Sharon Worcester

Critical illness survivors who experienced a long period of delirium during an intensive care unit stay can have long-term global cognition and executive function scores similar to those seen in traumatic brain injury and Alzheimer’s patients, according to a multicenter prospective cohort study.

The finding of an association between longer duration of delirium and worse long-term global cognition and executive function was independent of sedative or analgesic medication use, age, preexisting cognitive impairment, the burden of coexisting conditions, and ongoing organ failure during ICU care, Dr. P.P. Pandharipande of Vanderbilt University, Nashville, Tenn., and his colleagues reported. The findings were published Oct. 2 in The New England Journal of Medicine.

Courtesy Vanderbilt University

Of 821 patients with respiratory failure, cardiogenic shock, or septic shock who were treated in a medical or surgical ICU, 6% had cognitive impairment at baseline and 74% experienced delirium during their hospital stay. Median global cognition scores at 3 and 12 months as assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were 79 and 80, respectively.

"These scores were approximately 1.5 [standard deviations] below the age-adjusted population mean of 100 plus or minus 15 and were similar to scores for patients with mild cognitive impairment. At 3-months, 40% of the patients had global cognition scores that were worse than those typically seen in patients with moderate traumatic brain injury, and 26% had scores 2 SD below the population means, which were similar to scores for patients with mild Alzheimer’s disease," the investigators reported.

The deficits occurred regardless of patient age and persisted to 12 months, with 34% and 24% of patients demonstrating scores similar to those for patients with moderate traumatic brain injury and for patients with mild Alzheimer’s disease, respectively, they said (N. Engl. J. Med. 2013;369:1306-16).

Duration of delirium was significantly associated with worse global cognition and significantly worse executive function at both 3- and 12-month follow-up. For example, patients with a 5-day mean duration of delirium had mean RBANS scores that were 6.3 points lower at 3 months and 5.6 points lower at 12 months than those with no delirium. They had Trails B executive-function scores that were 5.1 points lower at 3 months and 6.0 points lower at 12 months.

"A longer duration of delirium was also a risk factor for worse function in several individual RBANS domains," Dr. Pandharipande and his associates noted.

Although the investigators hypothesized that higher doses of sedative and analgesic use also would be independently associated with more severe cognitive impairment at 12 months, this did not prove to be the case. The use of higher benzodiazepine doses during hospitalization, however, was associated with worse executive function scores at 3 months.

The patients, who had a median age of 61 years and high severity of illness, were enrolled in the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study between March, 2007 and May, 2010. Delirium was assessed by the Confusion Assessment Method for the ICU, and level of consciousness was assessed using the Richmond Agitation-Sedation Scale.

It remains unclear whether any preventive or treatment strategies can reduce the risk of long-term cognitive impairment after critical illness, they said, noting that this is of concern, as "long-term cognitive impairment after critical illness may be a growing public health problem, given the large number of acutely ill patients being treated in intensive care units globally."

Though limited by an inability to test patients’ cognition before their emergent illness (although the investigators took several precautions to address this limitation), and by the fact that some patients were unable to complete all cognitive tests, the findings nevertheless demonstrate that cognitive impairment after critical illness is very common – even more so among those with longer duration of delirium – and can persist for at least 1 year, they said.

It is "possible that patients who are vulnerable to delirium owing to severe critical illness are also vulnerable to long-term cognitive impairment and that delirium does not play a causal role in the development of persistent cognitive impairment," investigators noted.

This study was supported by grants from the National Institutes of Health and the Veteran’s Affairs Clinical Science Research and Development Service, as well as by a Mentored Research Training Grant from the Foundation for Anesthesia Education and Research and the VA Tennessee Valley Geriatric Research Education and Clinical Center. Multiple study authors reported disclosures; details are available with the full text of the article at NEJM.org.

Critical illness survivors who experienced a long period of delirium during an intensive care unit stay can have long-term global cognition and executive function scores similar to those seen in traumatic brain injury and Alzheimer’s patients, according to a multicenter prospective cohort study.

The finding of an association between longer duration of delirium and worse long-term global cognition and executive function was independent of sedative or analgesic medication use, age, preexisting cognitive impairment, the burden of coexisting conditions, and ongoing organ failure during ICU care, Dr. P.P. Pandharipande of Vanderbilt University, Nashville, Tenn., and his colleagues reported. The findings were published Oct. 2 in The New England Journal of Medicine.

