Mary Ann Moon

Intracoronary delivery of bone marrow mononuclear cells to the infarct zone of patients who have undergone percutaneous coronary intervention following an ST-segment elevation myocardial infarction did not improve left ventricular function at 6 months in the TIME trial.

The trial was designed to examine the difference in effect of infusing the bone marrow mononuclear cells (BMCs) into the infarct-related artery at 7 days after PCI and at 3 days, Dr. Jay H. Traverse said at the American Heart Association meeting.

Unfortunately, neither of these approaches were any better than placebo infusion at improving the recovery of left ventricular function, improving left ventricular volume, or reducing infarct size at 6 months’ follow-up in this double-blind Timing in Myocardial Infarction Evaluation (TIME) clinical trial, reported Dr. Traverse, of the Minneapolis Heart Institute at Abbott Northwestern Hospital.

"However, long-term follow-up of these patients and the development of new composite end points may still reveal a role for this cell type after AMI [acute myocardial infarction]," Dr. Traverse and his associates said in an article published online simultaneously with his presentation (JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.28726]).

Recent research indicates that the timing of BMC infusion after PCI due to ST-segment elevation myocardial infarction (STEMI) might be critical. In the days following STEMI, there are significant temporal changes in the release of cytokines and growth factors "that may support stem-cell homing and angiogenesis, leading to improved cell survival and engraftment," they noted.

In the TIME trial, a total of 132 high-risk patients were enrolled during a 3-year period after they had experienced STEMI, shown a left ventricular ejection fraction (LVEF) of 45% or less, and were slated for PCI with stenting. These subjects were randomly assigned to have stem cell therapy on either day 3 or day 7 after PCI. After some of these patients were excluded or withdrawn from the study, the remaining 120 patients underwent a second randomization to receive either the autologous BMCs (79 patients) or placebo infusions (41 patients).

The primary end points of TIME were changes in global and regional left ventricular function on MRI scanning at 6 months post PCI. There were no significant differences in these outcomes between subjects who received stem-cell therapy 3 days after PCI and those who received it 7 days after PCI, the investigators reported. There also were no significant differences among the study groups in secondary outcomes such as reduction in infarct volume or change in ventricular volumes.

However, there also were no significant differences in any outcomes between subjects who received active BMCs and those who received placebo infusions.

Dr. Traverse reported no conflicts.

Intracoronary delivery of bone marrow mononuclear cells to the infarct zone of patients who have undergone percutaneous coronary intervention following an ST-segment elevation myocardial infarction did not improve left ventricular function at 6 months in the TIME trial.

The trial was designed to examine the difference in effect of infusing the bone marrow mononuclear cells (BMCs) into the infarct-related artery at 7 days after PCI and at 3 days, Dr. Jay H. Traverse said at the American Heart Association meeting.

Unfortunately, neither of these approaches were any better than placebo infusion at improving the recovery of left ventricular function, improving left ventricular volume, or reducing infarct size at 6 months’ follow-up in this double-blind Timing in Myocardial Infarction Evaluation (TIME) clinical trial, reported Dr. Traverse, of the Minneapolis Heart Institute at Abbott Northwestern Hospital.

"However, long-term follow-up of these patients and the development of new composite end points may still reveal a role for this cell type after AMI [acute myocardial infarction]," Dr. Traverse and his associates said in an article published online simultaneously with his presentation (JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.28726]).

Recent research indicates that the timing of BMC infusion after PCI due to ST-segment elevation myocardial infarction (STEMI) might be critical. In the days following STEMI, there are significant temporal changes in the release of cytokines and growth factors "that may support stem-cell homing and angiogenesis, leading to improved cell survival and engraftment," they noted.

In the TIME trial, a total of 132 high-risk patients were enrolled during a 3-year period after they had experienced STEMI, shown a left ventricular ejection fraction (LVEF) of 45% or less, and were slated for PCI with stenting. These subjects were randomly assigned to have stem cell therapy on either day 3 or day 7 after PCI. After some of these patients were excluded or withdrawn from the study, the remaining 120 patients underwent a second randomization to receive either the autologous BMCs (79 patients) or placebo infusions (41 patients).

The primary end points of TIME were changes in global and regional left ventricular function on MRI scanning at 6 months post PCI. There were no significant differences in these outcomes between subjects who received stem-cell therapy 3 days after PCI and those who received it 7 days after PCI, the investigators reported. There also were no significant differences among the study groups in secondary outcomes such as reduction in infarct volume or change in ventricular volumes.

However, there also were no significant differences in any outcomes between subjects who received active BMCs and those who received placebo infusions.

Dr. Traverse reported no conflicts.

Intracoronary delivery of bone marrow mononuclear cells to the infarct zone of patients who have undergone percutaneous coronary intervention following an ST-segment elevation myocardial infarction did not improve left ventricular function at 6 months in the TIME trial.

The trial was designed to examine the difference in effect of infusing the bone marrow mononuclear cells (BMCs) into the infarct-related artery at 7 days after PCI and at 3 days, Dr. Jay H. Traverse said at the American Heart Association meeting.

Unfortunately, neither of these approaches were any better than placebo infusion at improving the recovery of left ventricular function, improving left ventricular volume, or reducing infarct size at 6 months’ follow-up in this double-blind Timing in Myocardial Infarction Evaluation (TIME) clinical trial, reported Dr. Traverse, of the Minneapolis Heart Institute at Abbott Northwestern Hospital.

"However, long-term follow-up of these patients and the development of new composite end points may still reveal a role for this cell type after AMI [acute myocardial infarction]," Dr. Traverse and his associates said in an article published online simultaneously with his presentation (JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.28726]).

Recent research indicates that the timing of BMC infusion after PCI due to ST-segment elevation myocardial infarction (STEMI) might be critical. In the days following STEMI, there are significant temporal changes in the release of cytokines and growth factors "that may support stem-cell homing and angiogenesis, leading to improved cell survival and engraftment," they noted.

In the TIME trial, a total of 132 high-risk patients were enrolled during a 3-year period after they had experienced STEMI, shown a left ventricular ejection fraction (LVEF) of 45% or less, and were slated for PCI with stenting. These subjects were randomly assigned to have stem cell therapy on either day 3 or day 7 after PCI. After some of these patients were excluded or withdrawn from the study, the remaining 120 patients underwent a second randomization to receive either the autologous BMCs (79 patients) or placebo infusions (41 patients).

The primary end points of TIME were changes in global and regional left ventricular function on MRI scanning at 6 months post PCI. There were no significant differences in these outcomes between subjects who received stem-cell therapy 3 days after PCI and those who received it 7 days after PCI, the investigators reported. There also were no significant differences among the study groups in secondary outcomes such as reduction in infarct volume or change in ventricular volumes.

However, there also were no significant differences in any outcomes between subjects who received active BMCs and those who received placebo infusions.

Dr. Traverse reported no conflicts.

The levonorgestrel-releasing intrauterine system is superior to a variety of medical therapies at improving quality of life for women with menorrhagia, according to a report published online Jan. 10 in the New England Journal of Medicine.

In a randomized clinical trial that followed 571 subjects for 2 years, levonorgestrel-IUS (Mirena, Bayer HealthCare) was more effective than the usual medical treatments at combating the adverse effects of heavy menstrual bleeding on women’s daily lives, as well as at improving their psychological and physical well-being, said Dr. Janesh Gupta of the University of Birmingham (England) and his associates for the ECLIPSE (Effectiveness and Cost-Effectiveness of Levonorgestrel-Containing Intrauterine System in Primary Care against Standard Treatment for Menorrhagia) Trial Collaborative Group.

Previous studies gauging the effectiveness of various treatments for menorrhagia have focused on their control of menstrual blood loss, but there is great discordance between objective measures of blood loss and women’s perception of the amount they bleed. "Only about half the women with menorrhagia who present to health care providers have blood loss greater than the traditional threshold of 80 mL per menstrual cycle," the investigators wrote.

Moreover, the amount of bleeding doesn’t correlate with a woman’s experience of what is burdensome for her. "Clinical guidelines now advocate a shift in emphasis from the amount of menstrual blood loss to the more patient-centered definition of heavy menstrual bleeding that interferes with a woman’s physical, emotional, and social life," they noted.

Dr. Gupta and his colleagues compared levonorgestrel-IUS with standard medical therapies using these factors rather than the amount of blood loss as the primary outcome measures. They assessed the effect of menorrhagia on six domains of daily life – practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships – using the condition-specific Menorrhagia Multi-Attribute Scale (MMAS). Scores on the MMAS can range from 0 ("severely affected") to 100 ("not affected at all").

The researchers also assessed general health-related quality of life using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), which also has a 100-point scoring system, and the EuroQOL Group 5-Dimension Self-Report Questionnaire (EQ-5D), which has two 100-point scores. They used the Sexual Activity Questionnaire to measure pleasure and discomfort associated with sex, as well as the frequency of sexual activity, relative to the patient’s usual levels.

The study subjects were women aged 25-50 years who presented with menorrhagia to their primary care physicians at 63 U.K. medical centers during a 4-year period. These women were randomly assigned to receive either levonorgestrel-IUS (285 subjects) or medical therapies (286 subjects) such as mefenamic acid, tranexamic acid, norethindrone, estrogen-progestogen OCs, progesterone-only OCs, medroxyprogesterone acetate injections, or some combination of these. The medical treatments were chosen by the patient and her physician according to her contraceptive needs and wishes regarding hormonal therapy.

The two study groups were balanced with respect to subject age (younger than or older than 35 years), body-mass index (over or under 25), duration of symptoms (less than or more than 1 year), need for contraception (yes or no), and the presence or absence of menstrual pain.

The primary outcome measure was improvement on MMAS scores after 2 years of follow-up. These scores improved in all patients, but the improvement in all six domains of the MMAS was significantly greater among women in the levonorgestrel-IUS group, not just at 2 years but at every time point that was assessed.

The mean difference between baseline and final MMAS scores was 13.4 points for these women, a change that was both statistically significant and clinically meaningful. This represents an improvement from being substantially affected to minimally affected by menorrhagia, or from being minimally affected to being completely unaffected.

A sensitivity analysis was performed that included only study subjects who did not cross over from their assigned treatment to a different treatment. This analysis confirmed the findings of the main analysis, showing an improvement of 17.8 points in MMAS scores in women given levonorgestrel-IUS.

Similarly, scores on the SF-36 favored levonorgestrel-IUS over standard medical therapy at all time points in seven of the eight domains assessed, the investigators said (N. Engl. J. Med. 2013 Jan. 10 [doi:10.1056/NEJMoa1204724]).

The two study groups did not differ significantly on EQ-5D scores or on any factor in the Sexual Activity Questionnaire.

The frequency of surgical interventions for menorrhagia during follow-up also did not differ significantly, with 6% of both study groups undergoing hysterectomy; endometrial ablation was performed in 4% of the levonorgestrel-IUS patients and 6% of the medical treatment–group patients.

Given that menorrhagia often persists for years, longer follow-up of these study subjects is planned. Additional intention-to-treat analyses will be done at 5 and 10 years, Dr. Gupta and his associates said.

This study was supported by the National Institute of Health Research Health Technology Assessment Programme. Dr. Gupta reported ties to Hodder Arnold Publishing, Ethicon Gynecare, and Femcare-Nikomed.

The levonorgestrel-releasing intrauterine system is superior to a variety of medical therapies at improving quality of life for women with menorrhagia, according to a report published online Jan. 10 in the New England Journal of Medicine.

In a randomized clinical trial that followed 571 subjects for 2 years, levonorgestrel-IUS (Mirena, Bayer HealthCare) was more effective than the usual medical treatments at combating the adverse effects of heavy menstrual bleeding on women’s daily lives, as well as at improving their psychological and physical well-being, said Dr. Janesh Gupta of the University of Birmingham (England) and his associates for the ECLIPSE (Effectiveness and Cost-Effectiveness of Levonorgestrel-Containing Intrauterine System in Primary Care against Standard Treatment for Menorrhagia) Trial Collaborative Group.

Previous studies gauging the effectiveness of various treatments for menorrhagia have focused on their control of menstrual blood loss, but there is great discordance between objective measures of blood loss and women’s perception of the amount they bleed. "Only about half the women with menorrhagia who present to health care providers have blood loss greater than the traditional threshold of 80 mL per menstrual cycle," the investigators wrote.

Moreover, the amount of bleeding doesn’t correlate with a woman’s experience of what is burdensome for her. "Clinical guidelines now advocate a shift in emphasis from the amount of menstrual blood loss to the more patient-centered definition of heavy menstrual bleeding that interferes with a woman’s physical, emotional, and social life," they noted.

Dr. Gupta and his colleagues compared levonorgestrel-IUS with standard medical therapies using these factors rather than the amount of blood loss as the primary outcome measures. They assessed the effect of menorrhagia on six domains of daily life – practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships – using the condition-specific Menorrhagia Multi-Attribute Scale (MMAS). Scores on the MMAS can range from 0 ("severely affected") to 100 ("not affected at all").

