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No unexpected leiomyosarcomas in chart review of TVH and LAVH cases
WASHINGTON – There were no cases of unexpected leiomyosarcomas in a retrospective chart study of about 1,600 cases of vaginal or laparoscopic-assisted vaginal hysterectomies performed over a 7-year period.
In the study, the rate of endometrial adenocarcinomas was about 1 in 200, and while the overall manual vaginal morcellation rate was 19%, no uterine malignancies were morcellated, said Dr. Pedro Maldonado of the division of female pelvic medicine and reconstructive surgery at the University of Texas Southwestern Medical Center, Dallas.
The review looked at all total vaginal hysterectomy (TVH) and laparoscopic-assisted vaginal hysterectomy (LAVH) cases performed at the three main teaching hospitals of the university from July 2006 through March 2013. Malignancies known before surgery were excluded.
There were a total of 1,608 cases: 1,091 TVH and 517 LAVH procedures. The overall morcellation rate was 19%: 32% in the TVH group and 13% in the LAVH group, Dr. Maldonado reported at the scientific meetings of the American Urogynecologic Society and the International Urogynecological Association.
Among the 1,608 cases, there were no cases of leiomyosarcoma (LMS) diagnosed on pathology. There was one case of an endometrial adenosarcoma (0.06%) in a 37-year-old patient with a preoperative diagnosis of menorrhagia and fibroids, and one case of a low-grade endometrial stromal tumor (0.06%) in a 39-year-old patient also diagnosed with menorrhagia and fibroids preoperatively. Neither of these patients underwent morcellation.
Three patients (0.19%) – aged 32, 38, and 47 years – who had preoperative diagnoses of menorrhagia, fibroids, and/or anemia had a pathologic diagnosis of smooth muscle tumor of uncertain malignant potential. One of these three patients underwent morcellation.
Another 8 (0.50%) of the patients with a preoperative diagnosis of endometrial hyperplasia were diagnosed with endometrial adenocarcinoma on pathology; none of them underwent morcellation, Dr. Maldonado said.
The risk of intraperitoneal dissemination of an unexpected LMS during endoscopic power morcellation has become a major issue since the Food and Drug Administration recommended in April 2014 that the use of power morcellation during a hysterectomy or myomectomy for uterine fibroids be discouraged because of the risk of disseminating cancerous tissue and upstaging disease. The FDA estimates that about 1 in 350 women undergoing hysterectomy or myomectomy for presumed fibroids have an unsuspected uterine sarcoma and that the risk of an unsuspected LMS is about 1 in 500.
Dr. Maldonado said he had no relevant financial disclosures.
WASHINGTON – There were no cases of unexpected leiomyosarcomas in a retrospective chart study of about 1,600 cases of vaginal or laparoscopic-assisted vaginal hysterectomies performed over a 7-year period.
In the study, the rate of endometrial adenocarcinomas was about 1 in 200, and while the overall manual vaginal morcellation rate was 19%, no uterine malignancies were morcellated, said Dr. Pedro Maldonado of the division of female pelvic medicine and reconstructive surgery at the University of Texas Southwestern Medical Center, Dallas.
The review looked at all total vaginal hysterectomy (TVH) and laparoscopic-assisted vaginal hysterectomy (LAVH) cases performed at the three main teaching hospitals of the university from July 2006 through March 2013. Malignancies known before surgery were excluded.
There were a total of 1,608 cases: 1,091 TVH and 517 LAVH procedures. The overall morcellation rate was 19%: 32% in the TVH group and 13% in the LAVH group, Dr. Maldonado reported at the scientific meetings of the American Urogynecologic Society and the International Urogynecological Association.
Among the 1,608 cases, there were no cases of leiomyosarcoma (LMS) diagnosed on pathology. There was one case of an endometrial adenosarcoma (0.06%) in a 37-year-old patient with a preoperative diagnosis of menorrhagia and fibroids, and one case of a low-grade endometrial stromal tumor (0.06%) in a 39-year-old patient also diagnosed with menorrhagia and fibroids preoperatively. Neither of these patients underwent morcellation.
Three patients (0.19%) – aged 32, 38, and 47 years – who had preoperative diagnoses of menorrhagia, fibroids, and/or anemia had a pathologic diagnosis of smooth muscle tumor of uncertain malignant potential. One of these three patients underwent morcellation.
Another 8 (0.50%) of the patients with a preoperative diagnosis of endometrial hyperplasia were diagnosed with endometrial adenocarcinoma on pathology; none of them underwent morcellation, Dr. Maldonado said.
The risk of intraperitoneal dissemination of an unexpected LMS during endoscopic power morcellation has become a major issue since the Food and Drug Administration recommended in April 2014 that the use of power morcellation during a hysterectomy or myomectomy for uterine fibroids be discouraged because of the risk of disseminating cancerous tissue and upstaging disease. The FDA estimates that about 1 in 350 women undergoing hysterectomy or myomectomy for presumed fibroids have an unsuspected uterine sarcoma and that the risk of an unsuspected LMS is about 1 in 500.
Dr. Maldonado said he had no relevant financial disclosures.
WASHINGTON – There were no cases of unexpected leiomyosarcomas in a retrospective chart study of about 1,600 cases of vaginal or laparoscopic-assisted vaginal hysterectomies performed over a 7-year period.
In the study, the rate of endometrial adenocarcinomas was about 1 in 200, and while the overall manual vaginal morcellation rate was 19%, no uterine malignancies were morcellated, said Dr. Pedro Maldonado of the division of female pelvic medicine and reconstructive surgery at the University of Texas Southwestern Medical Center, Dallas.
The review looked at all total vaginal hysterectomy (TVH) and laparoscopic-assisted vaginal hysterectomy (LAVH) cases performed at the three main teaching hospitals of the university from July 2006 through March 2013. Malignancies known before surgery were excluded.
There were a total of 1,608 cases: 1,091 TVH and 517 LAVH procedures. The overall morcellation rate was 19%: 32% in the TVH group and 13% in the LAVH group, Dr. Maldonado reported at the scientific meetings of the American Urogynecologic Society and the International Urogynecological Association.
Among the 1,608 cases, there were no cases of leiomyosarcoma (LMS) diagnosed on pathology. There was one case of an endometrial adenosarcoma (0.06%) in a 37-year-old patient with a preoperative diagnosis of menorrhagia and fibroids, and one case of a low-grade endometrial stromal tumor (0.06%) in a 39-year-old patient also diagnosed with menorrhagia and fibroids preoperatively. Neither of these patients underwent morcellation.
Three patients (0.19%) – aged 32, 38, and 47 years – who had preoperative diagnoses of menorrhagia, fibroids, and/or anemia had a pathologic diagnosis of smooth muscle tumor of uncertain malignant potential. One of these three patients underwent morcellation.
Another 8 (0.50%) of the patients with a preoperative diagnosis of endometrial hyperplasia were diagnosed with endometrial adenocarcinoma on pathology; none of them underwent morcellation, Dr. Maldonado said.
The risk of intraperitoneal dissemination of an unexpected LMS during endoscopic power morcellation has become a major issue since the Food and Drug Administration recommended in April 2014 that the use of power morcellation during a hysterectomy or myomectomy for uterine fibroids be discouraged because of the risk of disseminating cancerous tissue and upstaging disease. The FDA estimates that about 1 in 350 women undergoing hysterectomy or myomectomy for presumed fibroids have an unsuspected uterine sarcoma and that the risk of an unsuspected LMS is about 1 in 500.
Dr. Maldonado said he had no relevant financial disclosures.
AT AUGS/IUGA 2014
Key clinical point: This study provides another estimate of the rate of unexpected leiomyosarcomas in women undergoing hysterectomy for presumably benign conditions, an issue that is currently under FDA review because of heightened concerns over the risk of spreading malignancies if morcellation also is performed during these procedures.
Major finding: There were no unexpected leiomyosarcomas, and no uterine malignancies were morcellated in a series of 1,608 cases of vaginal or laparoscopic-assisted vaginal hysterectomies performed for presumably benign conditions over a 7-year period
Data source: A retrospective study of 1,608 cases of TVH or LAVH performed over 7 years at three teaching hospitals that looked at the rate of unexpected uterine malignancies and cases of malignancies that were morcellated.
Disclosures: Dr. Maldonado said he had no disclosures.
Disposable, self-administered new anal insert device effective for anal leakage
WASHINGTON – A single-use, self-administered anal insert made of soft silicone was effective and safe in reducing episodes of accidental bowel leakage, in a multi-center, prospective open-label single-arm study, Dr. Emily Lukacz reported at the scientific meetings of the American Urogynecologic Society and the International Urogynecological Association.
The device provides a nonsurgical option for managing accidental bowel leakage (ABL), as an alternative or as an adjunct to invasive therapy, said Dr. Lukacz, professor of clinical reproductive medicine at the University of California, San Diego.
The device is designed to prevent leakage of solid and liquid stool, and is expelled with each bowel movement and subsequently replaced. The manufacturer, Renew Medical, hopes to make it available by the end of 2014 and is negotiating with the Centers for Medicare & Medicaid Services for coverage, she noted.
The study enrolled 91 people with moderate to severe bowel incontinence, who experienced at least weekly leakage of solid and/or liquid stool, with a Wexner severity score of 12 or greater (ranging from 0, fully continent, to 20, full incontinence); most were female (90%) and white (91%); their mean age was almost 69 years. Seven participants withdrew because they were not satisfied with the device.
Among the 85 participants who completed at least 1 week of treatment, the frequency of ABL dropped from eight episodes per week at baseline to one-two episodes per week at 12 weeks, an 82% reduction that was statistically significant (P less than or equal to .001), Dr. Lukacz said. Of the 85 participants, 78% experienced at least a 50% reduction in ABL frequency, and 8 (9%) achieved total continence.
The mean Wexner scores improved by about 32% after treatment, from about 16 to about 11, which was also statistically significant (P less than or equal to .001). Of the 73 who completed the full 12 weeks of the study, 57 (78%) were "very or extremely satisfied with the device," Dr. Lukacz noted.
There were no serious adverse events. The three moderate adverse events were fecal urgency, soreness, and bleeding related to the use of the insert in two participants. Almost one-quarter of the patients had episodes where the device was displaced "upward into the anal canal," but was expelled with the next bowel movement, she said.
Dr. Lukacz’s disclosures included being a paid consultant to Pfizer and Renew Medical. The study was sponsored by Renew.
WASHINGTON – A single-use, self-administered anal insert made of soft silicone was effective and safe in reducing episodes of accidental bowel leakage, in a multi-center, prospective open-label single-arm study, Dr. Emily Lukacz reported at the scientific meetings of the American Urogynecologic Society and the International Urogynecological Association.
The device provides a nonsurgical option for managing accidental bowel leakage (ABL), as an alternative or as an adjunct to invasive therapy, said Dr. Lukacz, professor of clinical reproductive medicine at the University of California, San Diego.
The device is designed to prevent leakage of solid and liquid stool, and is expelled with each bowel movement and subsequently replaced. The manufacturer, Renew Medical, hopes to make it available by the end of 2014 and is negotiating with the Centers for Medicare & Medicaid Services for coverage, she noted.
The study enrolled 91 people with moderate to severe bowel incontinence, who experienced at least weekly leakage of solid and/or liquid stool, with a Wexner severity score of 12 or greater (ranging from 0, fully continent, to 20, full incontinence); most were female (90%) and white (91%); their mean age was almost 69 years. Seven participants withdrew because they were not satisfied with the device.
Among the 85 participants who completed at least 1 week of treatment, the frequency of ABL dropped from eight episodes per week at baseline to one-two episodes per week at 12 weeks, an 82% reduction that was statistically significant (P less than or equal to .001), Dr. Lukacz said. Of the 85 participants, 78% experienced at least a 50% reduction in ABL frequency, and 8 (9%) achieved total continence.
The mean Wexner scores improved by about 32% after treatment, from about 16 to about 11, which was also statistically significant (P less than or equal to .001). Of the 73 who completed the full 12 weeks of the study, 57 (78%) were "very or extremely satisfied with the device," Dr. Lukacz noted.
There were no serious adverse events. The three moderate adverse events were fecal urgency, soreness, and bleeding related to the use of the insert in two participants. Almost one-quarter of the patients had episodes where the device was displaced "upward into the anal canal," but was expelled with the next bowel movement, she said.
Dr. Lukacz’s disclosures included being a paid consultant to Pfizer and Renew Medical. The study was sponsored by Renew.
WASHINGTON – A single-use, self-administered anal insert made of soft silicone was effective and safe in reducing episodes of accidental bowel leakage, in a multi-center, prospective open-label single-arm study, Dr. Emily Lukacz reported at the scientific meetings of the American Urogynecologic Society and the International Urogynecological Association.
The device provides a nonsurgical option for managing accidental bowel leakage (ABL), as an alternative or as an adjunct to invasive therapy, said Dr. Lukacz, professor of clinical reproductive medicine at the University of California, San Diego.
The device is designed to prevent leakage of solid and liquid stool, and is expelled with each bowel movement and subsequently replaced. The manufacturer, Renew Medical, hopes to make it available by the end of 2014 and is negotiating with the Centers for Medicare & Medicaid Services for coverage, she noted.
The study enrolled 91 people with moderate to severe bowel incontinence, who experienced at least weekly leakage of solid and/or liquid stool, with a Wexner severity score of 12 or greater (ranging from 0, fully continent, to 20, full incontinence); most were female (90%) and white (91%); their mean age was almost 69 years. Seven participants withdrew because they were not satisfied with the device.
Among the 85 participants who completed at least 1 week of treatment, the frequency of ABL dropped from eight episodes per week at baseline to one-two episodes per week at 12 weeks, an 82% reduction that was statistically significant (P less than or equal to .001), Dr. Lukacz said. Of the 85 participants, 78% experienced at least a 50% reduction in ABL frequency, and 8 (9%) achieved total continence.