Courtesy Vanderbilt University

Of 821 patients with respiratory failure, cardiogenic shock, or septic shock who were treated in a medical or surgical ICU, 6% had cognitive impairment at baseline and 74% experienced delirium during their hospital stay. Median global cognition scores at 3 and 12 months as assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were 79 and 80, respectively.

"These scores were approximately 1.5 [standard deviations] below the age-adjusted population mean of 100 plus or minus 15 and were similar to scores for patients with mild cognitive impairment. At 3-months, 40% of the patients had global cognition scores that were worse than those typically seen in patients with moderate traumatic brain injury, and 26% had scores 2 SD below the population means, which were similar to scores for patients with mild Alzheimer’s disease," the investigators reported.

The deficits occurred regardless of patient age and persisted to 12 months, with 34% and 24% of patients demonstrating scores similar to those for patients with moderate traumatic brain injury and for patients with mild Alzheimer’s disease, respectively, they said (N. Engl. J. Med. 2013;369:1306-16).

Duration of delirium was significantly associated with worse global cognition and significantly worse executive function at both 3- and 12-month follow-up. For example, patients with a 5-day mean duration of delirium had mean RBANS scores that were 6.3 points lower at 3 months and 5.6 points lower at 12 months than those with no delirium. They had Trails B executive-function scores that were 5.1 points lower at 3 months and 6.0 points lower at 12 months.

"A longer duration of delirium was also a risk factor for worse function in several individual RBANS domains," Dr. Pandharipande and his associates noted.

Although the investigators hypothesized that higher doses of sedative and analgesic use also would be independently associated with more severe cognitive impairment at 12 months, this did not prove to be the case. The use of higher benzodiazepine doses during hospitalization, however, was associated with worse executive function scores at 3 months.

The patients, who had a median age of 61 years and high severity of illness, were enrolled in the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study between March, 2007 and May, 2010. Delirium was assessed by the Confusion Assessment Method for the ICU, and level of consciousness was assessed using the Richmond Agitation-Sedation Scale.

It remains unclear whether any preventive or treatment strategies can reduce the risk of long-term cognitive impairment after critical illness, they said, noting that this is of concern, as "long-term cognitive impairment after critical illness may be a growing public health problem, given the large number of acutely ill patients being treated in intensive care units globally."

Though limited by an inability to test patients’ cognition before their emergent illness (although the investigators took several precautions to address this limitation), and by the fact that some patients were unable to complete all cognitive tests, the findings nevertheless demonstrate that cognitive impairment after critical illness is very common – even more so among those with longer duration of delirium – and can persist for at least 1 year, they said.

It is "possible that patients who are vulnerable to delirium owing to severe critical illness are also vulnerable to long-term cognitive impairment and that delirium does not play a causal role in the development of persistent cognitive impairment," investigators noted.

This study was supported by grants from the National Institutes of Health and the Veteran’s Affairs Clinical Science Research and Development Service, as well as by a Mentored Research Training Grant from the Foundation for Anesthesia Education and Research and the VA Tennessee Valley Geriatric Research Education and Clinical Center. Multiple study authors reported disclosures; details are available with the full text of the article at NEJM.org.

Critical illness survivors who experienced a long period of delirium during an intensive care unit stay can have long-term global cognition and executive function scores similar to those seen in traumatic brain injury and Alzheimer’s patients, according to a multicenter prospective cohort study.

The finding of an association between longer duration of delirium and worse long-term global cognition and executive function was independent of sedative or analgesic medication use, age, preexisting cognitive impairment, the burden of coexisting conditions, and ongoing organ failure during ICU care, Dr. P.P. Pandharipande of Vanderbilt University, Nashville, Tenn., and his colleagues reported. The findings were published Oct. 2 in The New England Journal of Medicine.

Courtesy Vanderbilt University

Of 821 patients with respiratory failure, cardiogenic shock, or septic shock who were treated in a medical or surgical ICU, 6% had cognitive impairment at baseline and 74% experienced delirium during their hospital stay. Median global cognition scores at 3 and 12 months as assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were 79 and 80, respectively.

