electrophysiology and pacing at VCU Health Pauley Heart Center and not associated with PULSED-AF.
That AA burden was linked to health care resource use in the study “is absolutely brilliant,” he said, “because that’s what the bean counters really want at the end of the day. And as doctors we care about patients feeling better – improving quality of life.”
PULSED-AF was funded by Medtronic. Dr. Verma disclosed financial relationships with Bayer, Biosense Webster, Medtronic, Thermedical, Kardium, and Galaxy Medical, as well as and research grants from Adagio Medical. Dr. Ellenbogen disclosed financial relationships with Boston Scientific, Medtronic, Kestra, Hylomorph, Biotronik, MediLynx, Impulse Dynamics USA, Abbott, Biosense Webster, Milestone Pharmaceuticals, Sanofi, Medpace, and Elsevier. Dr. Pathak disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
suggests a new analysis.
It’s the first study tying those outcomes to residual AFib burden after ablation achieved using the emerging pulsed-field ablation (PFA) technology, say researchers. These associations are already established for cath ablation using traditional radiofrequency energy or cryoablation.
The new findings come from a secondary analysis of the recently published PULSED-AF study, which highlighted the ablation efficacy of Medtronic’s investigational PulseSelect PFA system in patients with either paroxysmal AFib (PAF) or persistent AFib.
The trial had entered 300 adult candidates for catheter ablation of recurrent, symptomatic PAF or persistent AFib at 41 centers in Australia, Canada, Europe, Japan, and the United States.
After ablation, 69% of PAF patients and 62% of those who had persistent AFib showed no sign of atrial arrhythmia (AA) over 12 months, based on the trial’s method for estimating AA burden.
Residual AA burden less than 10% was seen in 87% and 82% of those initially with PAF and persistent AFib, respectively. Burdens in that lowest range, compared with greater AA burden, predicted a “clinically meaningful” improvement in QoL scores in PAF patients.
Those who entered the study with persistent AFib showed such improvement – defined as a more than 19-point gain on the Atrial Fibrillation Effect on Quality-of-Life Questionnaire – regardless of postablation AA burden.
Moreover, patients initially with either type of AFib and residual burdens in the lowest range went on to have fewer cardioversions and repeat ablations (P < .01), Atul Verma, MD, McGill University Health Centre, Montreal, reported at the annual scientific sessions of the Heart Rhythm Society.
Dr. Verma, the trial’s principal investigator, is also lead author on the same-day publication of the secondary analysis in Heart Rhythm.
Binary endpoint lacks relevance
The PULSED-AF primary analysis defined ablation efficacy partly as freedom from AA recurrence lasting at least 30 seconds, with or without symptoms, a traditional AFib-ablation trial endpoint that is nonetheless considered clinically unhelpful.
The secondary analysis recasts that binary endpoint as degree of reduction in AFib burden, a continuous variable. That potentially allows AFib ablation efficacy to be assessed in a more nuanced way likely to be more meaningful to patients and the health care system, observed Dr. Verma and colleagues.
The “30-second endpoint” is limited in clinical usefulness and “doesn’t mean much to the patient,” he said at a press conference on the analysis before formally presenting it at the HRS sessions.
Recent AFib ablation trials have explored AA burden as possibly a superior way to assess the procedure’s success “but also to see if it’s better correlated with quality of life and health care outcomes,” Dr. Verma said. “So that’s exactly what we’ve tried to do here using the PULSED-AF data.”
In the secondary analysis, he said, patients’ rate of freedom from the 30-second endpoint was about 70%, but “more than 85% of them had an AFib burden of less than 10%.”
“This efficacy endpoint of 30 seconds of atrial arrhythmia has been challenged and has been seen clinically as insignificant,” agreed Rajeev Pathak, MBBS, PhD, of Australian National University and director of cardiac electrophysiology at Canberra (Australia) Hospital.
In AFib radiofrequency ablation and cryoablation studies “there is clear disconnect between these 30-second episodes of atrial arrhythmias we see and the clinical relevance of health care utilization and quality of life,” said Dr. Pathak, invited discussant for Dr. Verma’s presentation at the sessions.
Now an AFib ablation trial using PFA catheters has yielded similar results, finding AA burden to be “a more objective and relevant measure of success,” he said. “A 30-second endpoint is arbitrary, lacks significance, and is highly dependent on the monitoring strategy.”
The more you look, the more you see
The new secondary analysis included a demonstration that success rates based on the 30-second endpoint indeed vary depending on how subsequent arrhythmias are monitored.
As described by Dr. Verma, PULSED-AF data were assessed for the 30-second endpoint captured using three separate intermittent monitoring strategies that it and other recent ablation trials have used:
- Strategy A: Transtelephonic monitoring weekly and in the event of symptoms, plus 24-hour Holter monitoring at 6 and 12 months and 12-lead ECG at 3, 6, and 12 months
- Strategy B: Transtelephonic monitoring weekly and at symptoms for 3-6 months followed by monthly and at symptoms from 6 to 12 months, plus 24-hour Holter monitoring at 6 and 12 months, plus 12-lead ECG at 3, 6, and 12 months
- Strategy C: The median of two 24-hour Holter monitoring sessions per patient over 12 months
As Dr. Verma reported, rates of freedom from the 30-second endpoint climbed with successive monitoring strategies. The rates for PAF and persistent AFib patients, respectively, were: Strategy A – 70% and 62%, Strategy B – 71% and 68%, Strategy C – 91% and 86%.
“If you’re using the ‘freedom-from-30-seconds’ endpoint, the results that you are going to get are highly dependent on the monitoring strategy,” Dr. Verma said. “The more you look, the more you see.”
Valid estimation of burden
For the main PULSED-AF secondary analysis, the investigators defined AA burden according to findings on either Holter monitoring or the 12-lead ECG. “So as not to bias these results,” Dr. Verma said, “for every patient, we picked the method that gave us the highest atrial arrhythmia burden.”
Ideally, Dr. Verma said in an interview, arrhythmia burden would be determined using devices such as implantable loop recorders. “The problem is, this is expensive and not practical” in both clinical practice and many trials, so PULSED-AF investigators went with the intermittent monitoring strategy to estimate burdens.
Their method appears valid, he said, given that the study identified a statistically relevant 10% AA burden cut off for predicting quality of life improvement or less health care resource use.
“If their residual atrial arrhythmia burden was greater than 10%, they did not have a statistically significant improvement in quality of life,” Dr. Verma observed. And “very few” of them had cardioversions or repeat ablation.
“I couldn’t agree more” that residual AA burden is preferable to the 30-second endpoint for gauging AFib ablation success, Kenneth Ellenbogen, MD, Virginia Commonwealth University Medical Center, Richmond, said in an interview. Dr. Ellenbogen is also director of clinical cardiac electrophysiology and pacing at VCU Health Pauley Heart Center and not associated with PULSED-AF.
That AA burden was linked to health care resource use in the study “is absolutely brilliant,” he said, “because that’s what the bean counters really want at the end of the day. And as doctors we care about patients feeling better – improving quality of life.”
PULSED-AF was funded by Medtronic. Dr. Verma disclosed financial relationships with Bayer, Biosense Webster, Medtronic, Thermedical, Kardium, and Galaxy Medical, as well as and research grants from Adagio Medical. Dr. Ellenbogen disclosed financial relationships with Boston Scientific, Medtronic, Kestra, Hylomorph, Biotronik, MediLynx, Impulse Dynamics USA, Abbott, Biosense Webster, Milestone Pharmaceuticals, Sanofi, Medpace, and Elsevier. Dr. Pathak disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
suggests a new analysis.
It’s the first study tying those outcomes to residual AFib burden after ablation achieved using the emerging pulsed-field ablation (PFA) technology, say researchers. These associations are already established for cath ablation using traditional radiofrequency energy or cryoablation.
The new findings come from a secondary analysis of the recently published PULSED-AF study, which highlighted the ablation efficacy of Medtronic’s investigational PulseSelect PFA system in patients with either paroxysmal AFib (PAF) or persistent AFib.
The trial had entered 300 adult candidates for catheter ablation of recurrent, symptomatic PAF or persistent AFib at 41 centers in Australia, Canada, Europe, Japan, and the United States.
After ablation, 69% of PAF patients and 62% of those who had persistent AFib showed no sign of atrial arrhythmia (AA) over 12 months, based on the trial’s method for estimating AA burden.