The mean Wexner scores improved by about 32% after treatment, from about 16 to about 11, which was also statistically significant (P less than or equal to .001). Of the 73 who completed the full 12 weeks of the study, 57 (78%) were "very or extremely satisfied with the device," Dr. Lukacz noted.
There were no serious adverse events. The three moderate adverse events were fecal urgency, soreness, and bleeding related to the use of the insert in two participants. Almost one-quarter of the patients had episodes where the device was displaced "upward into the anal canal," but was expelled with the next bowel movement, she said.
Dr. Lukacz’s disclosures included being a paid consultant to Pfizer and Renew Medical. The study was sponsored by Renew.
AT AUGS/IUGA 2014
Major finding: Once available, this soft silicone, self-administered anal insert could be an effective, safe alternative or adjunct to invasive treatment of accidental bowel leakage (ABL).
Key numerical finding: The frequency of ABL dropped by 82% after 12 weeks of using the anal insert, from 8 weekly episodes at baseline to 1-2 episodes per week.
Data source: A multicenter, prospective, open-label, single-arm study evaluated the effect of the device on the reduction of ABL episodes per week and severity of ABL over 12 weeks in 91 mostly female, white patients with moderate to severe anal leakage at baseline.
Disclosures: Dr. Lukacz’s disclosures included being a paid consultant to Pfizer and Renew Medical, the manufacturer of the anal insert. The study was sponsored by Renew.
Emotional exposure therapy studied for fibromyalgia
WASHINGTON – The use of "emotional exposure therapy," which addresses unresolved conflict, trauma, and other issues that might be contributing to fibromyalgia symptoms, is being studied as a treatment for the often debilitating illness.
During a symposium on medically complex illnesses at the annual convention of the American Psychological Association, Mark A. Lumley, Ph.D., provided some early observations from a multicenter randomized study comparing this approach with cognitive-behavioral therapy (CBT) and an education control group on 1-year outcomes. Because the wrong pathological processes might have been targeted, "relatively weak" techniques have been used to treat patients with fibromyalgia, said Dr. Lumley, professor of psychology, and head of the stress and health research laboratory at Wayne State University in Detroit.
Interpersonal and relational stress is typical among people with fibromyalgia and includes unresolved conflicts with parents, siblings, spouses, bosses, and others, he said, noting that being bullied on the job has been associated with a three- to fourfold increase in the risk of fibromyalgia. Moreover, 35%-50% of patients with fibromyalgia have evidence of posttraumatic stress disorder (PTSD), and 50%-70% have experienced "lifetime victimization and abuse in their lives," he said.
Therefore, since PTSD, stress, or conflict "tend to be maintained by the avoidance of emotions related to the stress," effective treatment should involve "some sort of exposure and processing of avoided emotionally laden experiences" dealing with memories, thoughts, or relationships, he explained.
Emotional exposure therapy (EET) techniques, based on the "experience-brain-emotion-symptom" model, entail reviewing physical symptoms and events over an individual’s lifetime and identifying key unresolved stressors or conflicts, "making the unspoken spoken," Dr. Lumley said. This approach also involves engaging in expressive writing "often as unsent letters to a key conflict person," and reenacting relational conflicts, "making the unexpressed expressed," he explained.
A few years after finding that expressive writing was beneficial in patients with fibromyalgia, he and his associates conducted a pilot study of 10 patients with fibromyalgia and unresolved stress who received 10 sessions of individualized therapy (Psychotherapy 2008;45:165-72). After treatment that included techniques to help the patients "confront and process avoided emotions, memories, and relationships," two patients showed substantial improvement with symptoms that were almost entirely resolved, and four experienced clinically meaningful improvements, Dr. Lumley said.
In the multicenter, randomized, controlled study of 230 patients with fibromyalgia, patients were treated in small groups with eight sessions of EET, CBT, or education control, and were followed up at 1 year. Almost all patients had a history of significant trauma or conflict, which included sexual abuse or assault in about half of the patients, substantial family of origin problems (in about two-thirds), conflicted or unhappy marriages (in about three-fourths) "and almost all had what I clinically view as emotional avoidance experiences," he said.
Participation has been high, with 84% in the EET group, 77% in the CBT group, and 87% in the education control group making it to the last session – indicating that EET does not frighten all patients away, Dr. Lumley observed.
After 8 weeks of treatment, 22% of those randomized to EET were judged by the therapists providing the treatment to have experienced substantial changes, described as having their lives transformed and being "a very different person," he reported. Another 29% were considered to have experienced "quite a bit of change," and 17% were described to have experienced a moderate amount of change, with "a good start but a lot of work to do." Another 19% experienced little change and 13% were resistant to or not open to treatment and did not change at all.
Patient reports reflected varied experiences, with comments that included, "It’s really hard, but I needed it." Three patients said that the treatment "cured" their fibromyalgia and they that no longer needed to take medication and were sleeping well. These patients "did profound work in their relationships and resolved some of the conflicts in the sessions," Dr. Lumley said.
But there were also some patients who said their pain increased after the sessions or that encouraging the expression of anger was dangerous, "so it can be a variable experience," more variable than CBT, he noted.
Among patients who seek treatment for fibromyalgia, "there’s a lot of unresolved trauma and conflict" and most – but not all – of these patients need EET, Dr. Lumley said. "Many patients can and will do emotionally intense work," while others might need a slower approach, possibly with expressive writing only or the use of emotional awareness techniques that do not involve expression, he added.
Others might benefit from learning "emotional downregulation strategies" with CBT first, he said, pointing out, "We need to figure out who is who."
CBT, one of the few treatment options for fibromyalgia, has been the "psychological treatment of choice," with techniques that include relaxation training, distraction and pleasant imagery, cognitive reappraisal of distressing thoughts, as well as scheduling and engaging in pleasant activities and healthy behaviors like exercise, he said.
The goal of CBT for fibromyalgia is to shift patients from a "medical treatment cure model" to a "chronic illness self-management" model. However, while CBT has resulted in significant changes over various control conditions, the effect sizes reported in studies have been too small to be noticed by patients, Dr. Lumley said. For example, based on the results of a 2013 Cochrane review, a patient with fibromyalgia could be told that with CBT, the "average patient’s pain improves about 0.5 points more on a 0-10 rating scale," compared with typical treatments, he said (<cf number=\"1\">ystematic reviews.\" </cf>Cochrane Database Syst. Rev. 2013 [doi:10.1002/14651858.CD009796.pub2]).
Fibromyalgia has been considered a psychosomatic condition or an unknown immune disorder in the past, but "a consensus is developing that it is sort of a central nervous system problem, [with] mostly brain, a little bit of spinal cord, and a little bit of the peripheral body involved," he said. In addition to chronic widespread pain and tenderness, symptoms include fatigue and sleep and cognitive problems.
Dr. Lumley had no disclosures; the multicenter study is funded by the National Institutes of Health.
WASHINGTON – The use of "emotional exposure therapy," which addresses unresolved conflict, trauma, and other issues that might be contributing to fibromyalgia symptoms, is being studied as a treatment for the often debilitating illness.
During a symposium on medically complex illnesses at the annual convention of the American Psychological Association, Mark A. Lumley, Ph.D., provided some early observations from a multicenter randomized study comparing this approach with cognitive-behavioral therapy (CBT) and an education control group on 1-year outcomes. Because the wrong pathological processes might have been targeted, "relatively weak" techniques have been used to treat patients with fibromyalgia, said Dr. Lumley, professor of psychology, and head of the stress and health research laboratory at Wayne State University in Detroit.
Interpersonal and relational stress is typical among people with fibromyalgia and includes unresolved conflicts with parents, siblings, spouses, bosses, and others, he said, noting that being bullied on the job has been associated with a three- to fourfold increase in the risk of fibromyalgia. Moreover, 35%-50% of patients with fibromyalgia have evidence of posttraumatic stress disorder (PTSD), and 50%-70% have experienced "lifetime victimization and abuse in their lives," he said.
Therefore, since PTSD, stress, or conflict "tend to be maintained by the avoidance of emotions related to the stress," effective treatment should involve "some sort of exposure and processing of avoided emotionally laden experiences" dealing with memories, thoughts, or relationships, he explained.
Emotional exposure therapy (EET) techniques, based on the "experience-brain-emotion-symptom" model, entail reviewing physical symptoms and events over an individual’s lifetime and identifying key unresolved stressors or conflicts, "making the unspoken spoken," Dr. Lumley said. This approach also involves engaging in expressive writing "often as unsent letters to a key conflict person," and reenacting relational conflicts, "making the unexpressed expressed," he explained.
A few years after finding that expressive writing was beneficial in patients with fibromyalgia, he and his associates conducted a pilot study of 10 patients with fibromyalgia and unresolved stress who received 10 sessions of individualized therapy (Psychotherapy 2008;45:165-72). After treatment that included techniques to help the patients "confront and process avoided emotions, memories, and relationships," two patients showed substantial improvement with symptoms that were almost entirely resolved, and four experienced clinically meaningful improvements, Dr. Lumley said.
In the multicenter, randomized, controlled study of 230 patients with fibromyalgia, patients were treated in small groups with eight sessions of EET, CBT, or education control, and were followed up at 1 year. Almost all patients had a history of significant trauma or conflict, which included sexual abuse or assault in about half of the patients, substantial family of origin problems (in about two-thirds), conflicted or unhappy marriages (in about three-fourths) "and almost all had what I clinically view as emotional avoidance experiences," he said.
Participation has been high, with 84% in the EET group, 77% in the CBT group, and 87% in the education control group making it to the last session – indicating that EET does not frighten all patients away, Dr. Lumley observed.
After 8 weeks of treatment, 22% of those randomized to EET were judged by the therapists providing the treatment to have experienced substantial changes, described as having their lives transformed and being "a very different person," he reported. Another 29% were considered to have experienced "quite a bit of change," and 17% were described to have experienced a moderate amount of change, with "a good start but a lot of work to do." Another 19% experienced little change and 13% were resistant to or not open to treatment and did not change at all.
Patient reports reflected varied experiences, with comments that included, "It’s really hard, but I needed it." Three patients said that the treatment "cured" their fibromyalgia and they that no longer needed to take medication and were sleeping well. These patients "did profound work in their relationships and resolved some of the conflicts in the sessions," Dr. Lumley said.
But there were also some patients who said their pain increased after the sessions or that encouraging the expression of anger was dangerous, "so it can be a variable experience," more variable than CBT, he noted.
Among patients who seek treatment for fibromyalgia, "there’s a lot of unresolved trauma and conflict" and most – but not all – of these patients need EET, Dr. Lumley said. "Many patients can and will do emotionally intense work," while others might need a slower approach, possibly with expressive writing only or the use of emotional awareness techniques that do not involve expression, he added.
Others might benefit from learning "emotional downregulation strategies" with CBT first, he said, pointing out, "We need to figure out who is who."
CBT, one of the few treatment options for fibromyalgia, has been the "psychological treatment of choice," with techniques that include relaxation training, distraction and pleasant imagery, cognitive reappraisal of distressing thoughts, as well as scheduling and engaging in pleasant activities and healthy behaviors like exercise, he said.
The goal of CBT for fibromyalgia is to shift patients from a "medical treatment cure model" to a "chronic illness self-management" model. However, while CBT has resulted in significant changes over various control conditions, the effect sizes reported in studies have been too small to be noticed by patients, Dr. Lumley said. For example, based on the results of a 2013 Cochrane review, a patient with fibromyalgia could be told that with CBT, the "average patient’s pain improves about 0.5 points more on a 0-10 rating scale," compared with typical treatments, he said (<cf number=\"1\">ystematic reviews.\" </cf>Cochrane Database Syst. Rev. 2013 [doi:10.1002/14651858.CD009796.pub2]).
Fibromyalgia has been considered a psychosomatic condition or an unknown immune disorder in the past, but "a consensus is developing that it is sort of a central nervous system problem, [with] mostly brain, a little bit of spinal cord, and a little bit of the peripheral body involved," he said. In addition to chronic widespread pain and tenderness, symptoms include fatigue and sleep and cognitive problems.
Dr. Lumley had no disclosures; the multicenter study is funded by the National Institutes of Health.
WASHINGTON – The use of "emotional exposure therapy," which addresses unresolved conflict, trauma, and other issues that might be contributing to fibromyalgia symptoms, is being studied as a treatment for the often debilitating illness.
During a symposium on medically complex illnesses at the annual convention of the American Psychological Association, Mark A. Lumley, Ph.D., provided some early observations from a multicenter randomized study comparing this approach with cognitive-behavioral therapy (CBT) and an education control group on 1-year outcomes. Because the wrong pathological processes might have been targeted, "relatively weak" techniques have been used to treat patients with fibromyalgia, said Dr. Lumley, professor of psychology, and head of the stress and health research laboratory at Wayne State University in Detroit.
Interpersonal and relational stress is typical among people with fibromyalgia and includes unresolved conflicts with parents, siblings, spouses, bosses, and others, he said, noting that being bullied on the job has been associated with a three- to fourfold increase in the risk of fibromyalgia. Moreover, 35%-50% of patients with fibromyalgia have evidence of posttraumatic stress disorder (PTSD), and 50%-70% have experienced "lifetime victimization and abuse in their lives," he said.
Therefore, since PTSD, stress, or conflict "tend to be maintained by the avoidance of emotions related to the stress," effective treatment should involve "some sort of exposure and processing of avoided emotionally laden experiences" dealing with memories, thoughts, or relationships, he explained.
Emotional exposure therapy (EET) techniques, based on the "experience-brain-emotion-symptom" model, entail reviewing physical symptoms and events over an individual’s lifetime and identifying key unresolved stressors or conflicts, "making the unspoken spoken," Dr. Lumley said. This approach also involves engaging in expressive writing "often as unsent letters to a key conflict person," and reenacting relational conflicts, "making the unexpressed expressed," he explained.