The researchers also assessed general health-related quality of life using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), which also has a 100-point scoring system, and the EuroQOL Group 5-Dimension Self-Report Questionnaire (EQ-5D), which has two 100-point scores. They used the Sexual Activity Questionnaire to measure pleasure and discomfort associated with sex, as well as the frequency of sexual activity, relative to the patient’s usual levels.

The study subjects were women aged 25-50 years who presented with menorrhagia to their primary care physicians at 63 U.K. medical centers during a 4-year period. These women were randomly assigned to receive either levonorgestrel-IUS (285 subjects) or medical therapies (286 subjects) such as mefenamic acid, tranexamic acid, norethindrone, estrogen-progestogen OCs, progesterone-only OCs, medroxyprogesterone acetate injections, or some combination of these. The medical treatments were chosen by the patient and her physician according to her contraceptive needs and wishes regarding hormonal therapy.

The two study groups were balanced with respect to subject age (younger than or older than 35 years), body-mass index (over or under 25), duration of symptoms (less than or more than 1 year), need for contraception (yes or no), and the presence or absence of menstrual pain.

The primary outcome measure was improvement on MMAS scores after 2 years of follow-up. These scores improved in all patients, but the improvement in all six domains of the MMAS was significantly greater among women in the levonorgestrel-IUS group, not just at 2 years but at every time point that was assessed.

The mean difference between baseline and final MMAS scores was 13.4 points for these women, a change that was both statistically significant and clinically meaningful. This represents an improvement from being substantially affected to minimally affected by menorrhagia, or from being minimally affected to being completely unaffected.

A sensitivity analysis was performed that included only study subjects who did not cross over from their assigned treatment to a different treatment. This analysis confirmed the findings of the main analysis, showing an improvement of 17.8 points in MMAS scores in women given levonorgestrel-IUS.

Similarly, scores on the SF-36 favored levonorgestrel-IUS over standard medical therapy at all time points in seven of the eight domains assessed, the investigators said (N. Engl. J. Med. 2013 Jan. 10 [doi:10.1056/NEJMoa1204724]).

The two study groups did not differ significantly on EQ-5D scores or on any factor in the Sexual Activity Questionnaire.

The frequency of surgical interventions for menorrhagia during follow-up also did not differ significantly, with 6% of both study groups undergoing hysterectomy; endometrial ablation was performed in 4% of the levonorgestrel-IUS patients and 6% of the medical treatment–group patients.

Given that menorrhagia often persists for years, longer follow-up of these study subjects is planned. Additional intention-to-treat analyses will be done at 5 and 10 years, Dr. Gupta and his associates said.

This study was supported by the National Institute of Health Research Health Technology Assessment Programme. Dr. Gupta reported ties to Hodder Arnold Publishing, Ethicon Gynecare, and Femcare-Nikomed.

The levonorgestrel-releasing intrauterine system is superior to a variety of medical therapies at improving quality of life for women with menorrhagia, according to a report published online Jan. 10 in the New England Journal of Medicine.

In a randomized clinical trial that followed 571 subjects for 2 years, levonorgestrel-IUS (Mirena, Bayer HealthCare) was more effective than the usual medical treatments at combating the adverse effects of heavy menstrual bleeding on women’s daily lives, as well as at improving their psychological and physical well-being, said Dr. Janesh Gupta of the University of Birmingham (England) and his associates for the ECLIPSE (Effectiveness and Cost-Effectiveness of Levonorgestrel-Containing Intrauterine System in Primary Care against Standard Treatment for Menorrhagia) Trial Collaborative Group.

Previous studies gauging the effectiveness of various treatments for menorrhagia have focused on their control of menstrual blood loss, but there is great discordance between objective measures of blood loss and women’s perception of the amount they bleed. "Only about half the women with menorrhagia who present to health care providers have blood loss greater than the traditional threshold of 80 mL per menstrual cycle," the investigators wrote.

Moreover, the amount of bleeding doesn’t correlate with a woman’s experience of what is burdensome for her. "Clinical guidelines now advocate a shift in emphasis from the amount of menstrual blood loss to the more patient-centered definition of heavy menstrual bleeding that interferes with a woman’s physical, emotional, and social life," they noted.

Dr. Gupta and his colleagues compared levonorgestrel-IUS with standard medical therapies using these factors rather than the amount of blood loss as the primary outcome measures. They assessed the effect of menorrhagia on six domains of daily life – practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships – using the condition-specific Menorrhagia Multi-Attribute Scale (MMAS). Scores on the MMAS can range from 0 ("severely affected") to 100 ("not affected at all").

The researchers also assessed general health-related quality of life using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), which also has a 100-point scoring system, and the EuroQOL Group 5-Dimension Self-Report Questionnaire (EQ-5D), which has two 100-point scores. They used the Sexual Activity Questionnaire to measure pleasure and discomfort associated with sex, as well as the frequency of sexual activity, relative to the patient’s usual levels.

The study subjects were women aged 25-50 years who presented with menorrhagia to their primary care physicians at 63 U.K. medical centers during a 4-year period. These women were randomly assigned to receive either levonorgestrel-IUS (285 subjects) or medical therapies (286 subjects) such as mefenamic acid, tranexamic acid, norethindrone, estrogen-progestogen OCs, progesterone-only OCs, medroxyprogesterone acetate injections, or some combination of these. The medical treatments were chosen by the patient and her physician according to her contraceptive needs and wishes regarding hormonal therapy.

The two study groups were balanced with respect to subject age (younger than or older than 35 years), body-mass index (over or under 25), duration of symptoms (less than or more than 1 year), need for contraception (yes or no), and the presence or absence of menstrual pain.

The primary outcome measure was improvement on MMAS scores after 2 years of follow-up. These scores improved in all patients, but the improvement in all six domains of the MMAS was significantly greater among women in the levonorgestrel-IUS group, not just at 2 years but at every time point that was assessed.

The mean difference between baseline and final MMAS scores was 13.4 points for these women, a change that was both statistically significant and clinically meaningful. This represents an improvement from being substantially affected to minimally affected by menorrhagia, or from being minimally affected to being completely unaffected.

A sensitivity analysis was performed that included only study subjects who did not cross over from their assigned treatment to a different treatment. This analysis confirmed the findings of the main analysis, showing an improvement of 17.8 points in MMAS scores in women given levonorgestrel-IUS.

Similarly, scores on the SF-36 favored levonorgestrel-IUS over standard medical therapy at all time points in seven of the eight domains assessed, the investigators said (N. Engl. J. Med. 2013 Jan. 10 [doi:10.1056/NEJMoa1204724]).

The two study groups did not differ significantly on EQ-5D scores or on any factor in the Sexual Activity Questionnaire.

The frequency of surgical interventions for menorrhagia during follow-up also did not differ significantly, with 6% of both study groups undergoing hysterectomy; endometrial ablation was performed in 4% of the levonorgestrel-IUS patients and 6% of the medical treatment–group patients.

Given that menorrhagia often persists for years, longer follow-up of these study subjects is planned. Additional intention-to-treat analyses will be done at 5 and 10 years, Dr. Gupta and his associates said.

This study was supported by the National Institute of Health Research Health Technology Assessment Programme. Dr. Gupta reported ties to Hodder Arnold Publishing, Ethicon Gynecare, and Femcare-Nikomed.

A change in Medicare policy regarding payments for consultations vs. office visits had the unintended consequence of raising overall costs the first year it was implemented, according to a report published online in Archives of Internal Medicine.

Prior to 2010, the Medicare Physician Fee Schedule provided higher payments for consultations than for office visits at every level of complexity. For example, in 2009 Medicare paid $124.79 on average for a consultation of medium complexity, compared with $91.97 for a new patient office visit and $61.31 for an established patient office visit of similar complexity.

Since primary care physicians billed primarily for office visits and specialists billed primarily for consultations, this resulted in a large discrepancy in reimbursement between primary and specialist physicians for doing similarly complex work, according to Zirui Song, Ph.D., of the department of health care policy, Harvard Medical School, Boston, and his associates.

thinkstockphotos.com

With the fee schedule for calendar 2010, the Centers for Medicare and Medicaid Services eliminated payments for consultations altogether, so that all outpatient physician encounters would be billed as office visits, and simultaneously raised the fees for office visits. The change was designed specifically to be budget-neutral for the Medicare program.

Dr. Song and his colleagues assessed the effects of this policy change on Medicare payments in 2010. They used data from a sample of 2.2 million Medicare beneficiaries who had a diagnosis related to diabetes or cardiovascular conditions, or prescriptions for any cardiovascular or cholesterol-reducing drugs, and who were seen as outpatients in 2007 through the end of 2010.

During 2010, payments for consultations decreased an average of $18.52 per beneficiary per quarter.

However, payments for new patient office visits rose by $13.64 per beneficiary per quarter and payments for established patient office visits rose by $15.08 per beneficiary per quarter. This represents an increase of 131% in the number of new patient office visits billed to Medicare and an increase of 12% in the number of established patient office visits billed to Medicare, compared with the preceding year.

"On net, spending on all physician encounters was higher by $10.20 per beneficiary per quarter after the policy" for an increase of 6.5%, Dr. Song and his associates said (Arch. Intern. Med. 2012 [doi:10.1001/jamainternmend.2013.1125]).

The volume of patient encounters did not increase during this period, the researchers found. Rather, it appears that "an increase in the intensity of coding" was responsible for approximately one-third of the 6.5% rise, while the fee increase for office visits was responsible for the other two-thirds.

The income gap between specialists and primary care physicians did narrow somewhat after this policy change was implemented. Primary care physicians accounted for a slightly greater proportion (58%) of the rise in spending than did specialists (42%), the researchers noted.

They added that this study pertained only to Medicare payments for outpatient encounters, and did not address all other physician services. "The overall discrepancy in Medicare payments" between primary care and specialist physicians "derives largely from procedural services, which this policy does not address," Dr. Song and his colleagues said.

Similarly, this study examined only the policy’s effect on the first year after implementation, and these results may not be generalizable to longer term effects, they said.

This study was supported by The Commonwealth Fund, the National Institute on Aging, and the National Bureau of Economic Research. The investigators reported no relevant financial conflicts of interest.

A change in Medicare policy regarding payments for consultations vs. office visits had the unintended consequence of raising overall costs the first year it was implemented, according to a report published online in Archives of Internal Medicine.

Prior to 2010, the Medicare Physician Fee Schedule provided higher payments for consultations than for office visits at every level of complexity. For example, in 2009 Medicare paid $124.79 on average for a consultation of medium complexity, compared with $91.97 for a new patient office visit and $61.31 for an established patient office visit of similar complexity.

Since primary care physicians billed primarily for office visits and specialists billed primarily for consultations, this resulted in a large discrepancy in reimbursement between primary and specialist physicians for doing similarly complex work, according to Zirui Song, Ph.D., of the department of health care policy, Harvard Medical School, Boston, and his associates.

thinkstockphotos.com

With the fee schedule for calendar 2010, the Centers for Medicare and Medicaid Services eliminated payments for consultations altogether, so that all outpatient physician encounters would be billed as office visits, and simultaneously raised the fees for office visits. The change was designed specifically to be budget-neutral for the Medicare program.

Dr. Song and his colleagues assessed the effects of this policy change on Medicare payments in 2010. They used data from a sample of 2.2 million Medicare beneficiaries who had a diagnosis related to diabetes or cardiovascular conditions, or prescriptions for any cardiovascular or cholesterol-reducing drugs, and who were seen as outpatients in 2007 through the end of 2010.

During 2010, payments for consultations decreased an average of $18.52 per beneficiary per quarter.

However, payments for new patient office visits rose by $13.64 per beneficiary per quarter and payments for established patient office visits rose by $15.08 per beneficiary per quarter. This represents an increase of 131% in the number of new patient office visits billed to Medicare and an increase of 12% in the number of established patient office visits billed to Medicare, compared with the preceding year.

"On net, spending on all physician encounters was higher by $10.20 per beneficiary per quarter after the policy" for an increase of 6.5%, Dr. Song and his associates said (Arch. Intern. Med. 2012 [doi:10.1001/jamainternmend.2013.1125]).

The volume of patient encounters did not increase during this period, the researchers found. Rather, it appears that "an increase in the intensity of coding" was responsible for approximately one-third of the 6.5% rise, while the fee increase for office visits was responsible for the other two-thirds.

The income gap between specialists and primary care physicians did narrow somewhat after this policy change was implemented. Primary care physicians accounted for a slightly greater proportion (58%) of the rise in spending than did specialists (42%), the researchers noted.

They added that this study pertained only to Medicare payments for outpatient encounters, and did not address all other physician services. "The overall discrepancy in Medicare payments" between primary care and specialist physicians "derives largely from procedural services, which this policy does not address," Dr. Song and his colleagues said.

Similarly, this study examined only the policy’s effect on the first year after implementation, and these results may not be generalizable to longer term effects, they said.

This study was supported by The Commonwealth Fund, the National Institute on Aging, and the National Bureau of Economic Research. The investigators reported no relevant financial conflicts of interest.