Residual AA burden less than 10% was seen in 87% and 82% of those initially with PAF and persistent AFib, respectively. Burdens in that lowest range, compared with greater AA burden, predicted a “clinically meaningful” improvement in QoL scores in PAF patients.
Those who entered the study with persistent AFib showed such improvement – defined as a more than 19-point gain on the Atrial Fibrillation Effect on Quality-of-Life Questionnaire – regardless of postablation AA burden.
Moreover, patients initially with either type of AFib and residual burdens in the lowest range went on to have fewer cardioversions and repeat ablations (P < .01), Atul Verma, MD, McGill University Health Centre, Montreal, reported at the annual scientific sessions of the Heart Rhythm Society.
Dr. Verma, the trial’s principal investigator, is also lead author on the same-day publication of the secondary analysis in Heart Rhythm.
Binary endpoint lacks relevance
The PULSED-AF primary analysis defined ablation efficacy partly as freedom from AA recurrence lasting at least 30 seconds, with or without symptoms, a traditional AFib-ablation trial endpoint that is nonetheless considered clinically unhelpful.
The secondary analysis recasts that binary endpoint as degree of reduction in AFib burden, a continuous variable. That potentially allows AFib ablation efficacy to be assessed in a more nuanced way likely to be more meaningful to patients and the health care system, observed Dr. Verma and colleagues.
The “30-second endpoint” is limited in clinical usefulness and “doesn’t mean much to the patient,” he said at a press conference on the analysis before formally presenting it at the HRS sessions.
Recent AFib ablation trials have explored AA burden as possibly a superior way to assess the procedure’s success “but also to see if it’s better correlated with quality of life and health care outcomes,” Dr. Verma said. “So that’s exactly what we’ve tried to do here using the PULSED-AF data.”
In the secondary analysis, he said, patients’ rate of freedom from the 30-second endpoint was about 70%, but “more than 85% of them had an AFib burden of less than 10%.”
“This efficacy endpoint of 30 seconds of atrial arrhythmia has been challenged and has been seen clinically as insignificant,” agreed Rajeev Pathak, MBBS, PhD, of Australian National University and director of cardiac electrophysiology at Canberra (Australia) Hospital.
In AFib radiofrequency ablation and cryoablation studies “there is clear disconnect between these 30-second episodes of atrial arrhythmias we see and the clinical relevance of health care utilization and quality of life,” said Dr. Pathak, invited discussant for Dr. Verma’s presentation at the sessions.
Now an AFib ablation trial using PFA catheters has yielded similar results, finding AA burden to be “a more objective and relevant measure of success,” he said. “A 30-second endpoint is arbitrary, lacks significance, and is highly dependent on the monitoring strategy.”
The more you look, the more you see
The new secondary analysis included a demonstration that success rates based on the 30-second endpoint indeed vary depending on how subsequent arrhythmias are monitored.
As described by Dr. Verma, PULSED-AF data were assessed for the 30-second endpoint captured using three separate intermittent monitoring strategies that it and other recent ablation trials have used:
- Strategy A: Transtelephonic monitoring weekly and in the event of symptoms, plus 24-hour Holter monitoring at 6 and 12 months and 12-lead ECG at 3, 6, and 12 months
- Strategy B: Transtelephonic monitoring weekly and at symptoms for 3-6 months followed by monthly and at symptoms from 6 to 12 months, plus 24-hour Holter monitoring at 6 and 12 months, plus 12-lead ECG at 3, 6, and 12 months
- Strategy C: The median of two 24-hour Holter monitoring sessions per patient over 12 months
As Dr. Verma reported, rates of freedom from the 30-second endpoint climbed with successive monitoring strategies. The rates for PAF and persistent AFib patients, respectively, were: Strategy A – 70% and 62%, Strategy B – 71% and 68%, Strategy C – 91% and 86%.
“If you’re using the ‘freedom-from-30-seconds’ endpoint, the results that you are going to get are highly dependent on the monitoring strategy,” Dr. Verma said. “The more you look, the more you see.”
Valid estimation of burden
For the main PULSED-AF secondary analysis, the investigators defined AA burden according to findings on either Holter monitoring or the 12-lead ECG. “So as not to bias these results,” Dr. Verma said, “for every patient, we picked the method that gave us the highest atrial arrhythmia burden.”
Ideally, Dr. Verma said in an interview, arrhythmia burden would be determined using devices such as implantable loop recorders. “The problem is, this is expensive and not practical” in both clinical practice and many trials, so PULSED-AF investigators went with the intermittent monitoring strategy to estimate burdens.
Their method appears valid, he said, given that the study identified a statistically relevant 10% AA burden cut off for predicting quality of life improvement or less health care resource use.
“If their residual atrial arrhythmia burden was greater than 10%, they did not have a statistically significant improvement in quality of life,” Dr. Verma observed. And “very few” of them had cardioversions or repeat ablation.
“I couldn’t agree more” that residual AA burden is preferable to the 30-second endpoint for gauging AFib ablation success, Kenneth Ellenbogen, MD, Virginia Commonwealth University Medical Center, Richmond, said in an interview. Dr. Ellenbogen is also director of clinical cardiac electrophysiology and pacing at VCU Health Pauley Heart Center and not associated with PULSED-AF.
That AA burden was linked to health care resource use in the study “is absolutely brilliant,” he said, “because that’s what the bean counters really want at the end of the day. And as doctors we care about patients feeling better – improving quality of life.”
PULSED-AF was funded by Medtronic. Dr. Verma disclosed financial relationships with Bayer, Biosense Webster, Medtronic, Thermedical, Kardium, and Galaxy Medical, as well as and research grants from Adagio Medical. Dr. Ellenbogen disclosed financial relationships with Boston Scientific, Medtronic, Kestra, Hylomorph, Biotronik, MediLynx, Impulse Dynamics USA, Abbott, Biosense Webster, Milestone Pharmaceuticals, Sanofi, Medpace, and Elsevier. Dr. Pathak disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM HRS 2023
Does Ozempic cause hair loss?
Should people be concerned about possible hair loss when taking Wegovy, Ozempic, or Mounjaro for weight loss (where the latter two drugs are being used off label) – as was recently claimed by some people on social media and reported in news stories?
The consensus among dermatologists and endocrinologists is no.
It’s up to the individual to weigh the benefits of treating obesity against the risks of the therapy, including the low risk of developing temporary hair loss, says one expert.
Wegovy, Ozempic, and Mounjaro
Of these three newer medications, only the glucagonlike peptide–1 (GLP-1) receptor agonist semaglutide (Wegovy) is approved by the Food and Drug Administration (since June 2021) for weight management – specifically for people with either obesity (body mass index ≥ 30 kg/m2) or overweight (BMI ≥ 27) plus at least one weight-related comorbidity such as hypertension, type 2 diabetes, and high cholesterol – with a dosage up to a 2.4-mg weekly injection.
When there was a short supply of Wegovy soon after it became available, some people turned to the same drug – semaglutide, but marketed as Ozempic for type 2 diabetes, which is titrated up to a 2-mg weekly injection. Still others opted for tirzepatide (Mounjaro), a dual GLP-1 agonist and glucose-dependent insulinotropic polypeptide (GIP) agonist. Tirzepatide is approved for type 2 diabetes in the United States but is not yet approved for weight loss.
Wegovy shortages continue to be reported.
; of interest, it was more common after bariatric surgery.
In clinical trials, 3% of patients receiving Wegovy (a 2.4-mg/wk injection) versus 1% of patients receiving placebo reported alopecia. Hair loss was not reported as a side effect in clinical trials of Ozempic (a 2-mg/wk injection) for type 2 diabetes. In a clinical trial of tirzepatide for weight loss in obesity, 5.7% of patients taking the highest dose (a 15-mg once-weekly injection) reported alopecia vs 1% of those who got a placebo.
In contrast, a review of 18 mostly observational studies reported that 57% of patients had hair loss after bariatric surgery.
Is it the drug or the rapid weight loss?
None of the experts consulted for this article had seen patients who came to them about hair loss while taking these drugs for weight loss.
“I have not seen patients complaining of hair loss from these medications, but perhaps it is just a matter of time,” said Lynne J. Goldberg, MD, a professor of dermatology and pathology and laboratory medicine, at Boston University, and director of the hair clinic at Boston Medical Center.