A few years after finding that expressive writing was beneficial in patients with fibromyalgia, he and his associates conducted a pilot study of 10 patients with fibromyalgia and unresolved stress who received 10 sessions of individualized therapy (Psychotherapy 2008;45:165-72). After treatment that included techniques to help the patients "confront and process avoided emotions, memories, and relationships," two patients showed substantial improvement with symptoms that were almost entirely resolved, and four experienced clinically meaningful improvements, Dr. Lumley said.
In the multicenter, randomized, controlled study of 230 patients with fibromyalgia, patients were treated in small groups with eight sessions of EET, CBT, or education control, and were followed up at 1 year. Almost all patients had a history of significant trauma or conflict, which included sexual abuse or assault in about half of the patients, substantial family of origin problems (in about two-thirds), conflicted or unhappy marriages (in about three-fourths) "and almost all had what I clinically view as emotional avoidance experiences," he said.
Participation has been high, with 84% in the EET group, 77% in the CBT group, and 87% in the education control group making it to the last session – indicating that EET does not frighten all patients away, Dr. Lumley observed.
After 8 weeks of treatment, 22% of those randomized to EET were judged by the therapists providing the treatment to have experienced substantial changes, described as having their lives transformed and being "a very different person," he reported. Another 29% were considered to have experienced "quite a bit of change," and 17% were described to have experienced a moderate amount of change, with "a good start but a lot of work to do." Another 19% experienced little change and 13% were resistant to or not open to treatment and did not change at all.
Patient reports reflected varied experiences, with comments that included, "It’s really hard, but I needed it." Three patients said that the treatment "cured" their fibromyalgia and they that no longer needed to take medication and were sleeping well. These patients "did profound work in their relationships and resolved some of the conflicts in the sessions," Dr. Lumley said.
But there were also some patients who said their pain increased after the sessions or that encouraging the expression of anger was dangerous, "so it can be a variable experience," more variable than CBT, he noted.
Among patients who seek treatment for fibromyalgia, "there’s a lot of unresolved trauma and conflict" and most – but not all – of these patients need EET, Dr. Lumley said. "Many patients can and will do emotionally intense work," while others might need a slower approach, possibly with expressive writing only or the use of emotional awareness techniques that do not involve expression, he added.
Others might benefit from learning "emotional downregulation strategies" with CBT first, he said, pointing out, "We need to figure out who is who."
CBT, one of the few treatment options for fibromyalgia, has been the "psychological treatment of choice," with techniques that include relaxation training, distraction and pleasant imagery, cognitive reappraisal of distressing thoughts, as well as scheduling and engaging in pleasant activities and healthy behaviors like exercise, he said.
The goal of CBT for fibromyalgia is to shift patients from a "medical treatment cure model" to a "chronic illness self-management" model. However, while CBT has resulted in significant changes over various control conditions, the effect sizes reported in studies have been too small to be noticed by patients, Dr. Lumley said. For example, based on the results of a 2013 Cochrane review, a patient with fibromyalgia could be told that with CBT, the "average patient’s pain improves about 0.5 points more on a 0-10 rating scale," compared with typical treatments, he said (<cf number=\"1\">ystematic reviews.\" </cf>Cochrane Database Syst. Rev. 2013 [doi:10.1002/14651858.CD009796.pub2]).
Fibromyalgia has been considered a psychosomatic condition or an unknown immune disorder in the past, but "a consensus is developing that it is sort of a central nervous system problem, [with] mostly brain, a little bit of spinal cord, and a little bit of the peripheral body involved," he said. In addition to chronic widespread pain and tenderness, symptoms include fatigue and sleep and cognitive problems.
Dr. Lumley had no disclosures; the multicenter study is funded by the National Institutes of Health.
EXPERT ANALYSIS AT THE 2014 APA CONVENTION
Early data indicate D-cycloserine augments effects of virtual reality treatment for PTSD
WASHINGTON – The use of D-cycloserine has promise as a way to augment the beneficial effects of virtual reality therapy of posttraumatic stress disorder, results of two recently published studies show. The results were discussed during a symposium at the annual convention of the American Psychological Association.
In one study of Iraq and Afghanistan veterans, the use of D-cycloserine (DCS) did not provide an advantage overall, compared with alprazolam or placebo. However, DCS was associated with favorable effects on cortisol and startle reactivity, compared with the other two groups, said one of the authors, Tanja Jovanovic, Ph.D. In another trial, a small proof-of concept study, the PTSD remission rate 6 months after treatment was almost 70% among those treated with a combination of virtual reality (VR) therapy and DCS, compared with 17% among those treated with VR therapy and placebo.
DCS, an NMDA (N-methyl-D-aspartate)-receptor partial agonist approved as an antibacterial by the Food and Drug Administration, has been found to enhance exposure therapy for conditions that include social anxiety and acrophobia in previous studies. NMDA also has been found to facilitate extinction learning in animal studies, said Dr. Jovanovic director of the neurophysiology laboratory at the Grady Trauma Project at Emory University, Atlanta.
In the study, 156 veterans of the Iraq and Afghanistan wars were randomized to treatment with DCS (50 mg), alprazolam (0.25 mg), or placebo plus five sessions of virtual reality exposure therapy (after an introductory VR session). Assessments of patients – which included evaluation of PTSD symptoms, psychophysiologic responses, and cortisol reactivity – were performed before treatment and 3, 6, and 12 months after treatment. Monitoring included placing electrodes under the eye to measure the contraction of the eye blink muscle and skin conductance testing during exposure to the VR scenes (two convoy explosion scenes and a city scene), said Dr. Jovanovic, one of the authors of the study, which was published in June (Am. J. Psychiatry 2014;171:640-8).
After five series of VR treatment, PTSD symptoms significantly decreased in all three groups after treatment, based on changes on the Clinician-Administered PTSD Scale (CAPS) score, but the greatest degree of reduction in symptoms at 12 months was observed in the DCS group, she said. Those treated with DCS "showed the biggest decline and actually maintained those gains at 6 months, which we did not see with the other groups."
In addition, those treated with DCS had a reduction in cortisol and startle reactivity that was greater than the changes observed in the two other groups. The magnitude of startle reactivity at baseline was related to the change in the CAPS score 6 months later, "so those gains they are maintaining at 6 months are predicted by their initial response to the virtual reality session pretreatment ... the more reactive, the better they got," Dr. Jovanovic reported.
The same also was true for skin conductance findings: The more reactive they were at baseline in this measure, the more improved the patients were at follow-up, but this association was only evident in the DCS-treated patients, Dr. Jovanovic said.
Measurements of cortisol levels before exposure to the VR scenes, immediately afterward, and 15 minutes afterward determined that cortisol reactivity was attenuated with treatment. Cortisol reactivity significantly dropped in all three groups, from before treatment to the 6-month follow-up but was the lowest in the DCS-treated patients. In the alprazolam-treated group, the higher the cortisol reactivity was before treatment, the worse the outcomes were with treatment, the reverse of what was seen with other psychophysiological measures, she added.
During the same symposium on the use of VR in the treatment of PTSD, JoAnn Difede, Ph.D., professor of psychiatry, Cornell University, New York, described the use of DCS "as a cognitive enhancer" for treatment of people with PTSD related to the World Trade Center attacks in 2001. "We see this as very promising," she said.
In one double-blind, proof-of-concept study, 25 people with PTSD were randomized to DCS (100 mg) or placebo administered 90 minutes before weekly sessions of VR therapy, timed so that plasma concentrations would peak during the session. In the placebo group, 3 dropped out, but none of the 13 patients in the DCS group dropped out (Neuropsychopharmacology 2014; 39:1052-8).
Six months after treatment, 9 of the 13 patients (69%) in the DCS group were in remission, compared with 2 of the 12 (17%) on placebo plus VR exposure. Remission was defined as a CAPS total score of 20 or less, and minimal or no impairment in social, occupational, and other important areas of function, as judged by an independent blinded assessor.
Dr. Difede, also director of the program for anxiety and traumatic stress studies at New York-Presbyterian Hospital, said the two groups began to diverge at the third session, and those who received DCS continued to improve 6 months later. A post-hoc analysis identified a "drastic improvement" in anger and sleep among those treated with DCS, a finding that she and her associates plan to look at more closely. The study presented by Dr. Jovanovic was funded by the National Institute of Mental Health. Dr. Difede received partial funding support from DeWitt-Wallace Fund of the New York Community Trust. The trust was not involved in the design, data collection, or in any other aspects of the study.
WASHINGTON – The use of D-cycloserine has promise as a way to augment the beneficial effects of virtual reality therapy of posttraumatic stress disorder, results of two recently published studies show. The results were discussed during a symposium at the annual convention of the American Psychological Association.
In one study of Iraq and Afghanistan veterans, the use of D-cycloserine (DCS) did not provide an advantage overall, compared with alprazolam or placebo. However, DCS was associated with favorable effects on cortisol and startle reactivity, compared with the other two groups, said one of the authors, Tanja Jovanovic, Ph.D. In another trial, a small proof-of concept study, the PTSD remission rate 6 months after treatment was almost 70% among those treated with a combination of virtual reality (VR) therapy and DCS, compared with 17% among those treated with VR therapy and placebo.
DCS, an NMDA (N-methyl-D-aspartate)-receptor partial agonist approved as an antibacterial by the Food and Drug Administration, has been found to enhance exposure therapy for conditions that include social anxiety and acrophobia in previous studies. NMDA also has been found to facilitate extinction learning in animal studies, said Dr. Jovanovic director of the neurophysiology laboratory at the Grady Trauma Project at Emory University, Atlanta.
In the study, 156 veterans of the Iraq and Afghanistan wars were randomized to treatment with DCS (50 mg), alprazolam (0.25 mg), or placebo plus five sessions of virtual reality exposure therapy (after an introductory VR session). Assessments of patients – which included evaluation of PTSD symptoms, psychophysiologic responses, and cortisol reactivity – were performed before treatment and 3, 6, and 12 months after treatment. Monitoring included placing electrodes under the eye to measure the contraction of the eye blink muscle and skin conductance testing during exposure to the VR scenes (two convoy explosion scenes and a city scene), said Dr. Jovanovic, one of the authors of the study, which was published in June (Am. J. Psychiatry 2014;171:640-8).
After five series of VR treatment, PTSD symptoms significantly decreased in all three groups after treatment, based on changes on the Clinician-Administered PTSD Scale (CAPS) score, but the greatest degree of reduction in symptoms at 12 months was observed in the DCS group, she said. Those treated with DCS "showed the biggest decline and actually maintained those gains at 6 months, which we did not see with the other groups."
In addition, those treated with DCS had a reduction in cortisol and startle reactivity that was greater than the changes observed in the two other groups. The magnitude of startle reactivity at baseline was related to the change in the CAPS score 6 months later, "so those gains they are maintaining at 6 months are predicted by their initial response to the virtual reality session pretreatment ... the more reactive, the better they got," Dr. Jovanovic reported.
The same also was true for skin conductance findings: The more reactive they were at baseline in this measure, the more improved the patients were at follow-up, but this association was only evident in the DCS-treated patients, Dr. Jovanovic said.
Measurements of cortisol levels before exposure to the VR scenes, immediately afterward, and 15 minutes afterward determined that cortisol reactivity was attenuated with treatment. Cortisol reactivity significantly dropped in all three groups, from before treatment to the 6-month follow-up but was the lowest in the DCS-treated patients. In the alprazolam-treated group, the higher the cortisol reactivity was before treatment, the worse the outcomes were with treatment, the reverse of what was seen with other psychophysiological measures, she added.
During the same symposium on the use of VR in the treatment of PTSD, JoAnn Difede, Ph.D., professor of psychiatry, Cornell University, New York, described the use of DCS "as a cognitive enhancer" for treatment of people with PTSD related to the World Trade Center attacks in 2001. "We see this as very promising," she said.
In one double-blind, proof-of-concept study, 25 people with PTSD were randomized to DCS (100 mg) or placebo administered 90 minutes before weekly sessions of VR therapy, timed so that plasma concentrations would peak during the session. In the placebo group, 3 dropped out, but none of the 13 patients in the DCS group dropped out (Neuropsychopharmacology 2014; 39:1052-8).
Six months after treatment, 9 of the 13 patients (69%) in the DCS group were in remission, compared with 2 of the 12 (17%) on placebo plus VR exposure. Remission was defined as a CAPS total score of 20 or less, and minimal or no impairment in social, occupational, and other important areas of function, as judged by an independent blinded assessor.
Dr. Difede, also director of the program for anxiety and traumatic stress studies at New York-Presbyterian Hospital, said the two groups began to diverge at the third session, and those who received DCS continued to improve 6 months later. A post-hoc analysis identified a "drastic improvement" in anger and sleep among those treated with DCS, a finding that she and her associates plan to look at more closely. The study presented by Dr. Jovanovic was funded by the National Institute of Mental Health. Dr. Difede received partial funding support from DeWitt-Wallace Fund of the New York Community Trust. The trust was not involved in the design, data collection, or in any other aspects of the study.
WASHINGTON – The use of D-cycloserine has promise as a way to augment the beneficial effects of virtual reality therapy of posttraumatic stress disorder, results of two recently published studies show. The results were discussed during a symposium at the annual convention of the American Psychological Association.
In one study of Iraq and Afghanistan veterans, the use of D-cycloserine (DCS) did not provide an advantage overall, compared with alprazolam or placebo. However, DCS was associated with favorable effects on cortisol and startle reactivity, compared with the other two groups, said one of the authors, Tanja Jovanovic, Ph.D. In another trial, a small proof-of concept study, the PTSD remission rate 6 months after treatment was almost 70% among those treated with a combination of virtual reality (VR) therapy and DCS, compared with 17% among those treated with VR therapy and placebo.
DCS, an NMDA (N-methyl-D-aspartate)-receptor partial agonist approved as an antibacterial by the Food and Drug Administration, has been found to enhance exposure therapy for conditions that include social anxiety and acrophobia in previous studies. NMDA also has been found to facilitate extinction learning in animal studies, said Dr. Jovanovic director of the neurophysiology laboratory at the Grady Trauma Project at Emory University, Atlanta.