A change in Medicare policy regarding payments for consultations vs. office visits had the unintended consequence of raising overall costs the first year it was implemented, according to a report published online in Archives of Internal Medicine.

Prior to 2010, the Medicare Physician Fee Schedule provided higher payments for consultations than for office visits at every level of complexity. For example, in 2009 Medicare paid $124.79 on average for a consultation of medium complexity, compared with $91.97 for a new patient office visit and $61.31 for an established patient office visit of similar complexity.

Since primary care physicians billed primarily for office visits and specialists billed primarily for consultations, this resulted in a large discrepancy in reimbursement between primary and specialist physicians for doing similarly complex work, according to Zirui Song, Ph.D., of the department of health care policy, Harvard Medical School, Boston, and his associates.

thinkstockphotos.com

With the fee schedule for calendar 2010, the Centers for Medicare and Medicaid Services eliminated payments for consultations altogether, so that all outpatient physician encounters would be billed as office visits, and simultaneously raised the fees for office visits. The change was designed specifically to be budget-neutral for the Medicare program.

Dr. Song and his colleagues assessed the effects of this policy change on Medicare payments in 2010. They used data from a sample of 2.2 million Medicare beneficiaries who had a diagnosis related to diabetes or cardiovascular conditions, or prescriptions for any cardiovascular or cholesterol-reducing drugs, and who were seen as outpatients in 2007 through the end of 2010.

During 2010, payments for consultations decreased an average of $18.52 per beneficiary per quarter.

However, payments for new patient office visits rose by $13.64 per beneficiary per quarter and payments for established patient office visits rose by $15.08 per beneficiary per quarter. This represents an increase of 131% in the number of new patient office visits billed to Medicare and an increase of 12% in the number of established patient office visits billed to Medicare, compared with the preceding year.

"On net, spending on all physician encounters was higher by $10.20 per beneficiary per quarter after the policy" for an increase of 6.5%, Dr. Song and his associates said (Arch. Intern. Med. 2012 [doi:10.1001/jamainternmend.2013.1125]).

The volume of patient encounters did not increase during this period, the researchers found. Rather, it appears that "an increase in the intensity of coding" was responsible for approximately one-third of the 6.5% rise, while the fee increase for office visits was responsible for the other two-thirds.

The income gap between specialists and primary care physicians did narrow somewhat after this policy change was implemented. Primary care physicians accounted for a slightly greater proportion (58%) of the rise in spending than did specialists (42%), the researchers noted.

They added that this study pertained only to Medicare payments for outpatient encounters, and did not address all other physician services. "The overall discrepancy in Medicare payments" between primary care and specialist physicians "derives largely from procedural services, which this policy does not address," Dr. Song and his colleagues said.

Similarly, this study examined only the policy’s effect on the first year after implementation, and these results may not be generalizable to longer term effects, they said.

This study was supported by The Commonwealth Fund, the National Institute on Aging, and the National Bureau of Economic Research. The investigators reported no relevant financial conflicts of interest.

Neonates and infants given intravenous acetaminophen as the primary analgesic during the 48 hours after major surgery required a 66% lower cumulative morphine dose than did those given a continuous morphine infusion as the primary analgesic, according to a report in the Jan. 9 issue of JAMA.

Patients given IV acetaminophen (paracetamol) achieved a level of analgesia similar to that of patients given a morphine infusion, judging by their equivalent need for rescue doses of morphine and their equivalent scores on two rating scales of pain and discomfort, reported Dr. Ilse Ceelie of the departments of intensive care and pediatric surgery at Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, and her associates.

"These results suggest that IV paracetamol may be an interesting alternative as primary analgesic in neonates and infants," they said.

Acetaminophen’s opioid-sparing effect has been demonstrated in older children and adults, but only two studies have assessed the drug’s opioid-sparing effect following surgery in the infant age group. Both of these studies used acetaminophen as an add-on therapy rather than as the primary analgesic, and they yielded conflicting results.

So Dr. Ceelie and her colleagues performed a single-center, randomized clinical trial to determine whether IV acetaminophen would reduce the cumulative morphine dose by at least 30%. They assessed 74 children younger than 1 year who were undergoing major abdominal or thoracic (but noncardiac) surgery during a 2-year period.

All the study subjects had been born at 37 weeks or later and weighed more than 1,500 g at the time of surgery. The most frequent procedures were closures of congenital diaphragmatic hernia, repair of intestinal atresia, and repair of esophageal atresia. All patients were given a loading dose of morphine 30 minutes before their surgery was expected to conclude. After the procedure they were transferred to the ICU, where the study medication was begun within 5 minutes.

Patients were randomly assigned in a double-blind fashion to receive either IV acetaminophen plus a placebo infusion mimicking morphine infusion (35 subjects) or a morphine infusion plus a placebo IV mimicking an acetaminophen drip (39 subjects). They were closely monitored for pain and distress by ICU nurses using the Numeric Rating Scale-11 and COMFORT-Behavior Scale. In addition, the surgeons computed a surgical stress score for each patient.

If discomfort was noted, midazolam was initiated. If pain was noted, rescue morphine boluses were administered as needed; if they were not sufficient, the maximum dose of morphine was given or the patient was switched to fentanyl.

The primary endpoint of the study was the cumulative dose of morphine – the sum of the intraoperative loading dose, the study dose of morphine (if applicable), and any rescue doses of morphine (if applicable).

The mean cumulative dose of morphine was 121 mcg/kg per 48 hours in the acetaminophen group, which was 66% lower than the mean cumulative dose of 357 mcg/kg per 48 hours in the morphine group, Dr. Ceelie and her associates reported (JAMA 2013;309;149-54).

The investigators also analyzed the data after dividing the study subjects into two age groups: those aged 0-10 days and those aged 11 days to 1 year. This was because "there are major changes in the pharmacokinetics of morphine during the first 10 days of life," but only minor changes thereafter.

In this analysis, the cumulative dose of morphine in the acetaminophen group (median, 111 mcg/kg per 48 hours) was 49% lower than that in the morphine group (median, 218 mcg/kg per 48 hours) among the neonates (aged 0-10 days). Among patients aged 11 days to 1 year, the difference in the cumulative dose of morphine was even more striking: The median was 152 mcg/kg/48 hours in the acetaminophen group and 553 in the morphine group, a difference of 73%.

The acetaminophen and morphine groups did not differ significantly in the total dose of rescue morphine, the number of morphine rescue doses, or the number of patients requiring rescue doses. In addition, the median scores on the two measures of pain and discomfort were similar between the two groups.

The overall rate of adverse effects was higher, but not significantly so, for morphine (34.2%) than for acetaminophen (27.3%). However, naloxone was administered to three infants in the morphine group because of respiratory depression, whereas none of the patients in the acetaminophen group developed respiratory depression.

"Despite the lack of statistical significance for this and other adverse effects, this observation does suggest a potential reduction in respiratory depression with use of acetaminophen," the researchers noted.

There were no cases of seizures, hypotension, or gastrointestinal adverse effects, they added.

Neonates have a lower risk of acetaminophen-induced hepatotoxicity than do older children and adults because the enzymes, such as CYP2E1, necessary for the hepatotoxic metabolite to develop are still immature, the researchers noted.

This study was limited in that it involved a strictly defined patient population at a single medical center, so the findings may not be widely generalizable. Moreover, liver function was not monitored in the acetaminophen group, and the study was underpowered to detect a difference in adverse effects, which "limits our ability to determine which treatment was safest," Dr. Ceelie and her colleagues said.

The study was supported by a grant from ZonMw Priority Medicines for Children. The authors reported no potential conflicts of interest.

Neonates and infants given intravenous acetaminophen as the primary analgesic during the 48 hours after major surgery required a 66% lower cumulative morphine dose than did those given a continuous morphine infusion as the primary analgesic, according to a report in the Jan. 9 issue of JAMA.

Patients given IV acetaminophen (paracetamol) achieved a level of analgesia similar to that of patients given a morphine infusion, judging by their equivalent need for rescue doses of morphine and their equivalent scores on two rating scales of pain and discomfort, reported Dr. Ilse Ceelie of the departments of intensive care and pediatric surgery at Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, and her associates.

"These results suggest that IV paracetamol may be an interesting alternative as primary analgesic in neonates and infants," they said.

Acetaminophen’s opioid-sparing effect has been demonstrated in older children and adults, but only two studies have assessed the drug’s opioid-sparing effect following surgery in the infant age group. Both of these studies used acetaminophen as an add-on therapy rather than as the primary analgesic, and they yielded conflicting results.

So Dr. Ceelie and her colleagues performed a single-center, randomized clinical trial to determine whether IV acetaminophen would reduce the cumulative morphine dose by at least 30%. They assessed 74 children younger than 1 year who were undergoing major abdominal or thoracic (but noncardiac) surgery during a 2-year period.

All the study subjects had been born at 37 weeks or later and weighed more than 1,500 g at the time of surgery. The most frequent procedures were closures of congenital diaphragmatic hernia, repair of intestinal atresia, and repair of esophageal atresia. All patients were given a loading dose of morphine 30 minutes before their surgery was expected to conclude. After the procedure they were transferred to the ICU, where the study medication was begun within 5 minutes.

Patients were randomly assigned in a double-blind fashion to receive either IV acetaminophen plus a placebo infusion mimicking morphine infusion (35 subjects) or a morphine infusion plus a placebo IV mimicking an acetaminophen drip (39 subjects). They were closely monitored for pain and distress by ICU nurses using the Numeric Rating Scale-11 and COMFORT-Behavior Scale. In addition, the surgeons computed a surgical stress score for each patient.

If discomfort was noted, midazolam was initiated. If pain was noted, rescue morphine boluses were administered as needed; if they were not sufficient, the maximum dose of morphine was given or the patient was switched to fentanyl.

The primary endpoint of the study was the cumulative dose of morphine – the sum of the intraoperative loading dose, the study dose of morphine (if applicable), and any rescue doses of morphine (if applicable).

The mean cumulative dose of morphine was 121 mcg/kg per 48 hours in the acetaminophen group, which was 66% lower than the mean cumulative dose of 357 mcg/kg per 48 hours in the morphine group, Dr. Ceelie and her associates reported (JAMA 2013;309;149-54).

The investigators also analyzed the data after dividing the study subjects into two age groups: those aged 0-10 days and those aged 11 days to 1 year. This was because "there are major changes in the pharmacokinetics of morphine during the first 10 days of life," but only minor changes thereafter.

In this analysis, the cumulative dose of morphine in the acetaminophen group (median, 111 mcg/kg per 48 hours) was 49% lower than that in the morphine group (median, 218 mcg/kg per 48 hours) among the neonates (aged 0-10 days). Among patients aged 11 days to 1 year, the difference in the cumulative dose of morphine was even more striking: The median was 152 mcg/kg/48 hours in the acetaminophen group and 553 in the morphine group, a difference of 73%.

The acetaminophen and morphine groups did not differ significantly in the total dose of rescue morphine, the number of morphine rescue doses, or the number of patients requiring rescue doses. In addition, the median scores on the two measures of pain and discomfort were similar between the two groups.

The overall rate of adverse effects was higher, but not significantly so, for morphine (34.2%) than for acetaminophen (27.3%). However, naloxone was administered to three infants in the morphine group because of respiratory depression, whereas none of the patients in the acetaminophen group developed respiratory depression.

"Despite the lack of statistical significance for this and other adverse effects, this observation does suggest a potential reduction in respiratory depression with use of acetaminophen," the researchers noted.

There were no cases of seizures, hypotension, or gastrointestinal adverse effects, they added.

Neonates have a lower risk of acetaminophen-induced hepatotoxicity than do older children and adults because the enzymes, such as CYP2E1, necessary for the hepatotoxic metabolite to develop are still immature, the researchers noted.

This study was limited in that it involved a strictly defined patient population at a single medical center, so the findings may not be widely generalizable. Moreover, liver function was not monitored in the acetaminophen group, and the study was underpowered to detect a difference in adverse effects, which "limits our ability to determine which treatment was safest," Dr. Ceelie and her colleagues said.

The study was supported by a grant from ZonMw Priority Medicines for Children. The authors reported no potential conflicts of interest.

Neonates and infants given intravenous acetaminophen as the primary analgesic during the 48 hours after major surgery required a 66% lower cumulative morphine dose than did those given a continuous morphine infusion as the primary analgesic, according to a report in the Jan. 9 issue of JAMA.

Patients given IV acetaminophen (paracetamol) achieved a level of analgesia similar to that of patients given a morphine infusion, judging by their equivalent need for rescue doses of morphine and their equivalent scores on two rating scales of pain and discomfort, reported Dr. Ilse Ceelie of the departments of intensive care and pediatric surgery at Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, and her associates.

"These results suggest that IV paracetamol may be an interesting alternative as primary analgesic in neonates and infants," they said.

Acetaminophen’s opioid-sparing effect has been demonstrated in older children and adults, but only two studies have assessed the drug’s opioid-sparing effect following surgery in the infant age group. Both of these studies used acetaminophen as an add-on therapy rather than as the primary analgesic, and they yielded conflicting results.