“Some of my patients lose hair when they lose weight, generally as a result of the weight loss itself and not as a side effect of these medications,” said Katharine H. Saunders, MD, an obesity medicine physician, cofounder of Intellihealth, and an assistant professor of medicine at Weill Cornell Medicine, New York.
“Hair loss from rapid weight loss is very common [and] not necessarily a side effect of the medication itself but more as a result of how quickly the weight loss occurs,” echoed Susan Massick, MD, associate professor of dermatology, Ohio State University, and a dermatologist at Ohio State’s Wexner Medical Center, both in Columbus.
“Hair loss is tricky,” observed Anne Peters, MD, director of clinical diabetes programs at the University of Southern California, Los Angeles. “Losing weight and/or changing your diet causes hair loss. Stress can cause hair loss. So, it is hard to separate weight loss from medication effect.”
Telogen effluvium (stress shedding) with rapid weight loss
The hair loss seems to be associated with rapid weight loss, the experts agreed.
“It is rare, but we can see patients who have a period of diffuse hair loss, called telogen effluvium, or ‘stress shedding’ with rapid weight loss,” said Michael A. Weintraub, MD, an endocrinologist at NYU Langone Health, New York.
This hair loss occurs in relation to either physical (surgery, pregnancy, illness) or emotional stress, added Dr. Weintraub, who is an assistant professor at NYU Grossman School of Medicine.
Hair loss caused by rapid weight loss could be caused by an antiobesity medication, but it could also occur with other obesity treatments, such as bariatric surgery or drastic dietary changes, he said. The hair shedding is typically short lived and reversible.
About 80%-85% of hair is in the anagen (growth) phase, about 5% is in a transitional (catagen) phase, and the rest is in telogen (resting, or shedding) phase, Dr. Massick explained. In telogen effluvium, hairs that are normally in the growth phase get suddenly shifted to telogen phase and are shed rapidly.
“Telogen effluvium can be caused by rapid weight loss, major surgery, severe COVID infection, high fever, or death in the family,” she noted. “You will not go bald with telogen effluvium, but you might find that you may lose a good volume of hair,” much more than the normal loss of up to 100 hairs a day.
“I counsel my patients about the possibility of losing hair before they undergo bariatric surgery,” Dr. Saunders said. “Generally, the health benefits of weight loss and weight maintenance outweigh the risk of temporary hair loss.”
Nutritional deficiencies and malnutrition can contribute to hair loss as well, and iron deficiency is sometimes a culprit, she added.
“If someone is worried” about hair loss associated with weight loss, “they should see their doctor,” Dr. Peters said. “If they are on thyroid hormone, in particular, the levels should be retested after weight loss.”
Hair loss appears more common after bariatric surgery than with antiobesity medications,” Dr. Weintraub observed, and it is unclear whether this is because the weight loss is more dramatic after surgery and thus a greater stressor, or whether it is caused by nutrient deficiency or a different mechanism entirely.
“Unlike certain forms of bariatric surgery, which can lead to malabsorption (e.g., Roux-en-Y gastric bypass), medications such as GLP-1 agonists and GLP-1/GIP dual agonists do not cause malabsorption,” Dr. Weintraub noted. “So nutritional deficiencies are less likely to be the cause of new hair loss in those taking antiobesity medications than [in] someone who underwent bariatric surgery.”
Iron and vitamin D deficiencies are the most common nutritional deficiencies that can cause hair loss, he noted.
Slow and steady weight loss rather than rapid
“I would suggest that patients try to keep the weight loss slow and steady, rather than rapid,” Dr. Goldberg said, “and follow any vitamin/mineral supplementation plan that they are given. Patients with bariatric surgery have nutritional guidance and a supplementation plan.”
“Follow a well-balanced dietary strategy with ample protein, vegetables, and some fruit,” Dr. Saunders said. Health care providers should monitor lab tests to check for and treat vitamin deficiencies, and registered dietitians can be crucial to ensure proper nutrition. She advises patients: “Find coping strategies to reduce stress and get enough sleep. If iron levels are low, start an iron supplement under your provider’s supervision.”
“Some of my patients swear by biotin supplements, prenatal vitamins or ‘hair, skin, and nails’ vitamins,” she added. If hair loss doesn’t stop, a dermatologist can look for other contributors and discuss strategies for hair restoration.
Individuals who undergo bariatric surgery require lifelong vitamin supplementation and yearly (or more frequent) lab testing, she noted.
“With, for example, bariatric surgery or any type of diet change you want to make sure you still maintain a balanced diet, whether its calories, protein, iron, zinc, vitamins (vitamin D for example),” Dr. Massick echoed.
Similarly, Dr. Peters advised: “I would say to maintain a normal healthy diet even if eating less. Exercise. Do all those healthy things. Taking a daily multivitamin isn’t a bad idea. Talk with a nutritionist. Use the appetite suppression of the medication to combine with healthy eating.”
“If someone is having new hair loss, they should see their clinician to evaluate for all possible causes,” Dr. Weintraub said. “Their provider can evaluate for underlying causes like thyroid dysfunction, iron deficiency, and vitamin D deficiency.”
However, if a patient’s pattern of hair loss is not diffuse but occurs in patches, this has an entirely different set of etiologies probably unrelated to antiobesity medication and should be evaluated.
Working with a nutritionist to ensure that patients have sufficient protein and micronutrient intake can lower the risk of developing hair loss and other complications, Dr. Weintraub said. “This is particularly important for certain forms of bariatric surgery such as Roux-en-Y gastric bypass, since that can lead to malabsorption of specific vitamins and minerals that need to be periodically measured and supplemented.”
In individuals starting an antiobesity medication, beginning a daily multivitamin has little harm, he added, and can ensure they are getting essential minerals and vitamins. However, no studies have specifically investigated this yet.
“Ultimately, it’s important to weigh the benefits of antiobesity medications against the potential risks, as we do with any medical intervention,” according to Dr. Weintraub.
“The purpose of treating obesity,” he stressed, “is to reduce the risk of heart disease, stroke, and multiple types of cancers. It’s up to the individual to weigh these benefits against the risks of the treatment, including the low risk of developing temporary hair loss.”
Dr. Peters writes a column for Medscape and disclosed that she served as a consultant for Blue Circle Health, Vertex, and Abbott Diabetes Care; received a research grant from Abbott Diabetes Care; and received stock options from Teladoc and Omada Health. Dr. Goldberg, Dr. Saunders, Dr. Massick, and Dr. Weintraub declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Should people be concerned about possible hair loss when taking Wegovy, Ozempic, or Mounjaro for weight loss (where the latter two drugs are being used off label) – as was recently claimed by some people on social media and reported in news stories?
The consensus among dermatologists and endocrinologists is no.
It’s up to the individual to weigh the benefits of treating obesity against the risks of the therapy, including the low risk of developing temporary hair loss, says one expert.
Wegovy, Ozempic, and Mounjaro
Of these three newer medications, only the glucagonlike peptide–1 (GLP-1) receptor agonist semaglutide (Wegovy) is approved by the Food and Drug Administration (since June 2021) for weight management – specifically for people with either obesity (body mass index ≥ 30 kg/m2) or overweight (BMI ≥ 27) plus at least one weight-related comorbidity such as hypertension, type 2 diabetes, and high cholesterol – with a dosage up to a 2.4-mg weekly injection.
When there was a short supply of Wegovy soon after it became available, some people turned to the same drug – semaglutide, but marketed as Ozempic for type 2 diabetes, which is titrated up to a 2-mg weekly injection. Still others opted for tirzepatide (Mounjaro), a dual GLP-1 agonist and glucose-dependent insulinotropic polypeptide (GIP) agonist. Tirzepatide is approved for type 2 diabetes in the United States but is not yet approved for weight loss.
Wegovy shortages continue to be reported.
; of interest, it was more common after bariatric surgery.
In clinical trials, 3% of patients receiving Wegovy (a 2.4-mg/wk injection) versus 1% of patients receiving placebo reported alopecia. Hair loss was not reported as a side effect in clinical trials of Ozempic (a 2-mg/wk injection) for type 2 diabetes. In a clinical trial of tirzepatide for weight loss in obesity, 5.7% of patients taking the highest dose (a 15-mg once-weekly injection) reported alopecia vs 1% of those who got a placebo.
In contrast, a review of 18 mostly observational studies reported that 57% of patients had hair loss after bariatric surgery.
Is it the drug or the rapid weight loss?
None of the experts consulted for this article had seen patients who came to them about hair loss while taking these drugs for weight loss.