In the study, 156 veterans of the Iraq and Afghanistan wars were randomized to treatment with DCS (50 mg), alprazolam (0.25 mg), or placebo plus five sessions of virtual reality exposure therapy (after an introductory VR session). Assessments of patients – which included evaluation of PTSD symptoms, psychophysiologic responses, and cortisol reactivity – were performed before treatment and 3, 6, and 12 months after treatment. Monitoring included placing electrodes under the eye to measure the contraction of the eye blink muscle and skin conductance testing during exposure to the VR scenes (two convoy explosion scenes and a city scene), said Dr. Jovanovic, one of the authors of the study, which was published in June (Am. J. Psychiatry 2014;171:640-8).
After five series of VR treatment, PTSD symptoms significantly decreased in all three groups after treatment, based on changes on the Clinician-Administered PTSD Scale (CAPS) score, but the greatest degree of reduction in symptoms at 12 months was observed in the DCS group, she said. Those treated with DCS "showed the biggest decline and actually maintained those gains at 6 months, which we did not see with the other groups."
In addition, those treated with DCS had a reduction in cortisol and startle reactivity that was greater than the changes observed in the two other groups. The magnitude of startle reactivity at baseline was related to the change in the CAPS score 6 months later, "so those gains they are maintaining at 6 months are predicted by their initial response to the virtual reality session pretreatment ... the more reactive, the better they got," Dr. Jovanovic reported.
The same also was true for skin conductance findings: The more reactive they were at baseline in this measure, the more improved the patients were at follow-up, but this association was only evident in the DCS-treated patients, Dr. Jovanovic said.
Measurements of cortisol levels before exposure to the VR scenes, immediately afterward, and 15 minutes afterward determined that cortisol reactivity was attenuated with treatment. Cortisol reactivity significantly dropped in all three groups, from before treatment to the 6-month follow-up but was the lowest in the DCS-treated patients. In the alprazolam-treated group, the higher the cortisol reactivity was before treatment, the worse the outcomes were with treatment, the reverse of what was seen with other psychophysiological measures, she added.
During the same symposium on the use of VR in the treatment of PTSD, JoAnn Difede, Ph.D., professor of psychiatry, Cornell University, New York, described the use of DCS "as a cognitive enhancer" for treatment of people with PTSD related to the World Trade Center attacks in 2001. "We see this as very promising," she said.
In one double-blind, proof-of-concept study, 25 people with PTSD were randomized to DCS (100 mg) or placebo administered 90 minutes before weekly sessions of VR therapy, timed so that plasma concentrations would peak during the session. In the placebo group, 3 dropped out, but none of the 13 patients in the DCS group dropped out (Neuropsychopharmacology 2014; 39:1052-8).
Six months after treatment, 9 of the 13 patients (69%) in the DCS group were in remission, compared with 2 of the 12 (17%) on placebo plus VR exposure. Remission was defined as a CAPS total score of 20 or less, and minimal or no impairment in social, occupational, and other important areas of function, as judged by an independent blinded assessor.
Dr. Difede, also director of the program for anxiety and traumatic stress studies at New York-Presbyterian Hospital, said the two groups began to diverge at the third session, and those who received DCS continued to improve 6 months later. A post-hoc analysis identified a "drastic improvement" in anger and sleep among those treated with DCS, a finding that she and her associates plan to look at more closely. The study presented by Dr. Jovanovic was funded by the National Institute of Mental Health. Dr. Difede received partial funding support from DeWitt-Wallace Fund of the New York Community Trust. The trust was not involved in the design, data collection, or in any other aspects of the study.
EXPERT ANALYSIS AT THE 2014 APA CONVENTION
Evidence questioned in debate over monitoring dabigatran levels to avert bleeds
The manufacturer of the oral anticoagulant dabigatran "withheld analyses that calculate how many major bleeds dose adjustment could prevent," the BMJ charges in an article based on internal documents released during litigation in the United States and freedom of information act requests obtained by the journal.
Boehringer Ingelheim "found that if the plasma levels of the drug were measured and the dose was adjusted accordingly major bleeds could be reduced by 30%-40%, compared with well-controlled warfarin," according to the article (BMJ 2014;349:g4670), which was published along with an editorial and an analysis. The article further stated that the manufacturer "has failed to share with regulators information about the potential benefits of monitoring anticoagulant activity and adjusting the dose to make sure the drug is working as safely and effectively as possible."
In the analysis, Thomas Moore, senior scientist at the Institute for Safe Medication Practices, Horsham, Pa., and his coauthors said that "the bleeding risk of dabigatran can be reduced and efficacy improved by individualizing the dose in patients based on plasma level, age, and kidney function" (BMJ 2014;349:g4517[doi:10.1136/bmj.g4517]).
Dr. Rita Redberg and Dr. Blake Charlton of the University of California, San Francisco, wrote in an accompanying editorial that the analysis "illuminates a lack of transparency about the safety of unmonitored dabigatran, compounded by the drug’s fickle pharmacokinetics, which can cause a fivefold variation of plasma concentration." (BMJ 2014;349:g4681 [doi:10.1136/bmj.g4681]).
The BMJ article, written by Deborah Cohen, includes responses from the manufacturer of dabigatran (Pradaxa).
Boehringer Ingelheim officials have asserted that no data were withheld. Additionally, the company has released a statement calling the BMJ article "biased" and "misleading."
Dabigatran is a direct thrombin inhibitor that was approved in the United States in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation at a fixed dose of 150 mg or 75 mg twice a day, with the lower dose recommended for those with renal impairment. Since its initial approval, dabigatran has gained indications for treating and reducing the risk of recurrence of deep venous thrombosis and pulmonary embolism.
The drug’s approval was based on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, which compared the drug to warfarin in 18,113 patients with nonvalvular atrial fibrillation and at least one other risk factor for stroke. The annual rate of stroke and systemic embolism in RE-LY was 1.5% in the patients on the 110-mg twice daily dose, 1.1% in those on the 150-mg twice daily dose, and 1.7% among those on warfarin. The risk reductions with dabigatran were 10% and 35% for the 110-mg and 150-mg doses, respectively, compared with warfarin.
"Our company has provided regulators with the complete data set and analyses of clinical evidence demonstrating Pradaxa’s benefits and safety," Boehringer Ingelheim said in its statement. "Contrary to the BMJ’s accusation that BI withheld analyses, here are the facts: In 2012, our scientists performed preliminary, exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve Pradaxa’s benefits and safety. Because the simulations did not offer reliable predictions of actual patient outcomes, they were not provided to regulators. However, all of the data that was used for the simulations had already been provided."
Dr. Sanjay Kaul, who was on the Food and Drug Administration’s advisory panel that recommended approval of dabigatran, said in an interview that the FDA reviewers raised questions at that meeting about the utility of using plasma concentrations to monitor individual subjects and adjust dose based on dabigatran concentrations. "But they also acknowledged an exposure-response relationship existed that demonstrated that going from the 10th to 90th percentile of dabigatran concentration (23 to 283 ng/mL) reduced the probability of having a stroke by 50% (from 1% to 0.5%) while increasing sixfold (from 0.3% to 1.8%) the probability of having major bleeding within 1 year."
It is well known that plasma concentration is one of the factors – among others, such as age, renal function, or history of stroke – that affect the benefit-risk balance, said Dr. Kaul, a cardiologist at Cedars-Sinai Medical Center, Los Angeles. Even in patients with moderate to severe renal dysfunction (up to creatinine clearance of 15-30 mL/min) and elevated plasma concentrations, benefit still exceeds risk.
"To what degree monitoring drug levels could potentially optimize benefit-risk balance remains an open question. For example, benefit-risk balance for dabigatran 150 mg vs 110 mg was not predicted by pharmacokinetic/pharmacodynamic modeling. Based on the PK/PD modeling, one stroke would be prevented at the cost of three extra major bleeds using 150 mg , compared with 110 mg. The RE-LY data indicate four strokes prevented and three major bleeding events incurred with the 150-mg dose as compared with the 110-mg dose," he said. "There is quite a discordance in predicted vs. observed benefit-risk balance."
Therefore, "while monitoring drug levels to optimize benefit-risk balance has intuitive appeal, given the complex exposure-response relationship and confounding effects of demographic variables, this should remain an area of active investigation. It is not ready for prime time to inform or guide clinical practice," Dr. Kaul said.
Dr. Kaul disclosed that he is a consultant for Boehringer Ingelheim and has equity interest in Johnson and Johnson.
At press time, the FDA had not responded to a request for a comment on the BMJ investigation.
The manufacturer of the oral anticoagulant dabigatran "withheld analyses that calculate how many major bleeds dose adjustment could prevent," the BMJ charges in an article based on internal documents released during litigation in the United States and freedom of information act requests obtained by the journal.
Boehringer Ingelheim "found that if the plasma levels of the drug were measured and the dose was adjusted accordingly major bleeds could be reduced by 30%-40%, compared with well-controlled warfarin," according to the article (BMJ 2014;349:g4670), which was published along with an editorial and an analysis. The article further stated that the manufacturer "has failed to share with regulators information about the potential benefits of monitoring anticoagulant activity and adjusting the dose to make sure the drug is working as safely and effectively as possible."
In the analysis, Thomas Moore, senior scientist at the Institute for Safe Medication Practices, Horsham, Pa., and his coauthors said that "the bleeding risk of dabigatran can be reduced and efficacy improved by individualizing the dose in patients based on plasma level, age, and kidney function" (BMJ 2014;349:g4517[doi:10.1136/bmj.g4517]).
Dr. Rita Redberg and Dr. Blake Charlton of the University of California, San Francisco, wrote in an accompanying editorial that the analysis "illuminates a lack of transparency about the safety of unmonitored dabigatran, compounded by the drug’s fickle pharmacokinetics, which can cause a fivefold variation of plasma concentration." (BMJ 2014;349:g4681 [doi:10.1136/bmj.g4681]).
The BMJ article, written by Deborah Cohen, includes responses from the manufacturer of dabigatran (Pradaxa).
Boehringer Ingelheim officials have asserted that no data were withheld. Additionally, the company has released a statement calling the BMJ article "biased" and "misleading."
Dabigatran is a direct thrombin inhibitor that was approved in the United States in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation at a fixed dose of 150 mg or 75 mg twice a day, with the lower dose recommended for those with renal impairment. Since its initial approval, dabigatran has gained indications for treating and reducing the risk of recurrence of deep venous thrombosis and pulmonary embolism.
The drug’s approval was based on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, which compared the drug to warfarin in 18,113 patients with nonvalvular atrial fibrillation and at least one other risk factor for stroke. The annual rate of stroke and systemic embolism in RE-LY was 1.5% in the patients on the 110-mg twice daily dose, 1.1% in those on the 150-mg twice daily dose, and 1.7% among those on warfarin. The risk reductions with dabigatran were 10% and 35% for the 110-mg and 150-mg doses, respectively, compared with warfarin.
"Our company has provided regulators with the complete data set and analyses of clinical evidence demonstrating Pradaxa’s benefits and safety," Boehringer Ingelheim said in its statement. "Contrary to the BMJ’s accusation that BI withheld analyses, here are the facts: In 2012, our scientists performed preliminary, exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve Pradaxa’s benefits and safety. Because the simulations did not offer reliable predictions of actual patient outcomes, they were not provided to regulators. However, all of the data that was used for the simulations had already been provided."
Dr. Sanjay Kaul, who was on the Food and Drug Administration’s advisory panel that recommended approval of dabigatran, said in an interview that the FDA reviewers raised questions at that meeting about the utility of using plasma concentrations to monitor individual subjects and adjust dose based on dabigatran concentrations. "But they also acknowledged an exposure-response relationship existed that demonstrated that going from the 10th to 90th percentile of dabigatran concentration (23 to 283 ng/mL) reduced the probability of having a stroke by 50% (from 1% to 0.5%) while increasing sixfold (from 0.3% to 1.8%) the probability of having major bleeding within 1 year."
It is well known that plasma concentration is one of the factors – among others, such as age, renal function, or history of stroke – that affect the benefit-risk balance, said Dr. Kaul, a cardiologist at Cedars-Sinai Medical Center, Los Angeles. Even in patients with moderate to severe renal dysfunction (up to creatinine clearance of 15-30 mL/min) and elevated plasma concentrations, benefit still exceeds risk.
"To what degree monitoring drug levels could potentially optimize benefit-risk balance remains an open question. For example, benefit-risk balance for dabigatran 150 mg vs 110 mg was not predicted by pharmacokinetic/pharmacodynamic modeling. Based on the PK/PD modeling, one stroke would be prevented at the cost of three extra major bleeds using 150 mg , compared with 110 mg. The RE-LY data indicate four strokes prevented and three major bleeding events incurred with the 150-mg dose as compared with the 110-mg dose," he said. "There is quite a discordance in predicted vs. observed benefit-risk balance."
Therefore, "while monitoring drug levels to optimize benefit-risk balance has intuitive appeal, given the complex exposure-response relationship and confounding effects of demographic variables, this should remain an area of active investigation. It is not ready for prime time to inform or guide clinical practice," Dr. Kaul said.
Dr. Kaul disclosed that he is a consultant for Boehringer Ingelheim and has equity interest in Johnson and Johnson.
At press time, the FDA had not responded to a request for a comment on the BMJ investigation.
The manufacturer of the oral anticoagulant dabigatran "withheld analyses that calculate how many major bleeds dose adjustment could prevent," the BMJ charges in an article based on internal documents released during litigation in the United States and freedom of information act requests obtained by the journal.
Boehringer Ingelheim "found that if the plasma levels of the drug were measured and the dose was adjusted accordingly major bleeds could be reduced by 30%-40%, compared with well-controlled warfarin," according to the article (BMJ 2014;349:g4670), which was published along with an editorial and an analysis. The article further stated that the manufacturer "has failed to share with regulators information about the potential benefits of monitoring anticoagulant activity and adjusting the dose to make sure the drug is working as safely and effectively as possible."