"These scores were approximately 1.5 [standard deviations] below the age-adjusted population mean of 100 plus or minus 15 and were similar to scores for patients with mild cognitive impairment. At 3-months, 40% of the patients had global cognition scores that were worse than those typically seen in patients with moderate traumatic brain injury, and 26% had scores 2 SD below the population means, which were similar to scores for patients with mild Alzheimer’s disease," the investigators reported.

The deficits occurred regardless of patient age and persisted to 12 months, with 34% and 24% of patients demonstrating scores similar to those for patients with moderate traumatic brain injury and for patients with mild Alzheimer’s disease, respectively, they said (N. Engl. J. Med. 2013;369:1306-16).

Duration of delirium was significantly associated with worse global cognition and significantly worse executive function at both 3- and 12-month follow-up. For example, patients with a 5-day mean duration of delirium had mean RBANS scores that were 6.3 points lower at 3 months and 5.6 points lower at 12 months than those with no delirium. They had Trails B executive-function scores that were 5.1 points lower at 3 months and 6.0 points lower at 12 months.

"A longer duration of delirium was also a risk factor for worse function in several individual RBANS domains," Dr. Pandharipande and his associates noted.

Although the investigators hypothesized that higher doses of sedative and analgesic use also would be independently associated with more severe cognitive impairment at 12 months, this did not prove to be the case. The use of higher benzodiazepine doses during hospitalization, however, was associated with worse executive function scores at 3 months.

The patients, who had a median age of 61 years and high severity of illness, were enrolled in the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study between March, 2007 and May, 2010. Delirium was assessed by the Confusion Assessment Method for the ICU, and level of consciousness was assessed using the Richmond Agitation-Sedation Scale.

It remains unclear whether any preventive or treatment strategies can reduce the risk of long-term cognitive impairment after critical illness, they said, noting that this is of concern, as "long-term cognitive impairment after critical illness may be a growing public health problem, given the large number of acutely ill patients being treated in intensive care units globally."

Though limited by an inability to test patients’ cognition before their emergent illness (although the investigators took several precautions to address this limitation), and by the fact that some patients were unable to complete all cognitive tests, the findings nevertheless demonstrate that cognitive impairment after critical illness is very common – even more so among those with longer duration of delirium – and can persist for at least 1 year, they said.

It is "possible that patients who are vulnerable to delirium owing to severe critical illness are also vulnerable to long-term cognitive impairment and that delirium does not play a causal role in the development of persistent cognitive impairment," investigators noted.

This study was supported by grants from the National Institutes of Health and the Veteran’s Affairs Clinical Science Research and Development Service, as well as by a Mentored Research Training Grant from the Foundation for Anesthesia Education and Research and the VA Tennessee Valley Geriatric Research Education and Clinical Center. Multiple study authors reported disclosures; details are available with the full text of the article at NEJM.org.

Exercise may be at least as effective as many drug interventions with respect to mortality outcomes for secondary prevention of coronary heart disease.

A "meta-epidemiological" study of 12 drug-related meta-analyses, 4 exercise-related meta-analyses, and 3 recent exercise trials, – including over 339,000 subjects from 305 trials – demonstrated no statistically detectable difference in mortality between exercise and drug interventions for the secondary prevention of coronary heart disease and primary prevention of diabetes and demonstrated a slight increase in the efficacy of physical activity over drug treatment for patients with stroke, judging from findings of a Cochrane review.

In coronary heart disease the risk of dying were reduced with the use of statins (odds ratio, 0.82), beta-blockers (OR, 0.85), angiotensin converting enzyme inhibitors (OR, 0.83), and antiplatelets (OR, 0.83), compared with control, and the credible intervals for these drugs ranged from 0.72 to 0.96. Exercise interventions, however, had similar point estimates but wider credible intervals that extended on both sides of 1.00 (OR, 0.89; 95% confidence interval, 0.76-1.04), Huseyin Naci, a doctoral candidate and research fellow at the London School of Economic and Political Science, and Dr. John P.A. Ioannidis, professor of medicine and director of the prevention research center at Stanford (Calif.) University, reported online Oct. 1 in BMJ.

"When compared head to head in network meta-analyses, all interventions were not different beyond chance: there were no statistically detectable differences among any of the exercise and drug intervention in terms of the effects on mortality outcomes," the investigators said (BMJ 2013 Oct. 1 [doi: 10.1136/bmj.f5577]).