“I have not seen patients complaining of hair loss from these medications, but perhaps it is just a matter of time,” said Lynne J. Goldberg, MD, a professor of dermatology and pathology and laboratory medicine, at Boston University, and director of the hair clinic at Boston Medical Center.
“Some of my patients lose hair when they lose weight, generally as a result of the weight loss itself and not as a side effect of these medications,” said Katharine H. Saunders, MD, an obesity medicine physician, cofounder of Intellihealth, and an assistant professor of medicine at Weill Cornell Medicine, New York.
“Hair loss from rapid weight loss is very common [and] not necessarily a side effect of the medication itself but more as a result of how quickly the weight loss occurs,” echoed Susan Massick, MD, associate professor of dermatology, Ohio State University, and a dermatologist at Ohio State’s Wexner Medical Center, both in Columbus.
“Hair loss is tricky,” observed Anne Peters, MD, director of clinical diabetes programs at the University of Southern California, Los Angeles. “Losing weight and/or changing your diet causes hair loss. Stress can cause hair loss. So, it is hard to separate weight loss from medication effect.”
Telogen effluvium (stress shedding) with rapid weight loss
The hair loss seems to be associated with rapid weight loss, the experts agreed.
“It is rare, but we can see patients who have a period of diffuse hair loss, called telogen effluvium, or ‘stress shedding’ with rapid weight loss,” said Michael A. Weintraub, MD, an endocrinologist at NYU Langone Health, New York.
This hair loss occurs in relation to either physical (surgery, pregnancy, illness) or emotional stress, added Dr. Weintraub, who is an assistant professor at NYU Grossman School of Medicine.
Hair loss caused by rapid weight loss could be caused by an antiobesity medication, but it could also occur with other obesity treatments, such as bariatric surgery or drastic dietary changes, he said. The hair shedding is typically short lived and reversible.
About 80%-85% of hair is in the anagen (growth) phase, about 5% is in a transitional (catagen) phase, and the rest is in telogen (resting, or shedding) phase, Dr. Massick explained. In telogen effluvium, hairs that are normally in the growth phase get suddenly shifted to telogen phase and are shed rapidly.
“Telogen effluvium can be caused by rapid weight loss, major surgery, severe COVID infection, high fever, or death in the family,” she noted. “You will not go bald with telogen effluvium, but you might find that you may lose a good volume of hair,” much more than the normal loss of up to 100 hairs a day.
“I counsel my patients about the possibility of losing hair before they undergo bariatric surgery,” Dr. Saunders said. “Generally, the health benefits of weight loss and weight maintenance outweigh the risk of temporary hair loss.”
Nutritional deficiencies and malnutrition can contribute to hair loss as well, and iron deficiency is sometimes a culprit, she added.
“If someone is worried” about hair loss associated with weight loss, “they should see their doctor,” Dr. Peters said. “If they are on thyroid hormone, in particular, the levels should be retested after weight loss.”
Hair loss appears more common after bariatric surgery than with antiobesity medications,” Dr. Weintraub observed, and it is unclear whether this is because the weight loss is more dramatic after surgery and thus a greater stressor, or whether it is caused by nutrient deficiency or a different mechanism entirely.
“Unlike certain forms of bariatric surgery, which can lead to malabsorption (e.g., Roux-en-Y gastric bypass), medications such as GLP-1 agonists and GLP-1/GIP dual agonists do not cause malabsorption,” Dr. Weintraub noted. “So nutritional deficiencies are less likely to be the cause of new hair loss in those taking antiobesity medications than [in] someone who underwent bariatric surgery.”
Iron and vitamin D deficiencies are the most common nutritional deficiencies that can cause hair loss, he noted.
Slow and steady weight loss rather than rapid
“I would suggest that patients try to keep the weight loss slow and steady, rather than rapid,” Dr. Goldberg said, “and follow any vitamin/mineral supplementation plan that they are given. Patients with bariatric surgery have nutritional guidance and a supplementation plan.”
“Follow a well-balanced dietary strategy with ample protein, vegetables, and some fruit,” Dr. Saunders said. Health care providers should monitor lab tests to check for and treat vitamin deficiencies, and registered dietitians can be crucial to ensure proper nutrition. She advises patients: “Find coping strategies to reduce stress and get enough sleep. If iron levels are low, start an iron supplement under your provider’s supervision.”
“Some of my patients swear by biotin supplements, prenatal vitamins or ‘hair, skin, and nails’ vitamins,” she added. If hair loss doesn’t stop, a dermatologist can look for other contributors and discuss strategies for hair restoration.
Individuals who undergo bariatric surgery require lifelong vitamin supplementation and yearly (or more frequent) lab testing, she noted.
“With, for example, bariatric surgery or any type of diet change you want to make sure you still maintain a balanced diet, whether its calories, protein, iron, zinc, vitamins (vitamin D for example),” Dr. Massick echoed.
Similarly, Dr. Peters advised: “I would say to maintain a normal healthy diet even if eating less. Exercise. Do all those healthy things. Taking a daily multivitamin isn’t a bad idea. Talk with a nutritionist. Use the appetite suppression of the medication to combine with healthy eating.”
“If someone is having new hair loss, they should see their clinician to evaluate for all possible causes,” Dr. Weintraub said. “Their provider can evaluate for underlying causes like thyroid dysfunction, iron deficiency, and vitamin D deficiency.”
However, if a patient’s pattern of hair loss is not diffuse but occurs in patches, this has an entirely different set of etiologies probably unrelated to antiobesity medication and should be evaluated.
Working with a nutritionist to ensure that patients have sufficient protein and micronutrient intake can lower the risk of developing hair loss and other complications, Dr. Weintraub said. “This is particularly important for certain forms of bariatric surgery such as Roux-en-Y gastric bypass, since that can lead to malabsorption of specific vitamins and minerals that need to be periodically measured and supplemented.”
In individuals starting an antiobesity medication, beginning a daily multivitamin has little harm, he added, and can ensure they are getting essential minerals and vitamins. However, no studies have specifically investigated this yet.
“Ultimately, it’s important to weigh the benefits of antiobesity medications against the potential risks, as we do with any medical intervention,” according to Dr. Weintraub.
“The purpose of treating obesity,” he stressed, “is to reduce the risk of heart disease, stroke, and multiple types of cancers. It’s up to the individual to weigh these benefits against the risks of the treatment, including the low risk of developing temporary hair loss.”
Dr. Peters writes a column for Medscape and disclosed that she served as a consultant for Blue Circle Health, Vertex, and Abbott Diabetes Care; received a research grant from Abbott Diabetes Care; and received stock options from Teladoc and Omada Health. Dr. Goldberg, Dr. Saunders, Dr. Massick, and Dr. Weintraub declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Should people be concerned about possible hair loss when taking Wegovy, Ozempic, or Mounjaro for weight loss (where the latter two drugs are being used off label) – as was recently claimed by some people on social media and reported in news stories?
The consensus among dermatologists and endocrinologists is no.
It’s up to the individual to weigh the benefits of treating obesity against the risks of the therapy, including the low risk of developing temporary hair loss, says one expert.
Wegovy, Ozempic, and Mounjaro
Of these three newer medications, only the glucagonlike peptide–1 (GLP-1) receptor agonist semaglutide (Wegovy) is approved by the Food and Drug Administration (since June 2021) for weight management – specifically for people with either obesity (body mass index ≥ 30 kg/m2) or overweight (BMI ≥ 27) plus at least one weight-related comorbidity such as hypertension, type 2 diabetes, and high cholesterol – with a dosage up to a 2.4-mg weekly injection.
When there was a short supply of Wegovy soon after it became available, some people turned to the same drug – semaglutide, but marketed as Ozempic for type 2 diabetes, which is titrated up to a 2-mg weekly injection. Still others opted for tirzepatide (Mounjaro), a dual GLP-1 agonist and glucose-dependent insulinotropic polypeptide (GIP) agonist. Tirzepatide is approved for type 2 diabetes in the United States but is not yet approved for weight loss.
Wegovy shortages continue to be reported.
; of interest, it was more common after bariatric surgery.
In clinical trials, 3% of patients receiving Wegovy (a 2.4-mg/wk injection) versus 1% of patients receiving placebo reported alopecia. Hair loss was not reported as a side effect in clinical trials of Ozempic (a 2-mg/wk injection) for type 2 diabetes. In a clinical trial of tirzepatide for weight loss in obesity, 5.7% of patients taking the highest dose (a 15-mg once-weekly injection) reported alopecia vs 1% of those who got a placebo.