In the analysis, Thomas Moore, senior scientist at the Institute for Safe Medication Practices, Horsham, Pa., and his coauthors said that "the bleeding risk of dabigatran can be reduced and efficacy improved by individualizing the dose in patients based on plasma level, age, and kidney function" (BMJ 2014;349:g4517[doi:10.1136/bmj.g4517]).
Dr. Rita Redberg and Dr. Blake Charlton of the University of California, San Francisco, wrote in an accompanying editorial that the analysis "illuminates a lack of transparency about the safety of unmonitored dabigatran, compounded by the drug’s fickle pharmacokinetics, which can cause a fivefold variation of plasma concentration." (BMJ 2014;349:g4681 [doi:10.1136/bmj.g4681]).
The BMJ article, written by Deborah Cohen, includes responses from the manufacturer of dabigatran (Pradaxa).
Boehringer Ingelheim officials have asserted that no data were withheld. Additionally, the company has released a statement calling the BMJ article "biased" and "misleading."
Dabigatran is a direct thrombin inhibitor that was approved in the United States in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation at a fixed dose of 150 mg or 75 mg twice a day, with the lower dose recommended for those with renal impairment. Since its initial approval, dabigatran has gained indications for treating and reducing the risk of recurrence of deep venous thrombosis and pulmonary embolism.
The drug’s approval was based on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, which compared the drug to warfarin in 18,113 patients with nonvalvular atrial fibrillation and at least one other risk factor for stroke. The annual rate of stroke and systemic embolism in RE-LY was 1.5% in the patients on the 110-mg twice daily dose, 1.1% in those on the 150-mg twice daily dose, and 1.7% among those on warfarin. The risk reductions with dabigatran were 10% and 35% for the 110-mg and 150-mg doses, respectively, compared with warfarin.
"Our company has provided regulators with the complete data set and analyses of clinical evidence demonstrating Pradaxa’s benefits and safety," Boehringer Ingelheim said in its statement. "Contrary to the BMJ’s accusation that BI withheld analyses, here are the facts: In 2012, our scientists performed preliminary, exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve Pradaxa’s benefits and safety. Because the simulations did not offer reliable predictions of actual patient outcomes, they were not provided to regulators. However, all of the data that was used for the simulations had already been provided."
Dr. Sanjay Kaul, who was on the Food and Drug Administration’s advisory panel that recommended approval of dabigatran, said in an interview that the FDA reviewers raised questions at that meeting about the utility of using plasma concentrations to monitor individual subjects and adjust dose based on dabigatran concentrations. "But they also acknowledged an exposure-response relationship existed that demonstrated that going from the 10th to 90th percentile of dabigatran concentration (23 to 283 ng/mL) reduced the probability of having a stroke by 50% (from 1% to 0.5%) while increasing sixfold (from 0.3% to 1.8%) the probability of having major bleeding within 1 year."
It is well known that plasma concentration is one of the factors – among others, such as age, renal function, or history of stroke – that affect the benefit-risk balance, said Dr. Kaul, a cardiologist at Cedars-Sinai Medical Center, Los Angeles. Even in patients with moderate to severe renal dysfunction (up to creatinine clearance of 15-30 mL/min) and elevated plasma concentrations, benefit still exceeds risk.
"To what degree monitoring drug levels could potentially optimize benefit-risk balance remains an open question. For example, benefit-risk balance for dabigatran 150 mg vs 110 mg was not predicted by pharmacokinetic/pharmacodynamic modeling. Based on the PK/PD modeling, one stroke would be prevented at the cost of three extra major bleeds using 150 mg , compared with 110 mg. The RE-LY data indicate four strokes prevented and three major bleeding events incurred with the 150-mg dose as compared with the 110-mg dose," he said. "There is quite a discordance in predicted vs. observed benefit-risk balance."
Therefore, "while monitoring drug levels to optimize benefit-risk balance has intuitive appeal, given the complex exposure-response relationship and confounding effects of demographic variables, this should remain an area of active investigation. It is not ready for prime time to inform or guide clinical practice," Dr. Kaul said.
Dr. Kaul disclosed that he is a consultant for Boehringer Ingelheim and has equity interest in Johnson and Johnson.
At press time, the FDA had not responded to a request for a comment on the BMJ investigation.
Successful bariatric surgery also may improve urinary incontinence
WASHINGTON – The majority of obese women who had urinary incontinence before bariatric surgery had complete or near-complete resolution of symptoms for up to 3 years after surgery in a study of more than 1,500 women, Dr. Leslee Subak reported at the scientific meetings of the American Urogynecologic Society and the International Urogynecological Association.
These results indicate that "improvement in incontinence may be another long-term benefit of weight loss, in this case surgical weight loss," said Dr. Subak, professor of obstetrics and gynecology and reproductive sciences, epidemiology and biostatistics, and urology at the University of California, San Francisco.
The study evaluated the effect of surgery on urinary incontinence in 1,565 severely obese women who were part of the multicenter Longitudinal Cohort Study of Bariatric Surgery-2 and had completed self-administered questionnaires about urinary incontinence episodes before surgery and at one or more annual follow-up assessments within 3 years of surgery.
The results were based on outcomes of the 772 women who reported experiencing episodes of incontinence at least weekly, with an average of about 11 incontinence episodes per week. Their median age was 46 years and most were white; about 7% had undergone previous incontinence surgery and about 8% had received or were receiving behavioral treatment or medication for incontinence.
Most of the patients underwent a Roux-en-Y gastric bypass (71%) or laparoscopic adjustable gastric banding (25%). After the first year, they had lost a median of about 30% of their baseline weight, which was maintained through the third year.
At all follow-up times after surgery, there were significantly fewer incontinence episodes, compared with baseline, with a remission rate of 60%-65%, Dr. Subak said.
Urinary incontinence episodes dropped from an average of about 11 episodes per week before surgery to an average of almost 3 episodes per week at 1 year and 4 episodes per week at 2 and 3 years, she noted. Episodes of stress incontinence also decreased from an average of about 5 episodes per week at baseline to about 1 episode per week at 1 year and almost 2 episodes per week at 2 and 3 years.
The remission rate – defined as less than 1 weekly urinary incontinence episode over the past 3 months – was 70% at 1 year, dropping to and stabilizing at about 61%-62% at 2 and 3 years. Moreover, 25% of the women had a complete remission (no episodes of incontinence during the past 3 months) at 3 years, a slight increase from almost 27% at 1 year, Dr. Subak said.
"The magnitude of weight loss was the strongest predictor of improvement in incontinence over time," she noted. "Incontinence and BMI [body mass index] seemed to track together, as [whenever] there’s a reduction in BMI ... there’s a reduction in urinary incontinence episode frequency."
A younger age also was significantly associated with a reduction in the frequency or a remission of urinary incontinence, while being pregnant in the previous year and having had a hysterectomy were associated with a lower likelihood of having a remission.
Dr. Subak noted that limitations of the study included the observational design and the lack of a control group, as well as the fact that data were based on self-reports.
She referred to urinary incontinence and obesity as "twin epidemics," with about a fourfold increased risk of urinary incontinence associated with obesity. About one-third of women in the United States are obese and about 70% of women with incontinence are obese, she pointed out.
The Longitudinal Cohort Study of Bariatric Surgery-2 is funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Subak received additional funding from the NIDDK; she had no other disclosures.
WASHINGTON – The majority of obese women who had urinary incontinence before bariatric surgery had complete or near-complete resolution of symptoms for up to 3 years after surgery in a study of more than 1,500 women, Dr. Leslee Subak reported at the scientific meetings of the American Urogynecologic Society and the International Urogynecological Association.
These results indicate that "improvement in incontinence may be another long-term benefit of weight loss, in this case surgical weight loss," said Dr. Subak, professor of obstetrics and gynecology and reproductive sciences, epidemiology and biostatistics, and urology at the University of California, San Francisco.
The study evaluated the effect of surgery on urinary incontinence in 1,565 severely obese women who were part of the multicenter Longitudinal Cohort Study of Bariatric Surgery-2 and had completed self-administered questionnaires about urinary incontinence episodes before surgery and at one or more annual follow-up assessments within 3 years of surgery.
The results were based on outcomes of the 772 women who reported experiencing episodes of incontinence at least weekly, with an average of about 11 incontinence episodes per week. Their median age was 46 years and most were white; about 7% had undergone previous incontinence surgery and about 8% had received or were receiving behavioral treatment or medication for incontinence.
Most of the patients underwent a Roux-en-Y gastric bypass (71%) or laparoscopic adjustable gastric banding (25%). After the first year, they had lost a median of about 30% of their baseline weight, which was maintained through the third year.
At all follow-up times after surgery, there were significantly fewer incontinence episodes, compared with baseline, with a remission rate of 60%-65%, Dr. Subak said.
Urinary incontinence episodes dropped from an average of about 11 episodes per week before surgery to an average of almost 3 episodes per week at 1 year and 4 episodes per week at 2 and 3 years, she noted. Episodes of stress incontinence also decreased from an average of about 5 episodes per week at baseline to about 1 episode per week at 1 year and almost 2 episodes per week at 2 and 3 years.
The remission rate – defined as less than 1 weekly urinary incontinence episode over the past 3 months – was 70% at 1 year, dropping to and stabilizing at about 61%-62% at 2 and 3 years. Moreover, 25% of the women had a complete remission (no episodes of incontinence during the past 3 months) at 3 years, a slight increase from almost 27% at 1 year, Dr. Subak said.
"The magnitude of weight loss was the strongest predictor of improvement in incontinence over time," she noted. "Incontinence and BMI [body mass index] seemed to track together, as [whenever] there’s a reduction in BMI ... there’s a reduction in urinary incontinence episode frequency."
A younger age also was significantly associated with a reduction in the frequency or a remission of urinary incontinence, while being pregnant in the previous year and having had a hysterectomy were associated with a lower likelihood of having a remission.
Dr. Subak noted that limitations of the study included the observational design and the lack of a control group, as well as the fact that data were based on self-reports.
She referred to urinary incontinence and obesity as "twin epidemics," with about a fourfold increased risk of urinary incontinence associated with obesity. About one-third of women in the United States are obese and about 70% of women with incontinence are obese, she pointed out.
The Longitudinal Cohort Study of Bariatric Surgery-2 is funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Subak received additional funding from the NIDDK; she had no other disclosures.
WASHINGTON – The majority of obese women who had urinary incontinence before bariatric surgery had complete or near-complete resolution of symptoms for up to 3 years after surgery in a study of more than 1,500 women, Dr. Leslee Subak reported at the scientific meetings of the American Urogynecologic Society and the International Urogynecological Association.
These results indicate that "improvement in incontinence may be another long-term benefit of weight loss, in this case surgical weight loss," said Dr. Subak, professor of obstetrics and gynecology and reproductive sciences, epidemiology and biostatistics, and urology at the University of California, San Francisco.
The study evaluated the effect of surgery on urinary incontinence in 1,565 severely obese women who were part of the multicenter Longitudinal Cohort Study of Bariatric Surgery-2 and had completed self-administered questionnaires about urinary incontinence episodes before surgery and at one or more annual follow-up assessments within 3 years of surgery.
The results were based on outcomes of the 772 women who reported experiencing episodes of incontinence at least weekly, with an average of about 11 incontinence episodes per week. Their median age was 46 years and most were white; about 7% had undergone previous incontinence surgery and about 8% had received or were receiving behavioral treatment or medication for incontinence.
Most of the patients underwent a Roux-en-Y gastric bypass (71%) or laparoscopic adjustable gastric banding (25%). After the first year, they had lost a median of about 30% of their baseline weight, which was maintained through the third year.
At all follow-up times after surgery, there were significantly fewer incontinence episodes, compared with baseline, with a remission rate of 60%-65%, Dr. Subak said.
Urinary incontinence episodes dropped from an average of about 11 episodes per week before surgery to an average of almost 3 episodes per week at 1 year and 4 episodes per week at 2 and 3 years, she noted. Episodes of stress incontinence also decreased from an average of about 5 episodes per week at baseline to about 1 episode per week at 1 year and almost 2 episodes per week at 2 and 3 years.
The remission rate – defined as less than 1 weekly urinary incontinence episode over the past 3 months – was 70% at 1 year, dropping to and stabilizing at about 61%-62% at 2 and 3 years. Moreover, 25% of the women had a complete remission (no episodes of incontinence during the past 3 months) at 3 years, a slight increase from almost 27% at 1 year, Dr. Subak said.
"The magnitude of weight loss was the strongest predictor of improvement in incontinence over time," she noted. "Incontinence and BMI [body mass index] seemed to track together, as [whenever] there’s a reduction in BMI ... there’s a reduction in urinary incontinence episode frequency."
A younger age also was significantly associated with a reduction in the frequency or a remission of urinary incontinence, while being pregnant in the previous year and having had a hysterectomy were associated with a lower likelihood of having a remission.
Dr. Subak noted that limitations of the study included the observational design and the lack of a control group, as well as the fact that data were based on self-reports.
She referred to urinary incontinence and obesity as "twin epidemics," with about a fourfold increased risk of urinary incontinence associated with obesity. About one-third of women in the United States are obese and about 70% of women with incontinence are obese, she pointed out.
The Longitudinal Cohort Study of Bariatric Surgery-2 is funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Subak received additional funding from the NIDDK; she had no other disclosures.
AT AUGS/IUGA 2014
Key clinical point: Obese women who report urinary incontinence may experience improvement or even resolution of symptoms after bariatric surgery.
Major finding: About one-quarter of the 772 severely obese women who reported having urinary incontinence before undergoing bariatric surgery had complete remission of urinary incontinence 3 years after surgery.
Data source: The frequency of urinary incontinence symptoms at baseline and for up to 3 years after bariatric surgery was evaluated in a substudy of 1,565 severely obese women who were enrolled in a multicenter, longitudinal cohort study based on self-administered questionnaires.