So Dr. Ceelie and her colleagues performed a single-center, randomized clinical trial to determine whether IV acetaminophen would reduce the cumulative morphine dose by at least 30%. They assessed 74 children younger than 1 year who were undergoing major abdominal or thoracic (but noncardiac) surgery during a 2-year period.

All the study subjects had been born at 37 weeks or later and weighed more than 1,500 g at the time of surgery. The most frequent procedures were closures of congenital diaphragmatic hernia, repair of intestinal atresia, and repair of esophageal atresia. All patients were given a loading dose of morphine 30 minutes before their surgery was expected to conclude. After the procedure they were transferred to the ICU, where the study medication was begun within 5 minutes.

Patients were randomly assigned in a double-blind fashion to receive either IV acetaminophen plus a placebo infusion mimicking morphine infusion (35 subjects) or a morphine infusion plus a placebo IV mimicking an acetaminophen drip (39 subjects). They were closely monitored for pain and distress by ICU nurses using the Numeric Rating Scale-11 and COMFORT-Behavior Scale. In addition, the surgeons computed a surgical stress score for each patient.

If discomfort was noted, midazolam was initiated. If pain was noted, rescue morphine boluses were administered as needed; if they were not sufficient, the maximum dose of morphine was given or the patient was switched to fentanyl.

The primary endpoint of the study was the cumulative dose of morphine – the sum of the intraoperative loading dose, the study dose of morphine (if applicable), and any rescue doses of morphine (if applicable).

The mean cumulative dose of morphine was 121 mcg/kg per 48 hours in the acetaminophen group, which was 66% lower than the mean cumulative dose of 357 mcg/kg per 48 hours in the morphine group, Dr. Ceelie and her associates reported (JAMA 2013;309;149-54).

The investigators also analyzed the data after dividing the study subjects into two age groups: those aged 0-10 days and those aged 11 days to 1 year. This was because "there are major changes in the pharmacokinetics of morphine during the first 10 days of life," but only minor changes thereafter.

In this analysis, the cumulative dose of morphine in the acetaminophen group (median, 111 mcg/kg per 48 hours) was 49% lower than that in the morphine group (median, 218 mcg/kg per 48 hours) among the neonates (aged 0-10 days). Among patients aged 11 days to 1 year, the difference in the cumulative dose of morphine was even more striking: The median was 152 mcg/kg/48 hours in the acetaminophen group and 553 in the morphine group, a difference of 73%.

The acetaminophen and morphine groups did not differ significantly in the total dose of rescue morphine, the number of morphine rescue doses, or the number of patients requiring rescue doses. In addition, the median scores on the two measures of pain and discomfort were similar between the two groups.

The overall rate of adverse effects was higher, but not significantly so, for morphine (34.2%) than for acetaminophen (27.3%). However, naloxone was administered to three infants in the morphine group because of respiratory depression, whereas none of the patients in the acetaminophen group developed respiratory depression.

"Despite the lack of statistical significance for this and other adverse effects, this observation does suggest a potential reduction in respiratory depression with use of acetaminophen," the researchers noted.

There were no cases of seizures, hypotension, or gastrointestinal adverse effects, they added.

Neonates have a lower risk of acetaminophen-induced hepatotoxicity than do older children and adults because the enzymes, such as CYP2E1, necessary for the hepatotoxic metabolite to develop are still immature, the researchers noted.

This study was limited in that it involved a strictly defined patient population at a single medical center, so the findings may not be widely generalizable. Moreover, liver function was not monitored in the acetaminophen group, and the study was underpowered to detect a difference in adverse effects, which "limits our ability to determine which treatment was safest," Dr. Ceelie and her colleagues said.

The study was supported by a grant from ZonMw Priority Medicines for Children. The authors reported no potential conflicts of interest.

Two years of vitamin D supplementation at a dose high enough to raise 25-hydroxyvitamin D plasma levels to more than 36 ng/mL failed to reduce knee pain or stem the loss of cartilage volume in patients with knee osteoarthritis, according to a report published Jan. 9 in JAMA.

These results from a single-center, randomized, double-blind, controlled clinical trial, taken together with recent observational data, indicate that vitamin D does not have a major effect on knee OA symptoms or progression among patients who already have sufficient vitamin D intake, said Dr. Timothy McAlindon of the division of rheumatology at Tufts Medical Center, Boston, and his associates.

©JOSS/FOTOLIA.COM

The investigators conducted the trial because vitamin D is known to influence bone health, and some epidemiologic studies have suggested that the progression of OA is slower in patients with higher plasma levels of 25-hydroxyvitamin D. They enrolled patients aged 45 years and older who had symptomatic knee OA and at least one osteophyte on radiography, including some with KL grade 4 knee OA indicating severe structural damage.

The 146 study subjects were randomly assigned in a double-blind fashion to receive either cholecalciferol capsules (73 patients) or identical placebo capsules (73 patients) for 2 years. The initial dose of active vitamin D was 2,000 IU daily and was adjusted at 4-month intervals to achieve a target 25-hydroxyvitamin D plasma level of 36-100 ng/mL. This is the level at which epidemiologic studies have reported that vitamin D may have an effect on OA.

The study subjects were monitored for the development of hypercalcemia, hypercalciuria, and hypervitaminosis D. They underwent regular clinical assessments as well as knee radiography at baseline and at 2 years; knee and hip dual x-ray absorptiometry; and MRI scanning of the affected knee at baseline, 12 months, and 24 months to assess cartilage volume loss.

The study subjects kept pill diaries, and pill counts were taken at every office visit. Mean adherence was 96% for the active-treatment group and 97% for the placebo group.

The mean plasma 25-hydroxyvitamin D level rose 16.1 ng/mL with active treatment, compared with only 2.1 ng/mL with placebo. A total of 61% of the active-treatment group reached the target level of at least 36 ng/mL by 2 years, compared with only 8% of the placebo group.

There were no significant differences between the groups in knee pain (they had a similar decline of about 2 points on the Western Ontario and McMaster Universities [WOMAC] pain scale) or in numerous secondary measures such as physical function at any interval assessment and at the conclusion of the study. Similarly, there were no significant between-group differences in combined tibial and femoral cartilage volume, with both groups losing a mean of about 4%. There also were no differences between the groups in cartilage thickness, the size of bone marrow lesions, or joint space width on knee radiographs.

In a sensitivity analysis, the investigators restricted their examination to data on only those subjects who showed a sustained response in 25-hydroxyvitamin D levels. This analysis confirmed the findings of the main analysis: Vitamin D supplementation failed to improve symptoms or preserve cartilage volume, compared with placebo.

"Thus, although there is a theoretical possibility that greater doses (or higher blood levels) of vitamin D are needed to exert a therapeutic effect, our data do not support this supposition," Dr. McAlindon and his associates wrote (JAMA 2013;309:155-62).

The number of serious adverse events was higher among subjects receiving vitamin D (31) than in those receiving placebo (23); however, 16 subjects in each group experienced a serious adverse event. Only one serious adverse event, a hip fracture, was judged to be possibly related to treatment.

There were no episodes of hypercalcemia. The number of cases of hypercalciuria (six in each group) and of kidney stones (one in each group) were comparable between the study groups.

There were no significant differences in the use of NSAIDs or opioids to control pain.

These findings add to "the overall data" in the literature suggesting that "vitamin D supplementation at a dose sufficient to elevate 25-hydroxyvitamin D levels to more than 36 ng/mL does not have major effects on clinical or structural outcomes in knee OA, at least in a U.S. sample," Dr. McAlindon and his colleagues said.

This study was funded by the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Office of Dietary Supplements, the National Center for Research Resources, and the Houston Veterans Affairs Health Services Research and Development Service. Dr. McAlindon reported ties to Flexion, Bioberica, and Sanofi-Aventis, and some of his associates reported ties to Sunovion, ImageIQ, Merck, Johnson & Johnson, Pfizer, General Electric, and NitroSci Pharmaceuticals.

Two years of vitamin D supplementation at a dose high enough to raise 25-hydroxyvitamin D plasma levels to more than 36 ng/mL failed to reduce knee pain or stem the loss of cartilage volume in patients with knee osteoarthritis, according to a report published Jan. 9 in JAMA.

These results from a single-center, randomized, double-blind, controlled clinical trial, taken together with recent observational data, indicate that vitamin D does not have a major effect on knee OA symptoms or progression among patients who already have sufficient vitamin D intake, said Dr. Timothy McAlindon of the division of rheumatology at Tufts Medical Center, Boston, and his associates.

©JOSS/FOTOLIA.COM

The investigators conducted the trial because vitamin D is known to influence bone health, and some epidemiologic studies have suggested that the progression of OA is slower in patients with higher plasma levels of 25-hydroxyvitamin D. They enrolled patients aged 45 years and older who had symptomatic knee OA and at least one osteophyte on radiography, including some with KL grade 4 knee OA indicating severe structural damage.

The 146 study subjects were randomly assigned in a double-blind fashion to receive either cholecalciferol capsules (73 patients) or identical placebo capsules (73 patients) for 2 years. The initial dose of active vitamin D was 2,000 IU daily and was adjusted at 4-month intervals to achieve a target 25-hydroxyvitamin D plasma level of 36-100 ng/mL. This is the level at which epidemiologic studies have reported that vitamin D may have an effect on OA.

The study subjects were monitored for the development of hypercalcemia, hypercalciuria, and hypervitaminosis D. They underwent regular clinical assessments as well as knee radiography at baseline and at 2 years; knee and hip dual x-ray absorptiometry; and MRI scanning of the affected knee at baseline, 12 months, and 24 months to assess cartilage volume loss.

The study subjects kept pill diaries, and pill counts were taken at every office visit. Mean adherence was 96% for the active-treatment group and 97% for the placebo group.

The mean plasma 25-hydroxyvitamin D level rose 16.1 ng/mL with active treatment, compared with only 2.1 ng/mL with placebo. A total of 61% of the active-treatment group reached the target level of at least 36 ng/mL by 2 years, compared with only 8% of the placebo group.

There were no significant differences between the groups in knee pain (they had a similar decline of about 2 points on the Western Ontario and McMaster Universities [WOMAC] pain scale) or in numerous secondary measures such as physical function at any interval assessment and at the conclusion of the study. Similarly, there were no significant between-group differences in combined tibial and femoral cartilage volume, with both groups losing a mean of about 4%. There also were no differences between the groups in cartilage thickness, the size of bone marrow lesions, or joint space width on knee radiographs.

In a sensitivity analysis, the investigators restricted their examination to data on only those subjects who showed a sustained response in 25-hydroxyvitamin D levels. This analysis confirmed the findings of the main analysis: Vitamin D supplementation failed to improve symptoms or preserve cartilage volume, compared with placebo.

"Thus, although there is a theoretical possibility that greater doses (or higher blood levels) of vitamin D are needed to exert a therapeutic effect, our data do not support this supposition," Dr. McAlindon and his associates wrote (JAMA 2013;309:155-62).

The number of serious adverse events was higher among subjects receiving vitamin D (31) than in those receiving placebo (23); however, 16 subjects in each group experienced a serious adverse event. Only one serious adverse event, a hip fracture, was judged to be possibly related to treatment.

There were no episodes of hypercalcemia. The number of cases of hypercalciuria (six in each group) and of kidney stones (one in each group) were comparable between the study groups.

There were no significant differences in the use of NSAIDs or opioids to control pain.

These findings add to "the overall data" in the literature suggesting that "vitamin D supplementation at a dose sufficient to elevate 25-hydroxyvitamin D levels to more than 36 ng/mL does not have major effects on clinical or structural outcomes in knee OA, at least in a U.S. sample," Dr. McAlindon and his colleagues said.

This study was funded by the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Office of Dietary Supplements, the National Center for Research Resources, and the Houston Veterans Affairs Health Services Research and Development Service. Dr. McAlindon reported ties to Flexion, Bioberica, and Sanofi-Aventis, and some of his associates reported ties to Sunovion, ImageIQ, Merck, Johnson & Johnson, Pfizer, General Electric, and NitroSci Pharmaceuticals.

Two years of vitamin D supplementation at a dose high enough to raise 25-hydroxyvitamin D plasma levels to more than 36 ng/mL failed to reduce knee pain or stem the loss of cartilage volume in patients with knee osteoarthritis, according to a report published Jan. 9 in JAMA.

These results from a single-center, randomized, double-blind, controlled clinical trial, taken together with recent observational data, indicate that vitamin D does not have a major effect on knee OA symptoms or progression among patients who already have sufficient vitamin D intake, said Dr. Timothy McAlindon of the division of rheumatology at Tufts Medical Center, Boston, and his associates.

©JOSS/FOTOLIA.COM

The investigators conducted the trial because vitamin D is known to influence bone health, and some epidemiologic studies have suggested that the progression of OA is slower in patients with higher plasma levels of 25-hydroxyvitamin D. They enrolled patients aged 45 years and older who had symptomatic knee OA and at least one osteophyte on radiography, including some with KL grade 4 knee OA indicating severe structural damage.