In contrast, a review of 18 mostly observational studies reported that 57% of patients had hair loss after bariatric surgery.
Is it the drug or the rapid weight loss?
None of the experts consulted for this article had seen patients who came to them about hair loss while taking these drugs for weight loss.
“I have not seen patients complaining of hair loss from these medications, but perhaps it is just a matter of time,” said Lynne J. Goldberg, MD, a professor of dermatology and pathology and laboratory medicine, at Boston University, and director of the hair clinic at Boston Medical Center.
“Some of my patients lose hair when they lose weight, generally as a result of the weight loss itself and not as a side effect of these medications,” said Katharine H. Saunders, MD, an obesity medicine physician, cofounder of Intellihealth, and an assistant professor of medicine at Weill Cornell Medicine, New York.
“Hair loss from rapid weight loss is very common [and] not necessarily a side effect of the medication itself but more as a result of how quickly the weight loss occurs,” echoed Susan Massick, MD, associate professor of dermatology, Ohio State University, and a dermatologist at Ohio State’s Wexner Medical Center, both in Columbus.
“Hair loss is tricky,” observed Anne Peters, MD, director of clinical diabetes programs at the University of Southern California, Los Angeles. “Losing weight and/or changing your diet causes hair loss. Stress can cause hair loss. So, it is hard to separate weight loss from medication effect.”
Telogen effluvium (stress shedding) with rapid weight loss
The hair loss seems to be associated with rapid weight loss, the experts agreed.
“It is rare, but we can see patients who have a period of diffuse hair loss, called telogen effluvium, or ‘stress shedding’ with rapid weight loss,” said Michael A. Weintraub, MD, an endocrinologist at NYU Langone Health, New York.
This hair loss occurs in relation to either physical (surgery, pregnancy, illness) or emotional stress, added Dr. Weintraub, who is an assistant professor at NYU Grossman School of Medicine.
Hair loss caused by rapid weight loss could be caused by an antiobesity medication, but it could also occur with other obesity treatments, such as bariatric surgery or drastic dietary changes, he said. The hair shedding is typically short lived and reversible.
About 80%-85% of hair is in the anagen (growth) phase, about 5% is in a transitional (catagen) phase, and the rest is in telogen (resting, or shedding) phase, Dr. Massick explained. In telogen effluvium, hairs that are normally in the growth phase get suddenly shifted to telogen phase and are shed rapidly.
“Telogen effluvium can be caused by rapid weight loss, major surgery, severe COVID infection, high fever, or death in the family,” she noted. “You will not go bald with telogen effluvium, but you might find that you may lose a good volume of hair,” much more than the normal loss of up to 100 hairs a day.
“I counsel my patients about the possibility of losing hair before they undergo bariatric surgery,” Dr. Saunders said. “Generally, the health benefits of weight loss and weight maintenance outweigh the risk of temporary hair loss.”
Nutritional deficiencies and malnutrition can contribute to hair loss as well, and iron deficiency is sometimes a culprit, she added.
“If someone is worried” about hair loss associated with weight loss, “they should see their doctor,” Dr. Peters said. “If they are on thyroid hormone, in particular, the levels should be retested after weight loss.”
Hair loss appears more common after bariatric surgery than with antiobesity medications,” Dr. Weintraub observed, and it is unclear whether this is because the weight loss is more dramatic after surgery and thus a greater stressor, or whether it is caused by nutrient deficiency or a different mechanism entirely.
“Unlike certain forms of bariatric surgery, which can lead to malabsorption (e.g., Roux-en-Y gastric bypass), medications such as GLP-1 agonists and GLP-1/GIP dual agonists do not cause malabsorption,” Dr. Weintraub noted. “So nutritional deficiencies are less likely to be the cause of new hair loss in those taking antiobesity medications than [in] someone who underwent bariatric surgery.”
Iron and vitamin D deficiencies are the most common nutritional deficiencies that can cause hair loss, he noted.
Slow and steady weight loss rather than rapid
“I would suggest that patients try to keep the weight loss slow and steady, rather than rapid,” Dr. Goldberg said, “and follow any vitamin/mineral supplementation plan that they are given. Patients with bariatric surgery have nutritional guidance and a supplementation plan.”
“Follow a well-balanced dietary strategy with ample protein, vegetables, and some fruit,” Dr. Saunders said. Health care providers should monitor lab tests to check for and treat vitamin deficiencies, and registered dietitians can be crucial to ensure proper nutrition. She advises patients: “Find coping strategies to reduce stress and get enough sleep. If iron levels are low, start an iron supplement under your provider’s supervision.”
“Some of my patients swear by biotin supplements, prenatal vitamins or ‘hair, skin, and nails’ vitamins,” she added. If hair loss doesn’t stop, a dermatologist can look for other contributors and discuss strategies for hair restoration.
Individuals who undergo bariatric surgery require lifelong vitamin supplementation and yearly (or more frequent) lab testing, she noted.
“With, for example, bariatric surgery or any type of diet change you want to make sure you still maintain a balanced diet, whether its calories, protein, iron, zinc, vitamins (vitamin D for example),” Dr. Massick echoed.
Similarly, Dr. Peters advised: “I would say to maintain a normal healthy diet even if eating less. Exercise. Do all those healthy things. Taking a daily multivitamin isn’t a bad idea. Talk with a nutritionist. Use the appetite suppression of the medication to combine with healthy eating.”
“If someone is having new hair loss, they should see their clinician to evaluate for all possible causes,” Dr. Weintraub said. “Their provider can evaluate for underlying causes like thyroid dysfunction, iron deficiency, and vitamin D deficiency.”
However, if a patient’s pattern of hair loss is not diffuse but occurs in patches, this has an entirely different set of etiologies probably unrelated to antiobesity medication and should be evaluated.
Working with a nutritionist to ensure that patients have sufficient protein and micronutrient intake can lower the risk of developing hair loss and other complications, Dr. Weintraub said. “This is particularly important for certain forms of bariatric surgery such as Roux-en-Y gastric bypass, since that can lead to malabsorption of specific vitamins and minerals that need to be periodically measured and supplemented.”
In individuals starting an antiobesity medication, beginning a daily multivitamin has little harm, he added, and can ensure they are getting essential minerals and vitamins. However, no studies have specifically investigated this yet.
“Ultimately, it’s important to weigh the benefits of antiobesity medications against the potential risks, as we do with any medical intervention,” according to Dr. Weintraub.
“The purpose of treating obesity,” he stressed, “is to reduce the risk of heart disease, stroke, and multiple types of cancers. It’s up to the individual to weigh these benefits against the risks of the treatment, including the low risk of developing temporary hair loss.”
Dr. Peters writes a column for Medscape and disclosed that she served as a consultant for Blue Circle Health, Vertex, and Abbott Diabetes Care; received a research grant from Abbott Diabetes Care; and received stock options from Teladoc and Omada Health. Dr. Goldberg, Dr. Saunders, Dr. Massick, and Dr. Weintraub declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ChatGPT bot flunks gastroenterology exam
Versions 3 and 4 of the chatbot scored only 65% and 62%, respectively, on the American College of Gastroenterology Self-Assessment Test. The minimum passing grade is 70%.
“You might expect a physician to score 99%, or at least 95%,” lead author Arvind J. Trindade, MD, regional director of endoscopy at Northwell Health (Central Region) in New Hyde Park, New York, said in an interview.
The study was published online in the American Journal of Gastroenterology.
Dr. Trindade and colleagues undertook the study amid growing reports of students using the tool across many academic areas, including law and medicine, and growing interest in the chatbot’s potential in medical education.
“I saw gastroenterology students typing questions into it. I wanted to know how accurate it was in gastroenterology – if it was going to be used in medical education and patient care,” said Dr. Trindade, who is also an associate professor at Feinstein Institutes for Medical Research in Manhasset, New York. “Based on our research, ChatGPT should not be used for medical education in gastroenterology at this time, and it has a way to go before it should be implemented into the health care field.”
Poor showing
The researchers tested the two versions of ChatGPT on both the 2021 and 2022 online ACG Self-Assessment Test, a multiple-choice exam designed to gauge how well a trainee would do on the American Board of Internal Medicine Gastroenterology board examination.