Disclosures: The Longitudinal Cohort Study of Bariatric Surgery-2 is funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Subak received additional funding from the NIDDK; she had no other disclosures.
Autism sibling studies beginning to yield data
WASHINGTON – Studies of the younger siblings of children with autism spectrum disorders are beginning to yield information that has important implications for screening, reducing the age at diagnosis, and identifying the window of time during which still unidentified interventions might be able to affect the course, according to experts who spoke at the annual convention of the American Psychological Association.
During a symposium on early development and predictors of outcomes in infant siblings of children with autism, several experts summarized the results of studies evaluating the emergence of autism spectrum disorders (ASD) and ASD-like symptoms in the younger siblings of children with ASD, as well as tools that are being studied in high-risk sibling studies as potential methods of diagnosing ASD earlier.
The risk of ASD is 1 in 68 in the general population, but is almost 1 in 5 among the siblings of children diagnosed with ASD. An additional one in five siblings will have "shadow symptoms" of autism, which refers to children with some of the symptomatology but not enough to merit a diagnosis. In addition, another 1 in 10 will have nonautism developmental delays.
Therefore, about 50% of infant siblings of children with ASD "are vulnerable in their development to some degree, so that’s why we’re studying them so closely," said one of the speakers, Celine Saulnier, Ph.D., clinical director for research at the Marcus Autism Center, Emory University, Atlanta.
During the symposium, Alice Carter, Ph.D., professor of clinical psychology at the University of Massachusetts, Boston, provided the results of a prospective study that identified high-risk siblings who exhibited some ASD-like behaviors early on but were not diagnosed with autism at age 3.
A growing body of literature focusing on milder ASD symptoms in relatives of people diagnosed with ASD indicates that about 20%-30% of children who are at high genetic risk develop some symptoms of autism but not enough symptoms or symptoms that are severe enough to make the diagnosis, she said. This is often referred to as the broader autism phenotype (BAP), which affects an estimated 19% of unaffected siblings at age 12 months.
The prospective study followed 26 infants who had older siblings with ASD, the high-risk group, to 33 infants whose older siblings had typical development. None of these infants met the diagnostic criteria for ASD at 18, 24, and 36 months. Parents completed a questionnaire, the Brief Infant-Toddler Social Emotional Assessment (BITSEA), when the child was 12, 18, and 24 months.
Based on the results of these parent reports, unaffected siblings of the children with autism "displayed more ASD-relevant problem behaviors than the unaffected infants with typically developing siblings," Dr. Carter said. The former also appear to show "a somewhat different trajectory of these behaviors over time," with scores that were significantly different at 18 months from the low-risk group but "converging" by the time they were aged 24 months, when they appeared to be comparable.
These results support the importance of monitoring younger siblings of children diagnosed with ASD for the emergence of ASD symptoms with routine developmental screening and surveillance, "as they may benefit from early intervention services," Dr. Carter said. But even without such services, children may follow the "self-righting trajectory that takes them back on a normative developmental course," which was evident in the study, she added. (She noted that the limitations of the study included the small sample size in the Boston area. In addition, the participants, were mostly white and had higher than average annual family incomes above $65,000.)
Dr. Carter said future challenges will be to distinguish between three different groups of infants who do not meet the full criteria for an ASD diagnosis: Those manifesting symptoms that mark the beginning of the pathway toward ASD or the emergence of ASD (prodromal ASD); those whose symptoms are likely to resolve; and those who show signs of ASD that "will endure and reflect the broader autism phenotype." The primary target for early screening and detection is the identification of the prodromal group, she added.
Other studies involving high-risk siblings include the UC Davis Infant Sibling Study, which is prospectively following infants with an older sibling who has autism and infants with an older sibling who is developing typically, following the infants up to age 3 years, through the window of autism risk. The second phase of the study followed a small group of infants, enrolled between 6 and 9 months, to age 3 years, with testing that included retrospective and prospective parent ratings, and prospective examiner ratings. Most (89%) of the children who developed ASD showed a regressive onset in terms of their social communication behaviors.
Parents were able to identify those trajectories, indicating impending ASD, with prospective reports, "but not as well retrospectively" with the Autism Diagnostic Interview-Revised (ADI-R), which was accurate in only 30% of cases," said Meghan Miller, Ph.D., a postdoctoral fellow at the University of California, Davis, MIND Institute. These results suggest that while parental reports of regression on the ADI-R can be accurate, they might only pick up "the tip of the iceberg," she noted.
The findings, based on a small sample, raise concerns about the use of the ADI-R and other retrospective measures in research, but do provide "some hope for early screening using parent report data," Dr. Miller pointed out. Such reports would be more feasible than neuroimaging, eye tracking, and other sophisticated testing that could be used over several well child visits, to detect declines and help determine which children should be further evaluated further or referred for interventions, she added. Phase III of the study is currently underway.
In other sibling studies, Dr. Saulnier discussed the use of eye-tracking testing in studies that prospectively followed high-risk infants whose siblings have been diagnosed with ASD and low-risk infants with typically developing siblings.
Under eye-tracking methodology, the child watches prerecorded movies on a monitor of women acting as caregivers, singing, and talking to an infant. It is well established that when viewing a social scene, typically developing adults focus on the eye region of the face, but those with autism look less at the eyes and significantly more at the mouth, body, and objects in the social scene. Those findings have been replicated in school-aged children, adolescents, and toddlers down to aged 2 years, she noted.
In infant studies, eye-tracking testing is performed at least 10 times from birth to age 3, with vocal recordings and clinical assessments at different periods.
Summarizing the findings, Dr. Saulnier said infants at low risk who have a typical outcome show a steady fixation of eye gaze from birth. But infants who are at high risk for ASD and "develop ASD by age 3 show a rapid decline in eye fixation between 2 and 6 months of age that is more predictive of ASD than any clinical measure."
Autism cannot be diagnosed with this test alone, she said. (Most of this work was conducted at the Yale Child Study Center, before she moved to Emory, she said.)
She provided examples of a 5-month-old low-risk infant, who developed typically and focused at the eye region of the face, contrasting with another 5-month old infant, who went on to develop autism by agd 3, who was not looking at the eye region of the face, focusing on the mouth, body, and objects.
Another example she showed was an infant who had normal results at 3 and 6 months, but by 9 months, the researchers started to see a shift, which she described as the "unfolding of autism." This child was diagnosed with autism at 12 months. She added, however, that it is rare to see that symptomatology so early and pronounced.
While it would be assumed that the children who go on to develop autism manifest the lack of eye fixation from birth, another finding from eye fixation studies is that the opposite is true, and "babies who went on to develop autism actually had significantly more eye fixation in the first 2 months of life," Dr. Saulnier said.
Typically developing infants maintain this focus on the eyes, "but whatever is happening in autism to make social monitoring not as salient, they’re trailing off, and you’re seeing this derailment in this eye fixation."
Other results of eye-tracking sibling studies might provide information about a window of opportunity – at about age 9-12 months – for an intervention "that could capitalize on the potential for resilience, she noted.
In infants whose older siblings have ASD and are either unaffected or have "shadow symptoms" of autism at age 3 years, eye-tracking results indicate that after reduced eye fixation, they exhibit a "course correction" in increased eye fixation that appears to start around 9 months of age.
Why this occurs is not understood, but this observation sheds some light on a possible window of time during which something could be done, before autism fully unfolds, such as coaching strategies for parents on keeping their child engaged "to produce a course correction if it wasn’t naturally going to occur," Dr. Saulnier said.
She and her associates are now conducting a randomized, controlled study of infants at risk at 12 months, evaluating a potential way to correct the course.
Among the goals in the future is to reduce the mean age of an autism diagnosis so that, once recognized, effective interventions can be started that could affect outcomes, she said. Although autism can be reliably diagnosed by 18-24 months, the mean age of ASD diagnosis is currently about 4.5 years, she noted.
Dr. Carter disclosed that she is one of the developers of the BITSEA screening tool, used in the study she presented. Dr. Saulnier had no disclosures; the studies she presented received support from the National Institute of Mental Health, the National Institute of Child Health and Human Development, the Marcus Foundation, and the Whitehead and Woodruff Foundations. Dr. Miller said the UCSD study has been funded by NIMH, Autism Speaks, and the MINDlist.
A tutorial on recognizing the early signs of ASD, developed by the Kennedy Krieger Institute, Baltimore,is available at https://www.youtube.com/watch?v=YtvP5A5OHpU.
WASHINGTON – Studies of the younger siblings of children with autism spectrum disorders are beginning to yield information that has important implications for screening, reducing the age at diagnosis, and identifying the window of time during which still unidentified interventions might be able to affect the course, according to experts who spoke at the annual convention of the American Psychological Association.
During a symposium on early development and predictors of outcomes in infant siblings of children with autism, several experts summarized the results of studies evaluating the emergence of autism spectrum disorders (ASD) and ASD-like symptoms in the younger siblings of children with ASD, as well as tools that are being studied in high-risk sibling studies as potential methods of diagnosing ASD earlier.
The risk of ASD is 1 in 68 in the general population, but is almost 1 in 5 among the siblings of children diagnosed with ASD. An additional one in five siblings will have "shadow symptoms" of autism, which refers to children with some of the symptomatology but not enough to merit a diagnosis. In addition, another 1 in 10 will have nonautism developmental delays.
Therefore, about 50% of infant siblings of children with ASD "are vulnerable in their development to some degree, so that’s why we’re studying them so closely," said one of the speakers, Celine Saulnier, Ph.D., clinical director for research at the Marcus Autism Center, Emory University, Atlanta.
During the symposium, Alice Carter, Ph.D., professor of clinical psychology at the University of Massachusetts, Boston, provided the results of a prospective study that identified high-risk siblings who exhibited some ASD-like behaviors early on but were not diagnosed with autism at age 3.
A growing body of literature focusing on milder ASD symptoms in relatives of people diagnosed with ASD indicates that about 20%-30% of children who are at high genetic risk develop some symptoms of autism but not enough symptoms or symptoms that are severe enough to make the diagnosis, she said. This is often referred to as the broader autism phenotype (BAP), which affects an estimated 19% of unaffected siblings at age 12 months.
The prospective study followed 26 infants who had older siblings with ASD, the high-risk group, to 33 infants whose older siblings had typical development. None of these infants met the diagnostic criteria for ASD at 18, 24, and 36 months. Parents completed a questionnaire, the Brief Infant-Toddler Social Emotional Assessment (BITSEA), when the child was 12, 18, and 24 months.
Based on the results of these parent reports, unaffected siblings of the children with autism "displayed more ASD-relevant problem behaviors than the unaffected infants with typically developing siblings," Dr. Carter said. The former also appear to show "a somewhat different trajectory of these behaviors over time," with scores that were significantly different at 18 months from the low-risk group but "converging" by the time they were aged 24 months, when they appeared to be comparable.
These results support the importance of monitoring younger siblings of children diagnosed with ASD for the emergence of ASD symptoms with routine developmental screening and surveillance, "as they may benefit from early intervention services," Dr. Carter said. But even without such services, children may follow the "self-righting trajectory that takes them back on a normative developmental course," which was evident in the study, she added. (She noted that the limitations of the study included the small sample size in the Boston area. In addition, the participants, were mostly white and had higher than average annual family incomes above $65,000.)
Dr. Carter said future challenges will be to distinguish between three different groups of infants who do not meet the full criteria for an ASD diagnosis: Those manifesting symptoms that mark the beginning of the pathway toward ASD or the emergence of ASD (prodromal ASD); those whose symptoms are likely to resolve; and those who show signs of ASD that "will endure and reflect the broader autism phenotype." The primary target for early screening and detection is the identification of the prodromal group, she added.
Other studies involving high-risk siblings include the UC Davis Infant Sibling Study, which is prospectively following infants with an older sibling who has autism and infants with an older sibling who is developing typically, following the infants up to age 3 years, through the window of autism risk. The second phase of the study followed a small group of infants, enrolled between 6 and 9 months, to age 3 years, with testing that included retrospective and prospective parent ratings, and prospective examiner ratings. Most (89%) of the children who developed ASD showed a regressive onset in terms of their social communication behaviors.
Parents were able to identify those trajectories, indicating impending ASD, with prospective reports, "but not as well retrospectively" with the Autism Diagnostic Interview-Revised (ADI-R), which was accurate in only 30% of cases," said Meghan Miller, Ph.D., a postdoctoral fellow at the University of California, Davis, MIND Institute. These results suggest that while parental reports of regression on the ADI-R can be accurate, they might only pick up "the tip of the iceberg," she noted.
The findings, based on a small sample, raise concerns about the use of the ADI-R and other retrospective measures in research, but do provide "some hope for early screening using parent report data," Dr. Miller pointed out. Such reports would be more feasible than neuroimaging, eye tracking, and other sophisticated testing that could be used over several well child visits, to detect declines and help determine which children should be further evaluated further or referred for interventions, she added. Phase III of the study is currently underway.
In other sibling studies, Dr. Saulnier discussed the use of eye-tracking testing in studies that prospectively followed high-risk infants whose siblings have been diagnosed with ASD and low-risk infants with typically developing siblings.
Under eye-tracking methodology, the child watches prerecorded movies on a monitor of women acting as caregivers, singing, and talking to an infant. It is well established that when viewing a social scene, typically developing adults focus on the eye region of the face, but those with autism look less at the eyes and significantly more at the mouth, body, and objects in the social scene. Those findings have been replicated in school-aged children, adolescents, and toddlers down to aged 2 years, she noted.
In infant studies, eye-tracking testing is performed at least 10 times from birth to age 3, with vocal recordings and clinical assessments at different periods.
Summarizing the findings, Dr. Saulnier said infants at low risk who have a typical outcome show a steady fixation of eye gaze from birth. But infants who are at high risk for ASD and "develop ASD by age 3 show a rapid decline in eye fixation between 2 and 6 months of age that is more predictive of ASD than any clinical measure."