The 146 study subjects were randomly assigned in a double-blind fashion to receive either cholecalciferol capsules (73 patients) or identical placebo capsules (73 patients) for 2 years. The initial dose of active vitamin D was 2,000 IU daily and was adjusted at 4-month intervals to achieve a target 25-hydroxyvitamin D plasma level of 36-100 ng/mL. This is the level at which epidemiologic studies have reported that vitamin D may have an effect on OA.

The study subjects were monitored for the development of hypercalcemia, hypercalciuria, and hypervitaminosis D. They underwent regular clinical assessments as well as knee radiography at baseline and at 2 years; knee and hip dual x-ray absorptiometry; and MRI scanning of the affected knee at baseline, 12 months, and 24 months to assess cartilage volume loss.

The study subjects kept pill diaries, and pill counts were taken at every office visit. Mean adherence was 96% for the active-treatment group and 97% for the placebo group.

The mean plasma 25-hydroxyvitamin D level rose 16.1 ng/mL with active treatment, compared with only 2.1 ng/mL with placebo. A total of 61% of the active-treatment group reached the target level of at least 36 ng/mL by 2 years, compared with only 8% of the placebo group.

There were no significant differences between the groups in knee pain (they had a similar decline of about 2 points on the Western Ontario and McMaster Universities [WOMAC] pain scale) or in numerous secondary measures such as physical function at any interval assessment and at the conclusion of the study. Similarly, there were no significant between-group differences in combined tibial and femoral cartilage volume, with both groups losing a mean of about 4%. There also were no differences between the groups in cartilage thickness, the size of bone marrow lesions, or joint space width on knee radiographs.

In a sensitivity analysis, the investigators restricted their examination to data on only those subjects who showed a sustained response in 25-hydroxyvitamin D levels. This analysis confirmed the findings of the main analysis: Vitamin D supplementation failed to improve symptoms or preserve cartilage volume, compared with placebo.

"Thus, although there is a theoretical possibility that greater doses (or higher blood levels) of vitamin D are needed to exert a therapeutic effect, our data do not support this supposition," Dr. McAlindon and his associates wrote (JAMA 2013;309:155-62).

The number of serious adverse events was higher among subjects receiving vitamin D (31) than in those receiving placebo (23); however, 16 subjects in each group experienced a serious adverse event. Only one serious adverse event, a hip fracture, was judged to be possibly related to treatment.

There were no episodes of hypercalcemia. The number of cases of hypercalciuria (six in each group) and of kidney stones (one in each group) were comparable between the study groups.

There were no significant differences in the use of NSAIDs or opioids to control pain.

These findings add to "the overall data" in the literature suggesting that "vitamin D supplementation at a dose sufficient to elevate 25-hydroxyvitamin D levels to more than 36 ng/mL does not have major effects on clinical or structural outcomes in knee OA, at least in a U.S. sample," Dr. McAlindon and his colleagues said.

This study was funded by the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Office of Dietary Supplements, the National Center for Research Resources, and the Houston Veterans Affairs Health Services Research and Development Service. Dr. McAlindon reported ties to Flexion, Bioberica, and Sanofi-Aventis, and some of his associates reported ties to Sunovion, ImageIQ, Merck, Johnson & Johnson, Pfizer, General Electric, and NitroSci Pharmaceuticals.

Approximately 10% of neoplastic polyps that were 5-20 mm in size were not completely resected in a series of 1,427 patients undergoing colonoscopy, Dr. Heiko Pohl and his colleagues reported in the January issue of Gastroenterology.

Biopsies from the resection margins of 346 neoplastic polyps showed that some neoplastic tissue had been left behind in 35 cases in the Complete Adenoma Resection (CARE) study, which involved 11 experienced gastroenterologists practicing at two large academic medical centers.

Video source: American Gastroenterological Association YouTube channel

The rate of incomplete resections varied widely across the different endoscopists, from 6.5% to 22.7%. Moreover, these physicians were aware that they were participating in the study and may have been more careful than usual to accomplish complete resection.

"Our study provides plausible data that incomplete polyp resection in daily clinical practice is relatively common and may contribute to future interval cancers," said Dr. Pohl of White River Junction (Vt.) VA Medical Center and Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his associates.

The findings also suggest that quality measures for colonoscopy, which to date have focused primarily on detection rates, should now include the completeness of the resection. "The performance of high-quality and effective colonoscopy not only requires expertise in finding neoplastic polyps, but also removing them," the investigators noted (Gastroenterology 2013;144:74-80).

Until now, there has been "surprisingly little direct information on the adequacy of polyp resection. It is generally assumed that resection is complete if no apparent polyp tissue is visible after resection. Using a snare with electrocautery should further destroy any remaining polyp tissue," but whether it actually does so has never been tested, they said.

Dr. Pohl and his colleagues reviewed the cases of all adults aged 40-85 years who presented for outpatient colonoscopy at the two study centers, had no history of inflammatory bowel disease, had no coagulopathies, and were found to have at least one polyp that was 5-20 mm in size.

The board-certified gastroenterologists participating in the study used standard colonoscopes and polypectomy snares to remove the lesions, along with standard electrocautery equipment. The polyps were measured and resected, then the gastroenterologists inspected the resection margins macroscopically, obtained forceps biopsies of the resection margins, and attested that the removal was complete.

They also recorded whether the resection had been easy, moderately difficult, or difficult.

The use of narrow band imaging, chromoendoscopy, or argon plasma coagulation was not required by the study protocol but was allowed at the discretion of each gastroenterologist.

An expert gastrointestinal pathologist independently examined all the biopsies for residual adenomatous tissue, as well as to classify the polyps.

A total of 346 polyps (83%) were neoplastic.

Sixty-eight percent of these polyps were classified as tubular, tubulovillous, or villous adenomas. Twelve percent had a serrated histology, including 42 (10%) that were sessile serrated adenomas/polyps.

The expert reviewer found that overall, 10% of the neoplastic polyps were incompletely resected.

Large (10- to 20-mm) growths were more than twice as likely to be incompletely resected (17.3%) than were small (5- to 9-mm) growths (6.8%). Sessile serrated adenomas/polyps were four times more likely than other types to be incompletely resected (31% vs. 7%).

As a result, almost half (48%) of all large sessile serrated adenomas/polyps were incompletely resected.

"Because adenoma size is associated with both a higher prevalence of advanced histology and greater near-term risk of transition to cancer, incomplete resection of large neoplastic polyps is concerning," Dr. Pohl and his colleagues wrote.

No other factors were found to correspond with incomplete removal, including whether the resection was rated as difficult rather than easy, whether the polyps had to be removed piecemeal rather than all at once, whether the polyps were located in the right or left colon, and whether they had flat or other morphology.

"Our results raise questions regarding the quality of polyp resection and call for efforts to improve resection of neoplastic polyps, especially large polyps and sessile serrated adenomas/polyps," the researchers wrote.

In particular, increased attention to the polyp margin using special imaging may be warranted. Outlining and marking the margin before resection also might improve the completeness of the removal. And in some cases, adjunctive ablation of the margins after resection may be useful, they added.

The authors reported no relevant financial conflicts.

Approximately 10% of neoplastic polyps that were 5-20 mm in size were not completely resected in a series of 1,427 patients undergoing colonoscopy, Dr. Heiko Pohl and his colleagues reported in the January issue of Gastroenterology.

Biopsies from the resection margins of 346 neoplastic polyps showed that some neoplastic tissue had been left behind in 35 cases in the Complete Adenoma Resection (CARE) study, which involved 11 experienced gastroenterologists practicing at two large academic medical centers.

Video source: American Gastroenterological Association YouTube channel

The rate of incomplete resections varied widely across the different endoscopists, from 6.5% to 22.7%. Moreover, these physicians were aware that they were participating in the study and may have been more careful than usual to accomplish complete resection.

"Our study provides plausible data that incomplete polyp resection in daily clinical practice is relatively common and may contribute to future interval cancers," said Dr. Pohl of White River Junction (Vt.) VA Medical Center and Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his associates.

The findings also suggest that quality measures for colonoscopy, which to date have focused primarily on detection rates, should now include the completeness of the resection. "The performance of high-quality and effective colonoscopy not only requires expertise in finding neoplastic polyps, but also removing them," the investigators noted (Gastroenterology 2013;144:74-80).

Until now, there has been "surprisingly little direct information on the adequacy of polyp resection. It is generally assumed that resection is complete if no apparent polyp tissue is visible after resection. Using a snare with electrocautery should further destroy any remaining polyp tissue," but whether it actually does so has never been tested, they said.

Dr. Pohl and his colleagues reviewed the cases of all adults aged 40-85 years who presented for outpatient colonoscopy at the two study centers, had no history of inflammatory bowel disease, had no coagulopathies, and were found to have at least one polyp that was 5-20 mm in size.

The board-certified gastroenterologists participating in the study used standard colonoscopes and polypectomy snares to remove the lesions, along with standard electrocautery equipment. The polyps were measured and resected, then the gastroenterologists inspected the resection margins macroscopically, obtained forceps biopsies of the resection margins, and attested that the removal was complete.

They also recorded whether the resection had been easy, moderately difficult, or difficult.

The use of narrow band imaging, chromoendoscopy, or argon plasma coagulation was not required by the study protocol but was allowed at the discretion of each gastroenterologist.

An expert gastrointestinal pathologist independently examined all the biopsies for residual adenomatous tissue, as well as to classify the polyps.

A total of 346 polyps (83%) were neoplastic.

Sixty-eight percent of these polyps were classified as tubular, tubulovillous, or villous adenomas. Twelve percent had a serrated histology, including 42 (10%) that were sessile serrated adenomas/polyps.

The expert reviewer found that overall, 10% of the neoplastic polyps were incompletely resected.

Large (10- to 20-mm) growths were more than twice as likely to be incompletely resected (17.3%) than were small (5- to 9-mm) growths (6.8%). Sessile serrated adenomas/polyps were four times more likely than other types to be incompletely resected (31% vs. 7%).

As a result, almost half (48%) of all large sessile serrated adenomas/polyps were incompletely resected.

"Because adenoma size is associated with both a higher prevalence of advanced histology and greater near-term risk of transition to cancer, incomplete resection of large neoplastic polyps is concerning," Dr. Pohl and his colleagues wrote.

No other factors were found to correspond with incomplete removal, including whether the resection was rated as difficult rather than easy, whether the polyps had to be removed piecemeal rather than all at once, whether the polyps were located in the right or left colon, and whether they had flat or other morphology.

"Our results raise questions regarding the quality of polyp resection and call for efforts to improve resection of neoplastic polyps, especially large polyps and sessile serrated adenomas/polyps," the researchers wrote.

In particular, increased attention to the polyp margin using special imaging may be warranted. Outlining and marking the margin before resection also might improve the completeness of the removal. And in some cases, adjunctive ablation of the margins after resection may be useful, they added.

The authors reported no relevant financial conflicts.

Approximately 10% of neoplastic polyps that were 5-20 mm in size were not completely resected in a series of 1,427 patients undergoing colonoscopy, Dr. Heiko Pohl and his colleagues reported in the January issue of Gastroenterology.

Biopsies from the resection margins of 346 neoplastic polyps showed that some neoplastic tissue had been left behind in 35 cases in the Complete Adenoma Resection (CARE) study, which involved 11 experienced gastroenterologists practicing at two large academic medical centers.

Video source: American Gastroenterological Association YouTube channel

The rate of incomplete resections varied widely across the different endoscopists, from 6.5% to 22.7%. Moreover, these physicians were aware that they were participating in the study and may have been more careful than usual to accomplish complete resection.

"Our study provides plausible data that incomplete polyp resection in daily clinical practice is relatively common and may contribute to future interval cancers," said Dr. Pohl of White River Junction (Vt.) VA Medical Center and Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his associates.

The findings also suggest that quality measures for colonoscopy, which to date have focused primarily on detection rates, should now include the completeness of the resection. "The performance of high-quality and effective colonoscopy not only requires expertise in finding neoplastic polyps, but also removing them," the investigators noted (Gastroenterology 2013;144:74-80).

Until now, there has been "surprisingly little direct information on the adequacy of polyp resection. It is generally assumed that resection is complete if no apparent polyp tissue is visible after resection. Using a snare with electrocautery should further destroy any remaining polyp tissue," but whether it actually does so has never been tested, they said.

Dr. Pohl and his colleagues reviewed the cases of all adults aged 40-85 years who presented for outpatient colonoscopy at the two study centers, had no history of inflammatory bowel disease, had no coagulopathies, and were found to have at least one polyp that was 5-20 mm in size.

The board-certified gastroenterologists participating in the study used standard colonoscopes and polypectomy snares to remove the lesions, along with standard electrocautery equipment. The polyps were measured and resected, then the gastroenterologists inspected the resection margins macroscopically, obtained forceps biopsies of the resection margins, and attested that the removal was complete.