Questions that involved image selection were excluded from the study. For those that remained, the questions and answer choices were copied and pasted directly into ChatGPT, which returned answers and explanations. The corresponding answer was selected on the ACG website based on the chatbot’s response.
Of the 455 questions posed, ChatGPT-3 correctly answered 296, and ChatGPT-4 got 284 right. There was no discernible pattern in the type of question that the chatbot answered incorrectly, but questions on surveillance timing for various disease states, diagnosis, and pharmaceutical regimens were all answered incorrectly.
The reasons for the tool’s poor performance could lie with the large language model underpinning ChatGPT, the researchers write. The model was trained on freely available information – not specifically on medical literature and not on materials that require paid journal subscriptions – to be a general-purpose interactive program.
Additionally, the chatbot may use information from a variety of sources, including non- or quasi-medical sources, or out-of-date sources, which can lead to errors, they note. ChatGPT-3 was last updated in June 2021 and ChatGPT-4 in September 2021.
“ChatGPT does not have an intrinsic understanding of an issue,” Dr. Trindade said. “Its basic function is to predict the next word in a string of text to produce an expected response, regardless of whether such a response is factually correct or not.”
Previous research
In a previous study, ChatGPT was able to pass parts of the U.S. Medical Licensing Examination.
The chatbot may have performed better on the USMLE because the information tested on the exam may have been more widely available for ChatGPT’s language training, Dr. Trindade said. “In addition, the threshold for passing [the USMLE] is lower with regard to the percentage of questions correctly answered,” he said.
ChatGPT seems to fare better at helping to inform patients than it does on medical exams. The chatbot provided generally satisfactory answers to common patient queries about colonoscopy in one study and about hepatocellular carcinoma and liver cirrhosis in another study.
For ChatGPT to be valuable in medical education, “future versions would need to be updated with medical resources such as journal articles, society guidelines, and medical databases, such as UpToDate,” Dr. Trindade said. “With directed medical training in gastroenterology, it may be a future tool for education or patient use in this field, but not currently as it is now. Before it can be used in gastroenterology, it should be validated.”
That said, he noted, medical education has evolved from being based on textbooks and print journals to include Internet-based journal data and practice guidelines on specialty websites. If properly primed, resources such as ChatGPT may be the next logical step.
This study received no funding. Dr. Trindade is a consultant for Pentax Medical, Boston Scientific, Lucid Diagnostic, and Exact Science and receives research support from Lucid Diagnostics.
A version of this article first appeared on Medscape.com.
Versions 3 and 4 of the chatbot scored only 65% and 62%, respectively, on the American College of Gastroenterology Self-Assessment Test. The minimum passing grade is 70%.
“You might expect a physician to score 99%, or at least 95%,” lead author Arvind J. Trindade, MD, regional director of endoscopy at Northwell Health (Central Region) in New Hyde Park, New York, said in an interview.
The study was published online in the American Journal of Gastroenterology.
Dr. Trindade and colleagues undertook the study amid growing reports of students using the tool across many academic areas, including law and medicine, and growing interest in the chatbot’s potential in medical education.
“I saw gastroenterology students typing questions into it. I wanted to know how accurate it was in gastroenterology – if it was going to be used in medical education and patient care,” said Dr. Trindade, who is also an associate professor at Feinstein Institutes for Medical Research in Manhasset, New York. “Based on our research, ChatGPT should not be used for medical education in gastroenterology at this time, and it has a way to go before it should be implemented into the health care field.”
Poor showing
The researchers tested the two versions of ChatGPT on both the 2021 and 2022 online ACG Self-Assessment Test, a multiple-choice exam designed to gauge how well a trainee would do on the American Board of Internal Medicine Gastroenterology board examination.
Questions that involved image selection were excluded from the study. For those that remained, the questions and answer choices were copied and pasted directly into ChatGPT, which returned answers and explanations. The corresponding answer was selected on the ACG website based on the chatbot’s response.
Of the 455 questions posed, ChatGPT-3 correctly answered 296, and ChatGPT-4 got 284 right. There was no discernible pattern in the type of question that the chatbot answered incorrectly, but questions on surveillance timing for various disease states, diagnosis, and pharmaceutical regimens were all answered incorrectly.
The reasons for the tool’s poor performance could lie with the large language model underpinning ChatGPT, the researchers write. The model was trained on freely available information – not specifically on medical literature and not on materials that require paid journal subscriptions – to be a general-purpose interactive program.
Additionally, the chatbot may use information from a variety of sources, including non- or quasi-medical sources, or out-of-date sources, which can lead to errors, they note. ChatGPT-3 was last updated in June 2021 and ChatGPT-4 in September 2021.
“ChatGPT does not have an intrinsic understanding of an issue,” Dr. Trindade said. “Its basic function is to predict the next word in a string of text to produce an expected response, regardless of whether such a response is factually correct or not.”
Previous research
In a previous study, ChatGPT was able to pass parts of the U.S. Medical Licensing Examination.
The chatbot may have performed better on the USMLE because the information tested on the exam may have been more widely available for ChatGPT’s language training, Dr. Trindade said. “In addition, the threshold for passing [the USMLE] is lower with regard to the percentage of questions correctly answered,” he said.
ChatGPT seems to fare better at helping to inform patients than it does on medical exams. The chatbot provided generally satisfactory answers to common patient queries about colonoscopy in one study and about hepatocellular carcinoma and liver cirrhosis in another study.
For ChatGPT to be valuable in medical education, “future versions would need to be updated with medical resources such as journal articles, society guidelines, and medical databases, such as UpToDate,” Dr. Trindade said. “With directed medical training in gastroenterology, it may be a future tool for education or patient use in this field, but not currently as it is now. Before it can be used in gastroenterology, it should be validated.”
That said, he noted, medical education has evolved from being based on textbooks and print journals to include Internet-based journal data and practice guidelines on specialty websites. If properly primed, resources such as ChatGPT may be the next logical step.
This study received no funding. Dr. Trindade is a consultant for Pentax Medical, Boston Scientific, Lucid Diagnostic, and Exact Science and receives research support from Lucid Diagnostics.
A version of this article first appeared on Medscape.com.
Versions 3 and 4 of the chatbot scored only 65% and 62%, respectively, on the American College of Gastroenterology Self-Assessment Test. The minimum passing grade is 70%.
“You might expect a physician to score 99%, or at least 95%,” lead author Arvind J. Trindade, MD, regional director of endoscopy at Northwell Health (Central Region) in New Hyde Park, New York, said in an interview.
The study was published online in the American Journal of Gastroenterology.
Dr. Trindade and colleagues undertook the study amid growing reports of students using the tool across many academic areas, including law and medicine, and growing interest in the chatbot’s potential in medical education.
“I saw gastroenterology students typing questions into it. I wanted to know how accurate it was in gastroenterology – if it was going to be used in medical education and patient care,” said Dr. Trindade, who is also an associate professor at Feinstein Institutes for Medical Research in Manhasset, New York. “Based on our research, ChatGPT should not be used for medical education in gastroenterology at this time, and it has a way to go before it should be implemented into the health care field.”
Poor showing
The researchers tested the two versions of ChatGPT on both the 2021 and 2022 online ACG Self-Assessment Test, a multiple-choice exam designed to gauge how well a trainee would do on the American Board of Internal Medicine Gastroenterology board examination.
Questions that involved image selection were excluded from the study. For those that remained, the questions and answer choices were copied and pasted directly into ChatGPT, which returned answers and explanations. The corresponding answer was selected on the ACG website based on the chatbot’s response.
Of the 455 questions posed, ChatGPT-3 correctly answered 296, and ChatGPT-4 got 284 right. There was no discernible pattern in the type of question that the chatbot answered incorrectly, but questions on surveillance timing for various disease states, diagnosis, and pharmaceutical regimens were all answered incorrectly.
The reasons for the tool’s poor performance could lie with the large language model underpinning ChatGPT, the researchers write. The model was trained on freely available information – not specifically on medical literature and not on materials that require paid journal subscriptions – to be a general-purpose interactive program.
Additionally, the chatbot may use information from a variety of sources, including non- or quasi-medical sources, or out-of-date sources, which can lead to errors, they note. ChatGPT-3 was last updated in June 2021 and ChatGPT-4 in September 2021.
“ChatGPT does not have an intrinsic understanding of an issue,” Dr. Trindade said. “Its basic function is to predict the next word in a string of text to produce an expected response, regardless of whether such a response is factually correct or not.”