Autism cannot be diagnosed with this test alone, she said. (Most of this work was conducted at the Yale Child Study Center, before she moved to Emory, she said.)
She provided examples of a 5-month-old low-risk infant, who developed typically and focused at the eye region of the face, contrasting with another 5-month old infant, who went on to develop autism by agd 3, who was not looking at the eye region of the face, focusing on the mouth, body, and objects.
Another example she showed was an infant who had normal results at 3 and 6 months, but by 9 months, the researchers started to see a shift, which she described as the "unfolding of autism." This child was diagnosed with autism at 12 months. She added, however, that it is rare to see that symptomatology so early and pronounced.
While it would be assumed that the children who go on to develop autism manifest the lack of eye fixation from birth, another finding from eye fixation studies is that the opposite is true, and "babies who went on to develop autism actually had significantly more eye fixation in the first 2 months of life," Dr. Saulnier said.
Typically developing infants maintain this focus on the eyes, "but whatever is happening in autism to make social monitoring not as salient, they’re trailing off, and you’re seeing this derailment in this eye fixation."
Other results of eye-tracking sibling studies might provide information about a window of opportunity – at about age 9-12 months – for an intervention "that could capitalize on the potential for resilience, she noted.
In infants whose older siblings have ASD and are either unaffected or have "shadow symptoms" of autism at age 3 years, eye-tracking results indicate that after reduced eye fixation, they exhibit a "course correction" in increased eye fixation that appears to start around 9 months of age.
Why this occurs is not understood, but this observation sheds some light on a possible window of time during which something could be done, before autism fully unfolds, such as coaching strategies for parents on keeping their child engaged "to produce a course correction if it wasn’t naturally going to occur," Dr. Saulnier said.
She and her associates are now conducting a randomized, controlled study of infants at risk at 12 months, evaluating a potential way to correct the course.
Among the goals in the future is to reduce the mean age of an autism diagnosis so that, once recognized, effective interventions can be started that could affect outcomes, she said. Although autism can be reliably diagnosed by 18-24 months, the mean age of ASD diagnosis is currently about 4.5 years, she noted.
Dr. Carter disclosed that she is one of the developers of the BITSEA screening tool, used in the study she presented. Dr. Saulnier had no disclosures; the studies she presented received support from the National Institute of Mental Health, the National Institute of Child Health and Human Development, the Marcus Foundation, and the Whitehead and Woodruff Foundations. Dr. Miller said the UCSD study has been funded by NIMH, Autism Speaks, and the MINDlist.
A tutorial on recognizing the early signs of ASD, developed by the Kennedy Krieger Institute, Baltimore,is available at https://www.youtube.com/watch?v=YtvP5A5OHpU.
WASHINGTON – Studies of the younger siblings of children with autism spectrum disorders are beginning to yield information that has important implications for screening, reducing the age at diagnosis, and identifying the window of time during which still unidentified interventions might be able to affect the course, according to experts who spoke at the annual convention of the American Psychological Association.
During a symposium on early development and predictors of outcomes in infant siblings of children with autism, several experts summarized the results of studies evaluating the emergence of autism spectrum disorders (ASD) and ASD-like symptoms in the younger siblings of children with ASD, as well as tools that are being studied in high-risk sibling studies as potential methods of diagnosing ASD earlier.
The risk of ASD is 1 in 68 in the general population, but is almost 1 in 5 among the siblings of children diagnosed with ASD. An additional one in five siblings will have "shadow symptoms" of autism, which refers to children with some of the symptomatology but not enough to merit a diagnosis. In addition, another 1 in 10 will have nonautism developmental delays.
Therefore, about 50% of infant siblings of children with ASD "are vulnerable in their development to some degree, so that’s why we’re studying them so closely," said one of the speakers, Celine Saulnier, Ph.D., clinical director for research at the Marcus Autism Center, Emory University, Atlanta.
During the symposium, Alice Carter, Ph.D., professor of clinical psychology at the University of Massachusetts, Boston, provided the results of a prospective study that identified high-risk siblings who exhibited some ASD-like behaviors early on but were not diagnosed with autism at age 3.
A growing body of literature focusing on milder ASD symptoms in relatives of people diagnosed with ASD indicates that about 20%-30% of children who are at high genetic risk develop some symptoms of autism but not enough symptoms or symptoms that are severe enough to make the diagnosis, she said. This is often referred to as the broader autism phenotype (BAP), which affects an estimated 19% of unaffected siblings at age 12 months.
The prospective study followed 26 infants who had older siblings with ASD, the high-risk group, to 33 infants whose older siblings had typical development. None of these infants met the diagnostic criteria for ASD at 18, 24, and 36 months. Parents completed a questionnaire, the Brief Infant-Toddler Social Emotional Assessment (BITSEA), when the child was 12, 18, and 24 months.
Based on the results of these parent reports, unaffected siblings of the children with autism "displayed more ASD-relevant problem behaviors than the unaffected infants with typically developing siblings," Dr. Carter said. The former also appear to show "a somewhat different trajectory of these behaviors over time," with scores that were significantly different at 18 months from the low-risk group but "converging" by the time they were aged 24 months, when they appeared to be comparable.
These results support the importance of monitoring younger siblings of children diagnosed with ASD for the emergence of ASD symptoms with routine developmental screening and surveillance, "as they may benefit from early intervention services," Dr. Carter said. But even without such services, children may follow the "self-righting trajectory that takes them back on a normative developmental course," which was evident in the study, she added. (She noted that the limitations of the study included the small sample size in the Boston area. In addition, the participants, were mostly white and had higher than average annual family incomes above $65,000.)
Dr. Carter said future challenges will be to distinguish between three different groups of infants who do not meet the full criteria for an ASD diagnosis: Those manifesting symptoms that mark the beginning of the pathway toward ASD or the emergence of ASD (prodromal ASD); those whose symptoms are likely to resolve; and those who show signs of ASD that "will endure and reflect the broader autism phenotype." The primary target for early screening and detection is the identification of the prodromal group, she added.
Other studies involving high-risk siblings include the UC Davis Infant Sibling Study, which is prospectively following infants with an older sibling who has autism and infants with an older sibling who is developing typically, following the infants up to age 3 years, through the window of autism risk. The second phase of the study followed a small group of infants, enrolled between 6 and 9 months, to age 3 years, with testing that included retrospective and prospective parent ratings, and prospective examiner ratings. Most (89%) of the children who developed ASD showed a regressive onset in terms of their social communication behaviors.
Parents were able to identify those trajectories, indicating impending ASD, with prospective reports, "but not as well retrospectively" with the Autism Diagnostic Interview-Revised (ADI-R), which was accurate in only 30% of cases," said Meghan Miller, Ph.D., a postdoctoral fellow at the University of California, Davis, MIND Institute. These results suggest that while parental reports of regression on the ADI-R can be accurate, they might only pick up "the tip of the iceberg," she noted.
The findings, based on a small sample, raise concerns about the use of the ADI-R and other retrospective measures in research, but do provide "some hope for early screening using parent report data," Dr. Miller pointed out. Such reports would be more feasible than neuroimaging, eye tracking, and other sophisticated testing that could be used over several well child visits, to detect declines and help determine which children should be further evaluated further or referred for interventions, she added. Phase III of the study is currently underway.
In other sibling studies, Dr. Saulnier discussed the use of eye-tracking testing in studies that prospectively followed high-risk infants whose siblings have been diagnosed with ASD and low-risk infants with typically developing siblings.
Under eye-tracking methodology, the child watches prerecorded movies on a monitor of women acting as caregivers, singing, and talking to an infant. It is well established that when viewing a social scene, typically developing adults focus on the eye region of the face, but those with autism look less at the eyes and significantly more at the mouth, body, and objects in the social scene. Those findings have been replicated in school-aged children, adolescents, and toddlers down to aged 2 years, she noted.
In infant studies, eye-tracking testing is performed at least 10 times from birth to age 3, with vocal recordings and clinical assessments at different periods.
Summarizing the findings, Dr. Saulnier said infants at low risk who have a typical outcome show a steady fixation of eye gaze from birth. But infants who are at high risk for ASD and "develop ASD by age 3 show a rapid decline in eye fixation between 2 and 6 months of age that is more predictive of ASD than any clinical measure."
Autism cannot be diagnosed with this test alone, she said. (Most of this work was conducted at the Yale Child Study Center, before she moved to Emory, she said.)
She provided examples of a 5-month-old low-risk infant, who developed typically and focused at the eye region of the face, contrasting with another 5-month old infant, who went on to develop autism by agd 3, who was not looking at the eye region of the face, focusing on the mouth, body, and objects.
Another example she showed was an infant who had normal results at 3 and 6 months, but by 9 months, the researchers started to see a shift, which she described as the "unfolding of autism." This child was diagnosed with autism at 12 months. She added, however, that it is rare to see that symptomatology so early and pronounced.
While it would be assumed that the children who go on to develop autism manifest the lack of eye fixation from birth, another finding from eye fixation studies is that the opposite is true, and "babies who went on to develop autism actually had significantly more eye fixation in the first 2 months of life," Dr. Saulnier said.
Typically developing infants maintain this focus on the eyes, "but whatever is happening in autism to make social monitoring not as salient, they’re trailing off, and you’re seeing this derailment in this eye fixation."
Other results of eye-tracking sibling studies might provide information about a window of opportunity – at about age 9-12 months – for an intervention "that could capitalize on the potential for resilience, she noted.
In infants whose older siblings have ASD and are either unaffected or have "shadow symptoms" of autism at age 3 years, eye-tracking results indicate that after reduced eye fixation, they exhibit a "course correction" in increased eye fixation that appears to start around 9 months of age.
Why this occurs is not understood, but this observation sheds some light on a possible window of time during which something could be done, before autism fully unfolds, such as coaching strategies for parents on keeping their child engaged "to produce a course correction if it wasn’t naturally going to occur," Dr. Saulnier said.
She and her associates are now conducting a randomized, controlled study of infants at risk at 12 months, evaluating a potential way to correct the course.
Among the goals in the future is to reduce the mean age of an autism diagnosis so that, once recognized, effective interventions can be started that could affect outcomes, she said. Although autism can be reliably diagnosed by 18-24 months, the mean age of ASD diagnosis is currently about 4.5 years, she noted.
Dr. Carter disclosed that she is one of the developers of the BITSEA screening tool, used in the study she presented. Dr. Saulnier had no disclosures; the studies she presented received support from the National Institute of Mental Health, the National Institute of Child Health and Human Development, the Marcus Foundation, and the Whitehead and Woodruff Foundations. Dr. Miller said the UCSD study has been funded by NIMH, Autism Speaks, and the MINDlist.
A tutorial on recognizing the early signs of ASD, developed by the Kennedy Krieger Institute, Baltimore,is available at https://www.youtube.com/watch?v=YtvP5A5OHpU.
EXPERT ANAYSIS FROM THE 2014 APA CONVENTION
Apixaban approved for treating DVT, pulmonary embolism and reducing risk of recurrence
The oral factor Xa inhibitor apixaban is now approved for the treatment of deep vein thrombosis and pulmonary embolism, and for reducing the risk of recurrent DVT and PE following initial treatment, the manufacturers have announced.
This approval is based on the results of the AMPLIFY and AMPLIFY-EXT studies, according to the statement issued by Bristol-Myers Squibb and Pfizer Aug. 21.
Apixaban, initially approved in 2012 and marketed as Eliquis, is already approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of DVT, "which may lead to PE," after hip or knee surgery. The recommended dose for the treatment of DVT and PE is 10 mg twice a day for 7 days, followed by 5 mg twice a day. The recommended dose for reducing the risk for recurrent DVT and PE, after initial therapy, is 2.5 mg twice a day.
AMPLIFY was a noninferiority study of about 5,200 patients with symptomatic DVT or PE. It compared apixaban (10 mg twice a day for 1 week, followed by 5 mg twice a day for 6 months) with standard care using enoxaparin (1 mg/kg administered subcutaneously twice a day for at least 5 days [until the international normalized ratio was at least 2], followed by warfarin for at least 5 days [target INR range of 2.0-3.0] for 6 months). The primary efficacy endpoint, a composite of recurrent symptomatic VTE or VTE-related death over 6 months, was comparable in the two groups: 2.3% among those on apixaban and 2.7% among those on enoxaparin/warfarin, according to the prescribing information.
The primary safety endpoint, major bleeding, was 0.6% among those on apixaban vs. 1.8% among those on enoxaparin/warfarin, a statistically significant difference. Rates of clinically relevant nonmajor bleeding, a secondary safety endpoint, was 3.9% among those on apixaban vs. 8% among those on enoxaparin/warfarin.
In Amplify-EXT, almost 2,500 patients who had received anticoagulant therapy for DVT and/or PE for 6-12 months and had not had a recurrent event were randomized to treatment with apixaban 2.5 or 5 mg twice a day, or placebo, followed for a mean of almost 1 year. The rate of recurrent VTE or all-cause death was 3.8% among those on 2.5 mg twice daily and 4.2% among those on 5 mg twice daily, vs. 11.6% among those on placebo; the effects of both doses were significantly more effective in reducing risk than was placebo.
In this study, the rate of bleeding-related adverse reactions was 13.3% among those on apixaban vs. 8.7% among those on placebo. The rate of major bleeding was 0.2% among those on the 2.5 mg twice-daily dose and 0.1% among those on the 5 mg twice-daily dose, vs. 0.5% among those on placebo.
The apixaban label includes a boxed warning about an increased risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture while on the drug.
Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program.
The oral factor Xa inhibitor apixaban is now approved for the treatment of deep vein thrombosis and pulmonary embolism, and for reducing the risk of recurrent DVT and PE following initial treatment, the manufacturers have announced.
This approval is based on the results of the AMPLIFY and AMPLIFY-EXT studies, according to the statement issued by Bristol-Myers Squibb and Pfizer Aug. 21.