They also recorded whether the resection had been easy, moderately difficult, or difficult.

The use of narrow band imaging, chromoendoscopy, or argon plasma coagulation was not required by the study protocol but was allowed at the discretion of each gastroenterologist.

An expert gastrointestinal pathologist independently examined all the biopsies for residual adenomatous tissue, as well as to classify the polyps.

A total of 346 polyps (83%) were neoplastic.

Sixty-eight percent of these polyps were classified as tubular, tubulovillous, or villous adenomas. Twelve percent had a serrated histology, including 42 (10%) that were sessile serrated adenomas/polyps.

The expert reviewer found that overall, 10% of the neoplastic polyps were incompletely resected.

Large (10- to 20-mm) growths were more than twice as likely to be incompletely resected (17.3%) than were small (5- to 9-mm) growths (6.8%). Sessile serrated adenomas/polyps were four times more likely than other types to be incompletely resected (31% vs. 7%).

As a result, almost half (48%) of all large sessile serrated adenomas/polyps were incompletely resected.

"Because adenoma size is associated with both a higher prevalence of advanced histology and greater near-term risk of transition to cancer, incomplete resection of large neoplastic polyps is concerning," Dr. Pohl and his colleagues wrote.

No other factors were found to correspond with incomplete removal, including whether the resection was rated as difficult rather than easy, whether the polyps had to be removed piecemeal rather than all at once, whether the polyps were located in the right or left colon, and whether they had flat or other morphology.

"Our results raise questions regarding the quality of polyp resection and call for efforts to improve resection of neoplastic polyps, especially large polyps and sessile serrated adenomas/polyps," the researchers wrote.

In particular, increased attention to the polyp margin using special imaging may be warranted. Outlining and marking the margin before resection also might improve the completeness of the removal. And in some cases, adjunctive ablation of the margins after resection may be useful, they added.

The authors reported no relevant financial conflicts.

Only 3 of 12 gastroenterologists in a community practice were able to assess colon polyps 5 mm or less in size with 90% accuracy after completing a computer-based self-training program for "optical biopsy" using narrow band imaging, Dr. Uri Ladabaum and his colleagues reported in the January issue of Gastroenterology.

This performance was not as good as that reported for experts evaluated in clinical studies, but it was similar to that reported for students at academic medical centers.

Video Source: American Gastroenterological Association YouTube channel

Although it is "promising" that three gastroenterologists learned how to perform optical biopsy using this method, "better results in community practice must be achieved before NBI [narrow band imaging]-based optical biopsy methods can be used routinely to evaluate polyps," wrote Dr. Ladabaum of Stanford (Calif.) University and his associates (Gastroenterology 2013;144:81-91).

The American Society of Gastrointestinal Endoscopy recommends a negative predictive value threshold of 90% or greater for adenomatous histology of diminutive colorectal polyps using optical biopsy.

The investigators evaluated a self-training program that was designed to be practical to implement in a busy community gastroenterology practice. None of the study subjects had significant experience or formal training with NBI, which uses narrow band light filters to highlight colonic mucosal architecture and vasculature.

Participants first completed three self-administered units at their own pace during the first week of the program: a pretest, a learning module instructing them on using narrow band imaging to help distinguish adenomas from hyperplastic polyps, and a posttest. The two tests featured different sets of 25 endoscopic images of polyps and asked the study subjects to judge whether they were adenomas or hyperplastic, or to indicate that they couldn’t decide.

Next, the participants put their learning into practice, using optical biopsy with NBI on all colonoscopies they performed in which at least one polyp was removed. They noted the location, size, and morphology of each lesion; took photographs under white light and under NBI; classified the features they observed; predicted whether the lesions would prove to be adenomas or hyperplastic on pathologic examination; and recorded their level of confidence (high or low) in their predictions.

After the specimens were examined and classified by fellowship-trained GI pathologists, the study gastroenterologists were required to record the actual diagnosis for each lesion and encouraged to compare that with their own optical diagnoses. They received ongoing confidential feedback as to the accuracy of their work every 1-2 weeks.

Polyps were classified by size as diminutive (5 mm or smaller), small (6-9 mm), or large (10 mm or larger). The primary analysis focused on the study subjects’ success in optical diagnosis of diminutive polyps only, and each subject’s final evaluation was performed after he or she assessed at least 90 such lesions.

The 12 gastroenterologists who participated in both the ex vivo and in vivo study phases of the training program performed a total of 1,673 colonoscopies and removed 2,596 polyps. This included 1,858 diminutive, 547 small, and 177 large polyps; the size was not recorded for the remaining 14 polyps.

All 12 study subjects scored 90% or greater accuracy on the posttests they took after training.

However, only three of them performed that well in their real world practice. The other nine gastroenterologists did not achieve 90% or greater accuracy in assessing the histology of diminutive polyps using NBI.

The participants did not show typical learning curves with the technique over time. "There was no clear pattern of early learning with later stabilization of performance at a higher level," Dr. Ladabaum and his colleagues wrote.

Many factors that might have influenced subjects’ accuracy in distinguishing adenomas from hyperplasia actually proved to have no such effect. The location of the polyp within the colon, the endoscopists’ years in practice and colonoscopy volume, and the changes in subjects’ scores from pretest to posttest all showed no association with their final accuracy in optical biopsy.

One factor that predicted such accuracy was the participant’s confidence in each of his or her predictions.

Finally, there was some attrition over the course of the study, as some subjects who took part in the initial computer-based training did not proceed to the in vivo phase, "and not all participants remained engaged in the in vivo phase. Incentives may need to be developed for busy clinicians to learn and use optical biopsy techniques," the investigators wrote.

Overall, the study findings show that "high accuracy can be achieved ex vivo by community gastroenterologists after self-paced training with a computerized module." However, it remains to be seen whether a gastroenterologist’s ultimate proficiency in optical diagnosis "is determined by technical issues, dedication, motivation, or innate skill," they added.

This study was supported by Stanford University. One author reported receiving research support from and serving on the speakers bureau for Olympus Corp.

Only 3 of 12 gastroenterologists in a community practice were able to assess colon polyps 5 mm or less in size with 90% accuracy after completing a computer-based self-training program for "optical biopsy" using narrow band imaging, Dr. Uri Ladabaum and his colleagues reported in the January issue of Gastroenterology.

This performance was not as good as that reported for experts evaluated in clinical studies, but it was similar to that reported for students at academic medical centers.

Video Source: American Gastroenterological Association YouTube channel

Although it is "promising" that three gastroenterologists learned how to perform optical biopsy using this method, "better results in community practice must be achieved before NBI [narrow band imaging]-based optical biopsy methods can be used routinely to evaluate polyps," wrote Dr. Ladabaum of Stanford (Calif.) University and his associates (Gastroenterology 2013;144:81-91).

The American Society of Gastrointestinal Endoscopy recommends a negative predictive value threshold of 90% or greater for adenomatous histology of diminutive colorectal polyps using optical biopsy.

The investigators evaluated a self-training program that was designed to be practical to implement in a busy community gastroenterology practice. None of the study subjects had significant experience or formal training with NBI, which uses narrow band light filters to highlight colonic mucosal architecture and vasculature.

Participants first completed three self-administered units at their own pace during the first week of the program: a pretest, a learning module instructing them on using narrow band imaging to help distinguish adenomas from hyperplastic polyps, and a posttest. The two tests featured different sets of 25 endoscopic images of polyps and asked the study subjects to judge whether they were adenomas or hyperplastic, or to indicate that they couldn’t decide.

Next, the participants put their learning into practice, using optical biopsy with NBI on all colonoscopies they performed in which at least one polyp was removed. They noted the location, size, and morphology of each lesion; took photographs under white light and under NBI; classified the features they observed; predicted whether the lesions would prove to be adenomas or hyperplastic on pathologic examination; and recorded their level of confidence (high or low) in their predictions.

After the specimens were examined and classified by fellowship-trained GI pathologists, the study gastroenterologists were required to record the actual diagnosis for each lesion and encouraged to compare that with their own optical diagnoses. They received ongoing confidential feedback as to the accuracy of their work every 1-2 weeks.

Polyps were classified by size as diminutive (5 mm or smaller), small (6-9 mm), or large (10 mm or larger). The primary analysis focused on the study subjects’ success in optical diagnosis of diminutive polyps only, and each subject’s final evaluation was performed after he or she assessed at least 90 such lesions.

The 12 gastroenterologists who participated in both the ex vivo and in vivo study phases of the training program performed a total of 1,673 colonoscopies and removed 2,596 polyps. This included 1,858 diminutive, 547 small, and 177 large polyps; the size was not recorded for the remaining 14 polyps.

All 12 study subjects scored 90% or greater accuracy on the posttests they took after training.

However, only three of them performed that well in their real world practice. The other nine gastroenterologists did not achieve 90% or greater accuracy in assessing the histology of diminutive polyps using NBI.

The participants did not show typical learning curves with the technique over time. "There was no clear pattern of early learning with later stabilization of performance at a higher level," Dr. Ladabaum and his colleagues wrote.

Many factors that might have influenced subjects’ accuracy in distinguishing adenomas from hyperplasia actually proved to have no such effect. The location of the polyp within the colon, the endoscopists’ years in practice and colonoscopy volume, and the changes in subjects’ scores from pretest to posttest all showed no association with their final accuracy in optical biopsy.

One factor that predicted such accuracy was the participant’s confidence in each of his or her predictions.

Finally, there was some attrition over the course of the study, as some subjects who took part in the initial computer-based training did not proceed to the in vivo phase, "and not all participants remained engaged in the in vivo phase. Incentives may need to be developed for busy clinicians to learn and use optical biopsy techniques," the investigators wrote.

Overall, the study findings show that "high accuracy can be achieved ex vivo by community gastroenterologists after self-paced training with a computerized module." However, it remains to be seen whether a gastroenterologist’s ultimate proficiency in optical diagnosis "is determined by technical issues, dedication, motivation, or innate skill," they added.

This study was supported by Stanford University. One author reported receiving research support from and serving on the speakers bureau for Olympus Corp.

Only 3 of 12 gastroenterologists in a community practice were able to assess colon polyps 5 mm or less in size with 90% accuracy after completing a computer-based self-training program for "optical biopsy" using narrow band imaging, Dr. Uri Ladabaum and his colleagues reported in the January issue of Gastroenterology.

This performance was not as good as that reported for experts evaluated in clinical studies, but it was similar to that reported for students at academic medical centers.

Video Source: American Gastroenterological Association YouTube channel

Although it is "promising" that three gastroenterologists learned how to perform optical biopsy using this method, "better results in community practice must be achieved before NBI [narrow band imaging]-based optical biopsy methods can be used routinely to evaluate polyps," wrote Dr. Ladabaum of Stanford (Calif.) University and his associates (Gastroenterology 2013;144:81-91).

The American Society of Gastrointestinal Endoscopy recommends a negative predictive value threshold of 90% or greater for adenomatous histology of diminutive colorectal polyps using optical biopsy.

The investigators evaluated a self-training program that was designed to be practical to implement in a busy community gastroenterology practice. None of the study subjects had significant experience or formal training with NBI, which uses narrow band light filters to highlight colonic mucosal architecture and vasculature.

Participants first completed three self-administered units at their own pace during the first week of the program: a pretest, a learning module instructing them on using narrow band imaging to help distinguish adenomas from hyperplastic polyps, and a posttest. The two tests featured different sets of 25 endoscopic images of polyps and asked the study subjects to judge whether they were adenomas or hyperplastic, or to indicate that they couldn’t decide.

Next, the participants put their learning into practice, using optical biopsy with NBI on all colonoscopies they performed in which at least one polyp was removed. They noted the location, size, and morphology of each lesion; took photographs under white light and under NBI; classified the features they observed; predicted whether the lesions would prove to be adenomas or hyperplastic on pathologic examination; and recorded their level of confidence (high or low) in their predictions.

After the specimens were examined and classified by fellowship-trained GI pathologists, the study gastroenterologists were required to record the actual diagnosis for each lesion and encouraged to compare that with their own optical diagnoses. They received ongoing confidential feedback as to the accuracy of their work every 1-2 weeks.

Polyps were classified by size as diminutive (5 mm or smaller), small (6-9 mm), or large (10 mm or larger). The primary analysis focused on the study subjects’ success in optical diagnosis of diminutive polyps only, and each subject’s final evaluation was performed after he or she assessed at least 90 such lesions.

The 12 gastroenterologists who participated in both the ex vivo and in vivo study phases of the training program performed a total of 1,673 colonoscopies and removed 2,596 polyps. This included 1,858 diminutive, 547 small, and 177 large polyps; the size was not recorded for the remaining 14 polyps.

All 12 study subjects scored 90% or greater accuracy on the posttests they took after training.

However, only three of them performed that well in their real world practice. The other nine gastroenterologists did not achieve 90% or greater accuracy in assessing the histology of diminutive polyps using NBI.

The participants did not show typical learning curves with the technique over time. "There was no clear pattern of early learning with later stabilization of performance at a higher level," Dr. Ladabaum and his colleagues wrote.