Previous research
In a previous study, ChatGPT was able to pass parts of the U.S. Medical Licensing Examination.
The chatbot may have performed better on the USMLE because the information tested on the exam may have been more widely available for ChatGPT’s language training, Dr. Trindade said. “In addition, the threshold for passing [the USMLE] is lower with regard to the percentage of questions correctly answered,” he said.
ChatGPT seems to fare better at helping to inform patients than it does on medical exams. The chatbot provided generally satisfactory answers to common patient queries about colonoscopy in one study and about hepatocellular carcinoma and liver cirrhosis in another study.
For ChatGPT to be valuable in medical education, “future versions would need to be updated with medical resources such as journal articles, society guidelines, and medical databases, such as UpToDate,” Dr. Trindade said. “With directed medical training in gastroenterology, it may be a future tool for education or patient use in this field, but not currently as it is now. Before it can be used in gastroenterology, it should be validated.”
That said, he noted, medical education has evolved from being based on textbooks and print journals to include Internet-based journal data and practice guidelines on specialty websites. If properly primed, resources such as ChatGPT may be the next logical step.
This study received no funding. Dr. Trindade is a consultant for Pentax Medical, Boston Scientific, Lucid Diagnostic, and Exact Science and receives research support from Lucid Diagnostics.
A version of this article first appeared on Medscape.com.
FROM THE AMERICAN JOURNAL OF GASTROENTEROLOGY
Earlier anticoagulation safe in stroke with AFib: ELAN
, a new study suggests.
The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.
“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel (Switzerland), commented in an interview.
“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.
Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”
Dr. Fischer presented the results of the ELAN trial at the European Stroke Organisation Conference (ESOC) in Munich. The trial was also simultaneously published online in The New England Journal of Medicine.
He explained that patients presenting with acute ischemic stroke who are found to have atrial fibrillation need to be started on anticoagulation to reduce the risk for a recurrent stroke. But there are no clear guidelines on when to start anticoagulation in these patients at present, with concerns that starting very early may increase the risk for hemorrhagic transformation and ICH.
Based on observations that patients with larger strokes have a higher risk for ICH in the early post-stroke period, some guidelines advise different times for starting anticoagulation for different stroke severities: 1 day for a transient ischemic attack, 3 days for a minor stroke, 6 days for a moderate stroke, and 12 days for a severe stroke – known as the 1-, 3-, 6-, 12-day rule.
“But this is not based on evidence – just on expert opinion,” Dr. Fischer noted. “The ELAN trial was conducted to obtain more solid information on optimal timing for starting anticoagulation and whether we can safely start a DOAC earlier than these guidelines currently advise.”
For the trial, which was conducted in 15 countries, 2,013 patients with an acute ischemic stroke and found to have AFib were randomly selected to start DOAC treatment earlier or later.
The later-treatment strategy followed the current approach of starting treatment at day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke, whereas the earlier-treatment group started DOAC treatment within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke.
In terms of stroke severity, which was defined on imaging-based criteria, 37% of patients had a minor stroke, 40% had a moderate stroke, and 23% had a major stroke.
The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization.
Results showed that this occurred in 2.9% in the early-treatment group and 4.1% in the later-treatment group (risk difference, –1.18 percentage points; 95% confidence interval, –2.84-0.47) by 30 days.
Recurrent ischemic stroke occurred in 1.4% in the early-treatment group and 2.5% in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29-1.07). Symptomatic intracranial hemorrhage occurred in two participants (0.2%) in both groups by 30 days.
The rates of the outcomes increased only slightly more at 90 days than at 30 days, “findings that suggest there was not an excessive risk associated with early anticoagulation through that period,” the researchers report in the NEJM paper.
“Early treatment initiation can therefore be supported if indicated or if desired,” they conclude.
“The most important finding was that among 2,000 patients randomized, there was a very low rate of bleeding complications and no increase in any bleeding complication in the early DOAC group. This has been a major worry about starting anticoagulation early,” Dr. Fischer commented.
“These are very practical findings in that we can keep things simple,” Dr. Dawson added. “If the patient has a big stroke, anticoagulation with a DOAC can now be started at 6 days. For everyone else, we can start DOAC treatment as soon as possible without fear of causing harm. So, we can now confidently give patients with a minor or moderate stroke, as defined by imaging, a beneficial treatment as soon as we establish they are having an ischemic stroke and have AFib.”
Dr. Dawson pointed out that about 25% of patients with ischemic stroke are found to have AFib on admission ECG, and in another 4%-5%, AFib is found in the first 48 hours. “These are the patients we are targeting in this study.”
The researchers note that the trial did not have a statistical superiority or noninferiority design but rather aimed to estimate the treatment effects of early initiation versus later initiation of DOACs.
“This trial was slightly different in that we weren’t testing a strict statistical hypothesis because we didn’t have any data with which to formulate what sort of effect size to aim for, so we performed a qualitative trial to look at what the event rates were with the two approaches,” Dr. Fischer explained. “Our main findings are that ICH rates were not increased with early DOAC treatment and that ischemic event rates were numerically reduced, but because we didn’t have strict statistical limits, we can only say this is a high probability but not a certainty.”
Dr. Dawson added: “We can say from these results that there is a high level of probability that early DOAC treatment does not cause harm and a reasonable probability that it reduces risks of a recurrent stroke or other ischemic event.”
The researchers give an estimate of the effect size for the primary composite endpoint, which combines the major ischemic and bleeding events, ranging from a 2.8% lower risk to a 0.5% higher risk with early DOAC treatment.
“So, it is very likely that the composite endpoint would be lower,” Dr. Dawson said.
Dr. Fischer noted that a previous study (TIMING) tried to address the issue of earlier versus later anticoagulation in these patients but was stopped early after 880 patients had been enrolled because of slow recruitment.
“Results from this study failed to show superiority of early versus late DOAC treatment but they did suggest noninferiority, and they also found no increase in major bleeding complications, which is an added reassurance,” he commented.
Another trial looking at early versus late anticoagulation in these patients, OPTIMAS, is ongoing in the United Kingdom and is aiming to randomize 3,500 patients.
Imaging-based assessment of stroke severity
In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).
“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dr. Dawson explained. “This is very straightforward, as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”
He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.
Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.
“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.
“This is important because there are many thousands of patients with acute ischemic stroke and AFib, and now we have a large study showing we can treat them with a DOAC early, and this appears to be safe and it appears also be more effective in terms of outcome events,” Dr. Tsivgoulis said.
But he highlighted one important caveat: The majority of patients had mild or moderate stroke.
A version of this article first appeared on Medscape.com.
, a new study suggests.
The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.
“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel (Switzerland), commented in an interview.
“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.
Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”
Dr. Fischer presented the results of the ELAN trial at the European Stroke Organisation Conference (ESOC) in Munich. The trial was also simultaneously published online in The New England Journal of Medicine.
He explained that patients presenting with acute ischemic stroke who are found to have atrial fibrillation need to be started on anticoagulation to reduce the risk for a recurrent stroke. But there are no clear guidelines on when to start anticoagulation in these patients at present, with concerns that starting very early may increase the risk for hemorrhagic transformation and ICH.
Based on observations that patients with larger strokes have a higher risk for ICH in the early post-stroke period, some guidelines advise different times for starting anticoagulation for different stroke severities: 1 day for a transient ischemic attack, 3 days for a minor stroke, 6 days for a moderate stroke, and 12 days for a severe stroke – known as the 1-, 3-, 6-, 12-day rule.
“But this is not based on evidence – just on expert opinion,” Dr. Fischer noted. “The ELAN trial was conducted to obtain more solid information on optimal timing for starting anticoagulation and whether we can safely start a DOAC earlier than these guidelines currently advise.”
For the trial, which was conducted in 15 countries, 2,013 patients with an acute ischemic stroke and found to have AFib were randomly selected to start DOAC treatment earlier or later.
The later-treatment strategy followed the current approach of starting treatment at day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke, whereas the earlier-treatment group started DOAC treatment within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke.
In terms of stroke severity, which was defined on imaging-based criteria, 37% of patients had a minor stroke, 40% had a moderate stroke, and 23% had a major stroke.
The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization.
Results showed that this occurred in 2.9% in the early-treatment group and 4.1% in the later-treatment group (risk difference, –1.18 percentage points; 95% confidence interval, –2.84-0.47) by 30 days.