Apixaban, initially approved in 2012 and marketed as Eliquis, is already approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of DVT, "which may lead to PE," after hip or knee surgery. The recommended dose for the treatment of DVT and PE is 10 mg twice a day for 7 days, followed by 5 mg twice a day. The recommended dose for reducing the risk for recurrent DVT and PE, after initial therapy, is 2.5 mg twice a day.
AMPLIFY was a noninferiority study of about 5,200 patients with symptomatic DVT or PE. It compared apixaban (10 mg twice a day for 1 week, followed by 5 mg twice a day for 6 months) with standard care using enoxaparin (1 mg/kg administered subcutaneously twice a day for at least 5 days [until the international normalized ratio was at least 2], followed by warfarin for at least 5 days [target INR range of 2.0-3.0] for 6 months). The primary efficacy endpoint, a composite of recurrent symptomatic VTE or VTE-related death over 6 months, was comparable in the two groups: 2.3% among those on apixaban and 2.7% among those on enoxaparin/warfarin, according to the prescribing information.
The primary safety endpoint, major bleeding, was 0.6% among those on apixaban vs. 1.8% among those on enoxaparin/warfarin, a statistically significant difference. Rates of clinically relevant nonmajor bleeding, a secondary safety endpoint, was 3.9% among those on apixaban vs. 8% among those on enoxaparin/warfarin.
In Amplify-EXT, almost 2,500 patients who had received anticoagulant therapy for DVT and/or PE for 6-12 months and had not had a recurrent event were randomized to treatment with apixaban 2.5 or 5 mg twice a day, or placebo, followed for a mean of almost 1 year. The rate of recurrent VTE or all-cause death was 3.8% among those on 2.5 mg twice daily and 4.2% among those on 5 mg twice daily, vs. 11.6% among those on placebo; the effects of both doses were significantly more effective in reducing risk than was placebo.
In this study, the rate of bleeding-related adverse reactions was 13.3% among those on apixaban vs. 8.7% among those on placebo. The rate of major bleeding was 0.2% among those on the 2.5 mg twice-daily dose and 0.1% among those on the 5 mg twice-daily dose, vs. 0.5% among those on placebo.
The apixaban label includes a boxed warning about an increased risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture while on the drug.
Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program.
The oral factor Xa inhibitor apixaban is now approved for the treatment of deep vein thrombosis and pulmonary embolism, and for reducing the risk of recurrent DVT and PE following initial treatment, the manufacturers have announced.
This approval is based on the results of the AMPLIFY and AMPLIFY-EXT studies, according to the statement issued by Bristol-Myers Squibb and Pfizer Aug. 21.
Apixaban, initially approved in 2012 and marketed as Eliquis, is already approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of DVT, "which may lead to PE," after hip or knee surgery. The recommended dose for the treatment of DVT and PE is 10 mg twice a day for 7 days, followed by 5 mg twice a day. The recommended dose for reducing the risk for recurrent DVT and PE, after initial therapy, is 2.5 mg twice a day.
AMPLIFY was a noninferiority study of about 5,200 patients with symptomatic DVT or PE. It compared apixaban (10 mg twice a day for 1 week, followed by 5 mg twice a day for 6 months) with standard care using enoxaparin (1 mg/kg administered subcutaneously twice a day for at least 5 days [until the international normalized ratio was at least 2], followed by warfarin for at least 5 days [target INR range of 2.0-3.0] for 6 months). The primary efficacy endpoint, a composite of recurrent symptomatic VTE or VTE-related death over 6 months, was comparable in the two groups: 2.3% among those on apixaban and 2.7% among those on enoxaparin/warfarin, according to the prescribing information.
The primary safety endpoint, major bleeding, was 0.6% among those on apixaban vs. 1.8% among those on enoxaparin/warfarin, a statistically significant difference. Rates of clinically relevant nonmajor bleeding, a secondary safety endpoint, was 3.9% among those on apixaban vs. 8% among those on enoxaparin/warfarin.
In Amplify-EXT, almost 2,500 patients who had received anticoagulant therapy for DVT and/or PE for 6-12 months and had not had a recurrent event were randomized to treatment with apixaban 2.5 or 5 mg twice a day, or placebo, followed for a mean of almost 1 year. The rate of recurrent VTE or all-cause death was 3.8% among those on 2.5 mg twice daily and 4.2% among those on 5 mg twice daily, vs. 11.6% among those on placebo; the effects of both doses were significantly more effective in reducing risk than was placebo.
In this study, the rate of bleeding-related adverse reactions was 13.3% among those on apixaban vs. 8.7% among those on placebo. The rate of major bleeding was 0.2% among those on the 2.5 mg twice-daily dose and 0.1% among those on the 5 mg twice-daily dose, vs. 0.5% among those on placebo.
The apixaban label includes a boxed warning about an increased risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture while on the drug.
Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program.
Bariatric Surgery Results may Include Improved Sexual Function for Female Patients
WASHINGTON – Obese women experienced significant improvements in sexual function over 6-24 months after bariatric surgery in a multistudy review, indicating that this outcome should be listed among the possible benefits of surgery in this patient population, Dr. Kalaivani Ramalingam said at a joint annual meeting of the American Urogynecologic Society.
In a review of studies published between 1996 and 2013, Dr. Ramalingam of the department of gynecology at Kingston Hospital, Kingston upon Thames, England, and her associates identified five original studies of 254 obese women undergoing bariatric surgery that reported Female Sexual Function Index (FSFI) scores before and after surgery. Studies of nonsurgical weight loss treatments and those that included both men and women were not included. The FSFI evaluates sexual function in six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain.
Patients in the studies had statistically significant reductions in body mass index over 6-24 months of follow-up (P = .001). In one of the five studies, which enrolled 36 patients, FSFI scores did not improve after surgery.
But in the remaining four studies, there were statistically significant improvements in the overall FSFI scores after surgery (P = .003), Dr. Ramalingam said. In addition, statistically significant improvements in all domains of the score were observed after surgery: increased desire (P = .005), arousal (P = .001), lubrication (P = .003), satisfaction (P = .012) and orgasm (P =.003) – and a decrease in the levels of pain during intercourse (P = .014).
She noted that in one of the five studies, sexual function improved in women with pelvic floor dysfunction and that further studies in this specific group of patients are needed to evaluate the effect of surgery among obese women who are undergoing bariatric surgery and have pelvic floor dysfunction.
An estimated 51% of female bariatric surgery patients report sexual dysfunction, she said.
Dr. Ramalingam and one of her coauthors had no relevant disclosures. The third author disclosed being a speaker for and receiving honoraria from Pfizer, Astellas, and Shire; and serving on an advisory committee for Allergan.
WASHINGTON – Obese women experienced significant improvements in sexual function over 6-24 months after bariatric surgery in a multistudy review, indicating that this outcome should be listed among the possible benefits of surgery in this patient population, Dr. Kalaivani Ramalingam said at a joint annual meeting of the American Urogynecologic Society.
In a review of studies published between 1996 and 2013, Dr. Ramalingam of the department of gynecology at Kingston Hospital, Kingston upon Thames, England, and her associates identified five original studies of 254 obese women undergoing bariatric surgery that reported Female Sexual Function Index (FSFI) scores before and after surgery. Studies of nonsurgical weight loss treatments and those that included both men and women were not included. The FSFI evaluates sexual function in six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain.
Patients in the studies had statistically significant reductions in body mass index over 6-24 months of follow-up (P = .001). In one of the five studies, which enrolled 36 patients, FSFI scores did not improve after surgery.
But in the remaining four studies, there were statistically significant improvements in the overall FSFI scores after surgery (P = .003), Dr. Ramalingam said. In addition, statistically significant improvements in all domains of the score were observed after surgery: increased desire (P = .005), arousal (P = .001), lubrication (P = .003), satisfaction (P = .012) and orgasm (P =.003) – and a decrease in the levels of pain during intercourse (P = .014).
She noted that in one of the five studies, sexual function improved in women with pelvic floor dysfunction and that further studies in this specific group of patients are needed to evaluate the effect of surgery among obese women who are undergoing bariatric surgery and have pelvic floor dysfunction.
An estimated 51% of female bariatric surgery patients report sexual dysfunction, she said.
Dr. Ramalingam and one of her coauthors had no relevant disclosures. The third author disclosed being a speaker for and receiving honoraria from Pfizer, Astellas, and Shire; and serving on an advisory committee for Allergan.
WASHINGTON – Obese women experienced significant improvements in sexual function over 6-24 months after bariatric surgery in a multistudy review, indicating that this outcome should be listed among the possible benefits of surgery in this patient population, Dr. Kalaivani Ramalingam said at a joint annual meeting of the American Urogynecologic Society.
In a review of studies published between 1996 and 2013, Dr. Ramalingam of the department of gynecology at Kingston Hospital, Kingston upon Thames, England, and her associates identified five original studies of 254 obese women undergoing bariatric surgery that reported Female Sexual Function Index (FSFI) scores before and after surgery. Studies of nonsurgical weight loss treatments and those that included both men and women were not included. The FSFI evaluates sexual function in six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain.
Patients in the studies had statistically significant reductions in body mass index over 6-24 months of follow-up (P = .001). In one of the five studies, which enrolled 36 patients, FSFI scores did not improve after surgery.
But in the remaining four studies, there were statistically significant improvements in the overall FSFI scores after surgery (P = .003), Dr. Ramalingam said. In addition, statistically significant improvements in all domains of the score were observed after surgery: increased desire (P = .005), arousal (P = .001), lubrication (P = .003), satisfaction (P = .012) and orgasm (P =.003) – and a decrease in the levels of pain during intercourse (P = .014).
She noted that in one of the five studies, sexual function improved in women with pelvic floor dysfunction and that further studies in this specific group of patients are needed to evaluate the effect of surgery among obese women who are undergoing bariatric surgery and have pelvic floor dysfunction.
An estimated 51% of female bariatric surgery patients report sexual dysfunction, she said.
Dr. Ramalingam and one of her coauthors had no relevant disclosures. The third author disclosed being a speaker for and receiving honoraria from Pfizer, Astellas, and Shire; and serving on an advisory committee for Allergan.
AT THE AUGS ANNUAL MEETING
Lilly’s insulin glargine tentatively approved, pending patent litigation
The Food and Drug Administration has granted a "tentative" approval to the insulin glargine product developed by Boehringer Ingelheim Pharmaceuticals and Eli Lilly, according to an announcement by the companies issued Aug. 18.
The indication for the basal insulin, which has the trade name Basaglar, is to improve glycemic control in adults with type 2 diabetes and in combination with mealtime insulin in adult and pediatric patients with type 1 diabetes.
"With a tentative approval, the FDA has determined that Basaglar meets all of the regulatory requirements for approval, but it is subject to an automatic stay of up to 30 months as a result of litigation filed by Sanofi, claiming patent infringement," the Lilly statement says. Under the Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman act), "the FDA cannot give final approval until the end of the 30-month period in mid-2016, unless the court finds in favor of Lilly earlier," according to the statement.
The statement says that Basaglar "has the same amino acid sequence as the currently marketed insulin glargine product."
In Europe, where the product is considered a biosimilar, the Committee for Medicinal Products for Human Use (CHMP), has issued a positive recommendation for this product. The CHMP is a division of the European Medicines Agency, the equivalent of the FDA; the EMA defines a biosimilar as "a biological medicine that is similar to another biological medicine" that has already been authorized for use in Europe.
Sanofi’s insulin glargine was approved in 2000 and is marketed as Lantus.
The Food and Drug Administration has granted a "tentative" approval to the insulin glargine product developed by Boehringer Ingelheim Pharmaceuticals and Eli Lilly, according to an announcement by the companies issued Aug. 18.
The indication for the basal insulin, which has the trade name Basaglar, is to improve glycemic control in adults with type 2 diabetes and in combination with mealtime insulin in adult and pediatric patients with type 1 diabetes.
"With a tentative approval, the FDA has determined that Basaglar meets all of the regulatory requirements for approval, but it is subject to an automatic stay of up to 30 months as a result of litigation filed by Sanofi, claiming patent infringement," the Lilly statement says. Under the Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman act), "the FDA cannot give final approval until the end of the 30-month period in mid-2016, unless the court finds in favor of Lilly earlier," according to the statement.
The statement says that Basaglar "has the same amino acid sequence as the currently marketed insulin glargine product."
In Europe, where the product is considered a biosimilar, the Committee for Medicinal Products for Human Use (CHMP), has issued a positive recommendation for this product. The CHMP is a division of the European Medicines Agency, the equivalent of the FDA; the EMA defines a biosimilar as "a biological medicine that is similar to another biological medicine" that has already been authorized for use in Europe.
Sanofi’s insulin glargine was approved in 2000 and is marketed as Lantus.
The Food and Drug Administration has granted a "tentative" approval to the insulin glargine product developed by Boehringer Ingelheim Pharmaceuticals and Eli Lilly, according to an announcement by the companies issued Aug. 18.
The indication for the basal insulin, which has the trade name Basaglar, is to improve glycemic control in adults with type 2 diabetes and in combination with mealtime insulin in adult and pediatric patients with type 1 diabetes.
"With a tentative approval, the FDA has determined that Basaglar meets all of the regulatory requirements for approval, but it is subject to an automatic stay of up to 30 months as a result of litigation filed by Sanofi, claiming patent infringement," the Lilly statement says. Under the Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman act), "the FDA cannot give final approval until the end of the 30-month period in mid-2016, unless the court finds in favor of Lilly earlier," according to the statement.
The statement says that Basaglar "has the same amino acid sequence as the currently marketed insulin glargine product."
In Europe, where the product is considered a biosimilar, the Committee for Medicinal Products for Human Use (CHMP), has issued a positive recommendation for this product. The CHMP is a division of the European Medicines Agency, the equivalent of the FDA; the EMA defines a biosimilar as "a biological medicine that is similar to another biological medicine" that has already been authorized for use in Europe.
Sanofi’s insulin glargine was approved in 2000 and is marketed as Lantus.