Many factors that might have influenced subjects’ accuracy in distinguishing adenomas from hyperplasia actually proved to have no such effect. The location of the polyp within the colon, the endoscopists’ years in practice and colonoscopy volume, and the changes in subjects’ scores from pretest to posttest all showed no association with their final accuracy in optical biopsy.

One factor that predicted such accuracy was the participant’s confidence in each of his or her predictions.

Finally, there was some attrition over the course of the study, as some subjects who took part in the initial computer-based training did not proceed to the in vivo phase, "and not all participants remained engaged in the in vivo phase. Incentives may need to be developed for busy clinicians to learn and use optical biopsy techniques," the investigators wrote.

Overall, the study findings show that "high accuracy can be achieved ex vivo by community gastroenterologists after self-paced training with a computerized module." However, it remains to be seen whether a gastroenterologist’s ultimate proficiency in optical diagnosis "is determined by technical issues, dedication, motivation, or innate skill," they added.

This study was supported by Stanford University. One author reported receiving research support from and serving on the speakers bureau for Olympus Corp.

For patients with severe acute GI bleeding, outcomes are significantly better when a restrictive transfusion strategy is used – limiting the hemoglobin threshold to 7 g/dL – rather than a liberal transfusion strategy allowing a 9 g/dL threshold, according to a report published online Jan. 2 in the New England Journal of Medicine.

In a single-center randomized controlled trial involving 889 patients, the restrictive transfusion strategy resulted in significantly lower mortality, lower rates of rebleeding, less frequent need for rescue therapy, fewer complications, and shorter hospitalizations than did the liberal transfusion strategy. "Our results suggest that in patients with acute GI bleeding, a strategy of not performing transfusion until the hemoglobin concentration falls below 7 g/dL is a safe and effective approach," said Dr. Càndid Villanueva of Hospital de Sant Pau, Barcelona, and his associates.

"Current international guidelines recommend decreasing the hemoglobin threshold level for transfusion ... from 10g/dL to 7 g/dL" in such patients, but these recommendations are based on trials involving critically ill patients with normovolemic anemia that did not include subjects with acute bleeding. "Transfusion requirements may be different for patients with acute hemorrhage due to factors such as hemodynamic instability or rapid onset of anemia" resulting from extremely low hemoglobin levels.

In particular, results of animal studies suggest that transfusion can be especially harmful in patients with bleeding from portal hypertension sources, "since restitution of blood volume after hemorrhage can lead to a rebound increase in portal pressure, which is associated with a risk of rebleeding," the investigators noted.

To examine the effects of different transfusion strategies in this setting, Dr. Villanueva and his colleagues enrolled adults who presented with hematemesis, melena, or both, randomly assigning 444 to receive restrictive transfusion (with a target range for the posttransfusion hemoglobin level of 7-9 g/dL) and 445 to receive liberal transfusion (with a target range of 9-11 g/dL).

The study protocol permitted transfusions to be administered at the discretion of the attending physician any time symptoms or signs of anemia developed, massive bleeding occurred, or surgical intervention was needed, as well as when hemoglobin levels dipped below the assigned threshold.

All the study subjects underwent emergency gastroscopy within 6 hours of presentation, with appropriate treatment when the source of the bleeding was identified. Diagnoses included peptic ulcer, esophageal varices, cirrhosis, portal hypertension, and nonvariceal lesions.

The primary outcome measure, mortality from any cause at 45 days, was significantly lower in the restrictive-strategy group (5%) than the liberal-strategy group (9%). Death resulted from uncontrolled bleeding in 0.7% vs 3.1% of the 2 groups, respectively, the researchers said (N. Engl. J. Med. 2013 Jan. 2 [doi:10.1056/NEJMoa1211801]).

The rate of rebleeding also was significantly lower with the restrictive strategy (10% vs. 16%), and length of hospital stay was significantly shorter. In addition, rescue therapy for esophageal varices with balloon tamponade or a transjugular intrahepatic portosystemic shunt was required less often in the restrictive-strategy group than in the liberal-strategy group, as was emergency surgery to control further bleeding from peptic ulcer.

The rate of overall complications was significantly lower with the restrictive strategy (40%) than with the liberal strategy (48%), as was the rate of serious adverse events. In addition, transfusion reactions and cardiac events such as pulmonary edema were more frequent with the liberal strategy.

"Our results are consistent with those from previous observational studies and randomized trials performed in other settings, which have shown that a restrictive transfusion strategy did not increase, and even decreased, the mortality observed with a liberal transfusion strategy," Dr. Villanueva and his associates said.

For patients with severe acute GI bleeding, outcomes are significantly better when a restrictive transfusion strategy is used – limiting the hemoglobin threshold to 7 g/dL – rather than a liberal transfusion strategy allowing a 9 g/dL threshold, according to a report published online Jan. 2 in the New England Journal of Medicine.

In a single-center randomized controlled trial involving 889 patients, the restrictive transfusion strategy resulted in significantly lower mortality, lower rates of rebleeding, less frequent need for rescue therapy, fewer complications, and shorter hospitalizations than did the liberal transfusion strategy. "Our results suggest that in patients with acute GI bleeding, a strategy of not performing transfusion until the hemoglobin concentration falls below 7 g/dL is a safe and effective approach," said Dr. Càndid Villanueva of Hospital de Sant Pau, Barcelona, and his associates.

"Current international guidelines recommend decreasing the hemoglobin threshold level for transfusion ... from 10g/dL to 7 g/dL" in such patients, but these recommendations are based on trials involving critically ill patients with normovolemic anemia that did not include subjects with acute bleeding. "Transfusion requirements may be different for patients with acute hemorrhage due to factors such as hemodynamic instability or rapid onset of anemia" resulting from extremely low hemoglobin levels.

In particular, results of animal studies suggest that transfusion can be especially harmful in patients with bleeding from portal hypertension sources, "since restitution of blood volume after hemorrhage can lead to a rebound increase in portal pressure, which is associated with a risk of rebleeding," the investigators noted.

To examine the effects of different transfusion strategies in this setting, Dr. Villanueva and his colleagues enrolled adults who presented with hematemesis, melena, or both, randomly assigning 444 to receive restrictive transfusion (with a target range for the posttransfusion hemoglobin level of 7-9 g/dL) and 445 to receive liberal transfusion (with a target range of 9-11 g/dL).

The study protocol permitted transfusions to be administered at the discretion of the attending physician any time symptoms or signs of anemia developed, massive bleeding occurred, or surgical intervention was needed, as well as when hemoglobin levels dipped below the assigned threshold.

All the study subjects underwent emergency gastroscopy within 6 hours of presentation, with appropriate treatment when the source of the bleeding was identified. Diagnoses included peptic ulcer, esophageal varices, cirrhosis, portal hypertension, and nonvariceal lesions.

The primary outcome measure, mortality from any cause at 45 days, was significantly lower in the restrictive-strategy group (5%) than the liberal-strategy group (9%). Death resulted from uncontrolled bleeding in 0.7% vs 3.1% of the 2 groups, respectively, the researchers said (N. Engl. J. Med. 2013 Jan. 2 [doi:10.1056/NEJMoa1211801]).

The rate of rebleeding also was significantly lower with the restrictive strategy (10% vs. 16%), and length of hospital stay was significantly shorter. In addition, rescue therapy for esophageal varices with balloon tamponade or a transjugular intrahepatic portosystemic shunt was required less often in the restrictive-strategy group than in the liberal-strategy group, as was emergency surgery to control further bleeding from peptic ulcer.

The rate of overall complications was significantly lower with the restrictive strategy (40%) than with the liberal strategy (48%), as was the rate of serious adverse events. In addition, transfusion reactions and cardiac events such as pulmonary edema were more frequent with the liberal strategy.

"Our results are consistent with those from previous observational studies and randomized trials performed in other settings, which have shown that a restrictive transfusion strategy did not increase, and even decreased, the mortality observed with a liberal transfusion strategy," Dr. Villanueva and his associates said.

For patients with severe acute GI bleeding, outcomes are significantly better when a restrictive transfusion strategy is used – limiting the hemoglobin threshold to 7 g/dL – rather than a liberal transfusion strategy allowing a 9 g/dL threshold, according to a report published online Jan. 2 in the New England Journal of Medicine.

In a single-center randomized controlled trial involving 889 patients, the restrictive transfusion strategy resulted in significantly lower mortality, lower rates of rebleeding, less frequent need for rescue therapy, fewer complications, and shorter hospitalizations than did the liberal transfusion strategy. "Our results suggest that in patients with acute GI bleeding, a strategy of not performing transfusion until the hemoglobin concentration falls below 7 g/dL is a safe and effective approach," said Dr. Càndid Villanueva of Hospital de Sant Pau, Barcelona, and his associates.

"Current international guidelines recommend decreasing the hemoglobin threshold level for transfusion ... from 10g/dL to 7 g/dL" in such patients, but these recommendations are based on trials involving critically ill patients with normovolemic anemia that did not include subjects with acute bleeding. "Transfusion requirements may be different for patients with acute hemorrhage due to factors such as hemodynamic instability or rapid onset of anemia" resulting from extremely low hemoglobin levels.

In particular, results of animal studies suggest that transfusion can be especially harmful in patients with bleeding from portal hypertension sources, "since restitution of blood volume after hemorrhage can lead to a rebound increase in portal pressure, which is associated with a risk of rebleeding," the investigators noted.

To examine the effects of different transfusion strategies in this setting, Dr. Villanueva and his colleagues enrolled adults who presented with hematemesis, melena, or both, randomly assigning 444 to receive restrictive transfusion (with a target range for the posttransfusion hemoglobin level of 7-9 g/dL) and 445 to receive liberal transfusion (with a target range of 9-11 g/dL).

The study protocol permitted transfusions to be administered at the discretion of the attending physician any time symptoms or signs of anemia developed, massive bleeding occurred, or surgical intervention was needed, as well as when hemoglobin levels dipped below the assigned threshold.

All the study subjects underwent emergency gastroscopy within 6 hours of presentation, with appropriate treatment when the source of the bleeding was identified. Diagnoses included peptic ulcer, esophageal varices, cirrhosis, portal hypertension, and nonvariceal lesions.

The primary outcome measure, mortality from any cause at 45 days, was significantly lower in the restrictive-strategy group (5%) than the liberal-strategy group (9%). Death resulted from uncontrolled bleeding in 0.7% vs 3.1% of the 2 groups, respectively, the researchers said (N. Engl. J. Med. 2013 Jan. 2 [doi:10.1056/NEJMoa1211801]).

The rate of rebleeding also was significantly lower with the restrictive strategy (10% vs. 16%), and length of hospital stay was significantly shorter. In addition, rescue therapy for esophageal varices with balloon tamponade or a transjugular intrahepatic portosystemic shunt was required less often in the restrictive-strategy group than in the liberal-strategy group, as was emergency surgery to control further bleeding from peptic ulcer.

The rate of overall complications was significantly lower with the restrictive strategy (40%) than with the liberal strategy (48%), as was the rate of serious adverse events. In addition, transfusion reactions and cardiac events such as pulmonary edema were more frequent with the liberal strategy.

"Our results are consistent with those from previous observational studies and randomized trials performed in other settings, which have shown that a restrictive transfusion strategy did not increase, and even decreased, the mortality observed with a liberal transfusion strategy," Dr. Villanueva and his associates said.

Higher grades of obesity were associated with greater all-cause mortality than was normal weight, but low-grade obesity and overweight were linked to lower mortality in a meta-analysis of 97 clinical studies reported in the Jan. 2 issue of JAMA.

These findings, from a systematic review that included nearly 3 million study subjects on five continents, are "broadly consistent" with those of several previous studies and two previous meta-analyses: Excess mortality occurs only at the highest levels of obesity, while mortality is lower among overweight and slightly obese individuals than among people of normal weight, said Katherine M. Flegal, Ph.D., of the National Center for Health Statistics, Hyattsville, Md., and her associates.

The investigators reviewed the literature and included in their meta-analysis all prospective, observational cohort studies that reported all-cause mortality in adults whose body mass index was measured using standard categories. A BMI of less than 18.5 was underweight, that of 18.5 to less than 25 was normal weight, a BMI of 25 to less than 30 was overweight, that of 30 to less than 35 was grade 1 obesity, a BMI of 35 to less than 40 was grade 2 obesity, and a BMI of 40 or greater was grade 3 obesity.

The researchers included 41 studies from the United States or Canada, 37 from Europe, 7 from Australia, 4 from China or Taiwan, 2 from Japan, 2 from Israel, 2 from Brazil, 1 from India, and 1 from Mexico. Overall there were 2.8 million subjects and 270,000 deaths during follow-up.

Overweight and grade 1 obesity were associated with significantly lower mortality than was normal weight, with hazard ratios of 0.94 and 0.95, respectively. In contrast, grade 1 and grade 2 obesity were associated with significantly higher mortality than was normal weight, with an HR of 1.29, Dr. Flegal and her colleagues said (JAMA 2013;309:71-82).