Recurrent ischemic stroke occurred in 1.4% in the early-treatment group and 2.5% in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29-1.07). Symptomatic intracranial hemorrhage occurred in two participants (0.2%) in both groups by 30 days.
The rates of the outcomes increased only slightly more at 90 days than at 30 days, “findings that suggest there was not an excessive risk associated with early anticoagulation through that period,” the researchers report in the NEJM paper.
“Early treatment initiation can therefore be supported if indicated or if desired,” they conclude.
“The most important finding was that among 2,000 patients randomized, there was a very low rate of bleeding complications and no increase in any bleeding complication in the early DOAC group. This has been a major worry about starting anticoagulation early,” Dr. Fischer commented.
“These are very practical findings in that we can keep things simple,” Dr. Dawson added. “If the patient has a big stroke, anticoagulation with a DOAC can now be started at 6 days. For everyone else, we can start DOAC treatment as soon as possible without fear of causing harm. So, we can now confidently give patients with a minor or moderate stroke, as defined by imaging, a beneficial treatment as soon as we establish they are having an ischemic stroke and have AFib.”
Dr. Dawson pointed out that about 25% of patients with ischemic stroke are found to have AFib on admission ECG, and in another 4%-5%, AFib is found in the first 48 hours. “These are the patients we are targeting in this study.”
The researchers note that the trial did not have a statistical superiority or noninferiority design but rather aimed to estimate the treatment effects of early initiation versus later initiation of DOACs.
“This trial was slightly different in that we weren’t testing a strict statistical hypothesis because we didn’t have any data with which to formulate what sort of effect size to aim for, so we performed a qualitative trial to look at what the event rates were with the two approaches,” Dr. Fischer explained. “Our main findings are that ICH rates were not increased with early DOAC treatment and that ischemic event rates were numerically reduced, but because we didn’t have strict statistical limits, we can only say this is a high probability but not a certainty.”
Dr. Dawson added: “We can say from these results that there is a high level of probability that early DOAC treatment does not cause harm and a reasonable probability that it reduces risks of a recurrent stroke or other ischemic event.”
The researchers give an estimate of the effect size for the primary composite endpoint, which combines the major ischemic and bleeding events, ranging from a 2.8% lower risk to a 0.5% higher risk with early DOAC treatment.
“So, it is very likely that the composite endpoint would be lower,” Dr. Dawson said.
Dr. Fischer noted that a previous study (TIMING) tried to address the issue of earlier versus later anticoagulation in these patients but was stopped early after 880 patients had been enrolled because of slow recruitment.
“Results from this study failed to show superiority of early versus late DOAC treatment but they did suggest noninferiority, and they also found no increase in major bleeding complications, which is an added reassurance,” he commented.
Another trial looking at early versus late anticoagulation in these patients, OPTIMAS, is ongoing in the United Kingdom and is aiming to randomize 3,500 patients.
Imaging-based assessment of stroke severity
In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).
“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dr. Dawson explained. “This is very straightforward, as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”
He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.
Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.
“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.
“This is important because there are many thousands of patients with acute ischemic stroke and AFib, and now we have a large study showing we can treat them with a DOAC early, and this appears to be safe and it appears also be more effective in terms of outcome events,” Dr. Tsivgoulis said.
But he highlighted one important caveat: The majority of patients had mild or moderate stroke.
A version of this article first appeared on Medscape.com.
, a new study suggests.
The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.
“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel (Switzerland), commented in an interview.
“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.
Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”
Dr. Fischer presented the results of the ELAN trial at the European Stroke Organisation Conference (ESOC) in Munich. The trial was also simultaneously published online in The New England Journal of Medicine.
He explained that patients presenting with acute ischemic stroke who are found to have atrial fibrillation need to be started on anticoagulation to reduce the risk for a recurrent stroke. But there are no clear guidelines on when to start anticoagulation in these patients at present, with concerns that starting very early may increase the risk for hemorrhagic transformation and ICH.
Based on observations that patients with larger strokes have a higher risk for ICH in the early post-stroke period, some guidelines advise different times for starting anticoagulation for different stroke severities: 1 day for a transient ischemic attack, 3 days for a minor stroke, 6 days for a moderate stroke, and 12 days for a severe stroke – known as the 1-, 3-, 6-, 12-day rule.
“But this is not based on evidence – just on expert opinion,” Dr. Fischer noted. “The ELAN trial was conducted to obtain more solid information on optimal timing for starting anticoagulation and whether we can safely start a DOAC earlier than these guidelines currently advise.”
For the trial, which was conducted in 15 countries, 2,013 patients with an acute ischemic stroke and found to have AFib were randomly selected to start DOAC treatment earlier or later.
The later-treatment strategy followed the current approach of starting treatment at day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke, whereas the earlier-treatment group started DOAC treatment within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke.
In terms of stroke severity, which was defined on imaging-based criteria, 37% of patients had a minor stroke, 40% had a moderate stroke, and 23% had a major stroke.
The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization.
Results showed that this occurred in 2.9% in the early-treatment group and 4.1% in the later-treatment group (risk difference, –1.18 percentage points; 95% confidence interval, –2.84-0.47) by 30 days.
Recurrent ischemic stroke occurred in 1.4% in the early-treatment group and 2.5% in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29-1.07). Symptomatic intracranial hemorrhage occurred in two participants (0.2%) in both groups by 30 days.
The rates of the outcomes increased only slightly more at 90 days than at 30 days, “findings that suggest there was not an excessive risk associated with early anticoagulation through that period,” the researchers report in the NEJM paper.
“Early treatment initiation can therefore be supported if indicated or if desired,” they conclude.
“The most important finding was that among 2,000 patients randomized, there was a very low rate of bleeding complications and no increase in any bleeding complication in the early DOAC group. This has been a major worry about starting anticoagulation early,” Dr. Fischer commented.
“These are very practical findings in that we can keep things simple,” Dr. Dawson added. “If the patient has a big stroke, anticoagulation with a DOAC can now be started at 6 days. For everyone else, we can start DOAC treatment as soon as possible without fear of causing harm. So, we can now confidently give patients with a minor or moderate stroke, as defined by imaging, a beneficial treatment as soon as we establish they are having an ischemic stroke and have AFib.”
Dr. Dawson pointed out that about 25% of patients with ischemic stroke are found to have AFib on admission ECG, and in another 4%-5%, AFib is found in the first 48 hours. “These are the patients we are targeting in this study.”
The researchers note that the trial did not have a statistical superiority or noninferiority design but rather aimed to estimate the treatment effects of early initiation versus later initiation of DOACs.
“This trial was slightly different in that we weren’t testing a strict statistical hypothesis because we didn’t have any data with which to formulate what sort of effect size to aim for, so we performed a qualitative trial to look at what the event rates were with the two approaches,” Dr. Fischer explained. “Our main findings are that ICH rates were not increased with early DOAC treatment and that ischemic event rates were numerically reduced, but because we didn’t have strict statistical limits, we can only say this is a high probability but not a certainty.”
Dr. Dawson added: “We can say from these results that there is a high level of probability that early DOAC treatment does not cause harm and a reasonable probability that it reduces risks of a recurrent stroke or other ischemic event.”
The researchers give an estimate of the effect size for the primary composite endpoint, which combines the major ischemic and bleeding events, ranging from a 2.8% lower risk to a 0.5% higher risk with early DOAC treatment.
“So, it is very likely that the composite endpoint would be lower,” Dr. Dawson said.
Dr. Fischer noted that a previous study (TIMING) tried to address the issue of earlier versus later anticoagulation in these patients but was stopped early after 880 patients had been enrolled because of slow recruitment.
“Results from this study failed to show superiority of early versus late DOAC treatment but they did suggest noninferiority, and they also found no increase in major bleeding complications, which is an added reassurance,” he commented.
Another trial looking at early versus late anticoagulation in these patients, OPTIMAS, is ongoing in the United Kingdom and is aiming to randomize 3,500 patients.
Imaging-based assessment of stroke severity
In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).
“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dr. Dawson explained. “This is very straightforward, as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”
He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.
Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.
“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.
“This is important because there are many thousands of patients with acute ischemic stroke and AFib, and now we have a large study showing we can treat them with a DOAC early, and this appears to be safe and it appears also be more effective in terms of outcome events,” Dr. Tsivgoulis said.
But he highlighted one important caveat: The majority of patients had mild or moderate stroke.
A version of this article first appeared on Medscape.com.
FROM ESOC 2023