These findings remained robust in several sensitivity analyses.

The reasons why overweight and slight obesity might be protective are still unknown. Some have proposed that slightly heavy patients might present for medical care earlier than normal weight and severely obese patients when symptoms arise, and they also may be more likely to receive optimal medical treatment because caregivers recognize that their weight confers risk. It also is possible that slightly increased body fat may exert cardioprotective metabolic effects and provide better metabolic reserves when illness occurs, the investigators said.

Their meta-analysis also demonstrated that studies relying on patients’ self-report of weight and height are subject to important bias, because these measures are not accurately reported across all categories of age, sex, and race.

No financial conflicts of interest were reported.

Higher grades of obesity were associated with greater all-cause mortality than was normal weight, but low-grade obesity and overweight were linked to lower mortality in a meta-analysis of 97 clinical studies reported in the Jan. 2 issue of JAMA.

These findings, from a systematic review that included nearly 3 million study subjects on five continents, are "broadly consistent" with those of several previous studies and two previous meta-analyses: Excess mortality occurs only at the highest levels of obesity, while mortality is lower among overweight and slightly obese individuals than among people of normal weight, said Katherine M. Flegal, Ph.D., of the National Center for Health Statistics, Hyattsville, Md., and her associates.

The investigators reviewed the literature and included in their meta-analysis all prospective, observational cohort studies that reported all-cause mortality in adults whose body mass index was measured using standard categories. A BMI of less than 18.5 was underweight, that of 18.5 to less than 25 was normal weight, a BMI of 25 to less than 30 was overweight, that of 30 to less than 35 was grade 1 obesity, a BMI of 35 to less than 40 was grade 2 obesity, and a BMI of 40 or greater was grade 3 obesity.

The researchers included 41 studies from the United States or Canada, 37 from Europe, 7 from Australia, 4 from China or Taiwan, 2 from Japan, 2 from Israel, 2 from Brazil, 1 from India, and 1 from Mexico. Overall there were 2.8 million subjects and 270,000 deaths during follow-up.

Overweight and grade 1 obesity were associated with significantly lower mortality than was normal weight, with hazard ratios of 0.94 and 0.95, respectively. In contrast, grade 1 and grade 2 obesity were associated with significantly higher mortality than was normal weight, with an HR of 1.29, Dr. Flegal and her colleagues said (JAMA 2013;309:71-82).

These findings remained robust in several sensitivity analyses.

The reasons why overweight and slight obesity might be protective are still unknown. Some have proposed that slightly heavy patients might present for medical care earlier than normal weight and severely obese patients when symptoms arise, and they also may be more likely to receive optimal medical treatment because caregivers recognize that their weight confers risk. It also is possible that slightly increased body fat may exert cardioprotective metabolic effects and provide better metabolic reserves when illness occurs, the investigators said.

Their meta-analysis also demonstrated that studies relying on patients’ self-report of weight and height are subject to important bias, because these measures are not accurately reported across all categories of age, sex, and race.

No financial conflicts of interest were reported.

Higher grades of obesity were associated with greater all-cause mortality than was normal weight, but low-grade obesity and overweight were linked to lower mortality in a meta-analysis of 97 clinical studies reported in the Jan. 2 issue of JAMA.

These findings, from a systematic review that included nearly 3 million study subjects on five continents, are "broadly consistent" with those of several previous studies and two previous meta-analyses: Excess mortality occurs only at the highest levels of obesity, while mortality is lower among overweight and slightly obese individuals than among people of normal weight, said Katherine M. Flegal, Ph.D., of the National Center for Health Statistics, Hyattsville, Md., and her associates.

The investigators reviewed the literature and included in their meta-analysis all prospective, observational cohort studies that reported all-cause mortality in adults whose body mass index was measured using standard categories. A BMI of less than 18.5 was underweight, that of 18.5 to less than 25 was normal weight, a BMI of 25 to less than 30 was overweight, that of 30 to less than 35 was grade 1 obesity, a BMI of 35 to less than 40 was grade 2 obesity, and a BMI of 40 or greater was grade 3 obesity.

The researchers included 41 studies from the United States or Canada, 37 from Europe, 7 from Australia, 4 from China or Taiwan, 2 from Japan, 2 from Israel, 2 from Brazil, 1 from India, and 1 from Mexico. Overall there were 2.8 million subjects and 270,000 deaths during follow-up.

Overweight and grade 1 obesity were associated with significantly lower mortality than was normal weight, with hazard ratios of 0.94 and 0.95, respectively. In contrast, grade 1 and grade 2 obesity were associated with significantly higher mortality than was normal weight, with an HR of 1.29, Dr. Flegal and her colleagues said (JAMA 2013;309:71-82).

These findings remained robust in several sensitivity analyses.

The reasons why overweight and slight obesity might be protective are still unknown. Some have proposed that slightly heavy patients might present for medical care earlier than normal weight and severely obese patients when symptoms arise, and they also may be more likely to receive optimal medical treatment because caregivers recognize that their weight confers risk. It also is possible that slightly increased body fat may exert cardioprotective metabolic effects and provide better metabolic reserves when illness occurs, the investigators said.

Their meta-analysis also demonstrated that studies relying on patients’ self-report of weight and height are subject to important bias, because these measures are not accurately reported across all categories of age, sex, and race.

No financial conflicts of interest were reported.

Maternal use of selective serotonin reuptake inhibitors during pregnancy showed no association with stillbirth, neonatal mortality, or infant death up to 1 year of age in a large epidemiologic study reported in the Jan. 2 issue of JAMA.

An unadjusted preliminary analysis of the data, which covered 1.6 million recent singleton births in five Nordic countries, showed an association between SSRI use and both stillbirth and 1-year mortality. But that association disappeared once the data were adjusted to account for the severity of the mother’s underlying psychiatric disease and other maternal factors such as advanced age and smoking status, said Dr. Olof Stephansson of the Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, and his associates.

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"To our knowledge, only two studies have specifically addressed the risk of stillbirth or infant death after prenatal SSRI exposure," and neither one accounted for underlying maternal psychiatric disease. The findings of these two studies were somewhat equivocal.

Dr. Stephansson and his colleagues examined the issue using information in national registries of the entire populations of Denmark, Finland, Iceland, Norway, and Sweden. They analyzed prospectively collected data regarding 1,633,877 singleton births during several time periods between 1996 and 2007. In 29,228 (2%) of these cases, the mother had filled prescriptions for SSRIs during pregnancy.

The most frequently used SSRI was citalopram (6.49 prescriptions per 1,000 population), followed by fluoxetine (4.66/1,000) and sertraline (3.93/1,000). Paroxetine, fluvoxamine, and escitalopram also were included in the study.

There were 135 stillbirths, 74 neonatal deaths, and 40 postneonatal deaths among women who took SSRIs during pregnancy.

In a preliminary analysis, rates of stillbirth and postneonatal death were higher among women who took the antidepressants than among women who didn’t. However, in the final analysis that accounted for maternal characteristics including previous psychiatric hospitalizations, SSRI exposure was no longer associated with stillbirth or postneonatal death.

A sensitivity analysis produced essentially the same results, the investigators said (JAMA 2013;309:48-54).

In a further analysis of SSRI exposure by trimester, the risk of stillbirth appeared to be slightly elevated if exposure occurred during the first trimester, while the risks of neonatal and postneonatal death were not affected by trimester of exposure. However, this finding must be interpreted with caution because of the small number of study subjects in each category of exposure, the researchers said.

This study also was limited in that it did not include information on several variables that could affect rates of stillbirth, neonatal mortality, and infant mortality, such as the mothers’ alcohol intake or use of illegal drugs during pregnancy, their use of medications other than SSRIs, and the dosage levels of their SSRIs, Dr. Stephansson and his associates added.

This study was funded by the Swedish Pharmacy Co. and the investigators’ affiliated organizations. No financial conflicts of interest were reported.

Maternal use of selective serotonin reuptake inhibitors during pregnancy showed no association with stillbirth, neonatal mortality, or infant death up to 1 year of age in a large epidemiologic study reported in the Jan. 2 issue of JAMA.

An unadjusted preliminary analysis of the data, which covered 1.6 million recent singleton births in five Nordic countries, showed an association between SSRI use and both stillbirth and 1-year mortality. But that association disappeared once the data were adjusted to account for the severity of the mother’s underlying psychiatric disease and other maternal factors such as advanced age and smoking status, said Dr. Olof Stephansson of the Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, and his associates.

Creatas Images

"To our knowledge, only two studies have specifically addressed the risk of stillbirth or infant death after prenatal SSRI exposure," and neither one accounted for underlying maternal psychiatric disease. The findings of these two studies were somewhat equivocal.

Dr. Stephansson and his colleagues examined the issue using information in national registries of the entire populations of Denmark, Finland, Iceland, Norway, and Sweden. They analyzed prospectively collected data regarding 1,633,877 singleton births during several time periods between 1996 and 2007. In 29,228 (2%) of these cases, the mother had filled prescriptions for SSRIs during pregnancy.

The most frequently used SSRI was citalopram (6.49 prescriptions per 1,000 population), followed by fluoxetine (4.66/1,000) and sertraline (3.93/1,000). Paroxetine, fluvoxamine, and escitalopram also were included in the study.

There were 135 stillbirths, 74 neonatal deaths, and 40 postneonatal deaths among women who took SSRIs during pregnancy.

In a preliminary analysis, rates of stillbirth and postneonatal death were higher among women who took the antidepressants than among women who didn’t. However, in the final analysis that accounted for maternal characteristics including previous psychiatric hospitalizations, SSRI exposure was no longer associated with stillbirth or postneonatal death.

A sensitivity analysis produced essentially the same results, the investigators said (JAMA 2013;309:48-54).

In a further analysis of SSRI exposure by trimester, the risk of stillbirth appeared to be slightly elevated if exposure occurred during the first trimester, while the risks of neonatal and postneonatal death were not affected by trimester of exposure. However, this finding must be interpreted with caution because of the small number of study subjects in each category of exposure, the researchers said.

This study also was limited in that it did not include information on several variables that could affect rates of stillbirth, neonatal mortality, and infant mortality, such as the mothers’ alcohol intake or use of illegal drugs during pregnancy, their use of medications other than SSRIs, and the dosage levels of their SSRIs, Dr. Stephansson and his associates added.

This study was funded by the Swedish Pharmacy Co. and the investigators’ affiliated organizations. No financial conflicts of interest were reported.

Maternal use of selective serotonin reuptake inhibitors during pregnancy showed no association with stillbirth, neonatal mortality, or infant death up to 1 year of age in a large epidemiologic study reported in the Jan. 2 issue of JAMA.

An unadjusted preliminary analysis of the data, which covered 1.6 million recent singleton births in five Nordic countries, showed an association between SSRI use and both stillbirth and 1-year mortality. But that association disappeared once the data were adjusted to account for the severity of the mother’s underlying psychiatric disease and other maternal factors such as advanced age and smoking status, said Dr. Olof Stephansson of the Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, and his associates.

Creatas Images

"To our knowledge, only two studies have specifically addressed the risk of stillbirth or infant death after prenatal SSRI exposure," and neither one accounted for underlying maternal psychiatric disease. The findings of these two studies were somewhat equivocal.

Dr. Stephansson and his colleagues examined the issue using information in national registries of the entire populations of Denmark, Finland, Iceland, Norway, and Sweden. They analyzed prospectively collected data regarding 1,633,877 singleton births during several time periods between 1996 and 2007. In 29,228 (2%) of these cases, the mother had filled prescriptions for SSRIs during pregnancy.

The most frequently used SSRI was citalopram (6.49 prescriptions per 1,000 population), followed by fluoxetine (4.66/1,000) and sertraline (3.93/1,000). Paroxetine, fluvoxamine, and escitalopram also were included in the study.

There were 135 stillbirths, 74 neonatal deaths, and 40 postneonatal deaths among women who took SSRIs during pregnancy.

In a preliminary analysis, rates of stillbirth and postneonatal death were higher among women who took the antidepressants than among women who didn’t. However, in the final analysis that accounted for maternal characteristics including previous psychiatric hospitalizations, SSRI exposure was no longer associated with stillbirth or postneonatal death.

A sensitivity analysis produced essentially the same results, the investigators said (JAMA 2013;309:48-54).

In a further analysis of SSRI exposure by trimester, the risk of stillbirth appeared to be slightly elevated if exposure occurred during the first trimester, while the risks of neonatal and postneonatal death were not affected by trimester of exposure. However, this finding must be interpreted with caution because of the small number of study subjects in each category of exposure, the researchers said.

This study also was limited in that it did not include information on several variables that could affect rates of stillbirth, neonatal mortality, and infant mortality, such as the mothers’ alcohol intake or use of illegal drugs during pregnancy, their use of medications other than SSRIs, and the dosage levels of their SSRIs, Dr. Stephansson and his associates added.

This study was funded by the Swedish Pharmacy Co. and the investigators’ affiliated organizations. No financial conflicts of interest were reported.