Additionally, with respect to stroke, exercise was significantly more effective than drug interventions were for reducing the risk of dying (odds ratios for exercise vs. anticoagulants, 0.09; and for exercise vs. antiplatelets, 0.10). However, there was considerable uncertainty in these findings, owing to a small number of events in the exercise trials, the investigators noted.

For heart failure, on the other hand, fewer deaths occurred with diuretics and beta-blockers, compared with control (OR, 0.19 and 0.71, respectively), and diuretics were more effective than exercise, angiotensin converting enzyme inhibitors, beta-blockers, and angiotensin receptor blockers (OR, 0.24, 0.21, 0.27, 0.21, respectively). For prediabetes, neither exercise nor drug interventions were clearly effective for reducing mortality.

"In secondary analyses comparing exercise with the drug interventions pooled together, there was no definitive difference between drug and exercise intervention in coronary heart disease, heart failure, and prediabetes, but effect sizes had modestly substantial uncertainty for heart failure and prediabetes," the investigators noted

The study "highlights the near absence of evidence on the comparative effectiveness of exercise and drug interventions on mortality outcomes. Existing evidence on the mortality benefits of physical activity is limited to the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes," they said, adding that the amount of evidence on the mortality benefit of exercise is dwarfed by that of drug interventions, and there is a clear lack of exercise and drug comparisons.

"Albeit this considerable asymmetry in the evidence base, our analysis suggests that exercise potentially had similar effectiveness to drug interventions with two exceptions," they said, noting that exercise appeared more effective for stroke rehabilitation and that diuretics outperformed all comparators for heart failure.

But when the drug interventions were considered together in sensitivity analyses, exercise and drug interventions did not differ in terms of mortality benefit "in all conditions except for stroke rehabilitation, where exercise interventions were associated with a reduction in the odds of mortality more than drug interventions," they said.

The findings highlight a "blind spot" in available scientific evidence resulting from an apparent bias against testing exercise interventions – an observation that highlights "the changing landscape of medical research, which seems to increasingly favor drug interventions over strategies to modify lifestyle," they added, noting that this "lopsided nature of modern medical research" may prohibit detection of the most effective interventions for a given condition if that intervention does not involve a prescription drug.

Nevertheless, the current findings suggest that exercise interventions should be considered as a viable alternative to – or alongside – drug therapy, they said, adding that a more nuanced consideration of the effectiveness of different types of physical activity is warranted.

The findings also point to a need for additional randomized trials on the comparative effectiveness of exercise and drug interventions. Given the scarcity of financial resources to fund such trials, the investigators proposed requiring that pharmaceutical sponsors of new drugs include exercise intervention as an active comparator arm in drug trials.

"In cases where drug options provide only modest benefit, patients deserve to understand the relative impact that physical activity might have on their condition," they concluded.

The investigators reported having no disclosures.

Exercise may be at least as effective as many drug interventions with respect to mortality outcomes for secondary prevention of coronary heart disease.

A "meta-epidemiological" study of 12 drug-related meta-analyses, 4 exercise-related meta-analyses, and 3 recent exercise trials, – including over 339,000 subjects from 305 trials – demonstrated no statistically detectable difference in mortality between exercise and drug interventions for the secondary prevention of coronary heart disease and primary prevention of diabetes and demonstrated a slight increase in the efficacy of physical activity over drug treatment for patients with stroke, judging from findings of a Cochrane review.

In coronary heart disease the risk of dying were reduced with the use of statins (odds ratio, 0.82), beta-blockers (OR, 0.85), angiotensin converting enzyme inhibitors (OR, 0.83), and antiplatelets (OR, 0.83), compared with control, and the credible intervals for these drugs ranged from 0.72 to 0.96. Exercise interventions, however, had similar point estimates but wider credible intervals that extended on both sides of 1.00 (OR, 0.89; 95% confidence interval, 0.76-1.04), Huseyin Naci, a doctoral candidate and research fellow at the London School of Economic and Political Science, and Dr. John P.A. Ioannidis, professor of medicine and director of the prevention research center at Stanford (Calif.) University, reported online Oct. 1 in BMJ.

"When compared head to head in network meta-analyses, all interventions were not different beyond chance: there were no statistically detectable differences among any of the exercise and drug intervention in terms of the effects on mortality outcomes," the investigators said (BMJ 2013 Oct. 1 [doi: 10.1136/bmj.f5577]).

Additionally, with respect to stroke, exercise was significantly more effective than drug interventions were for reducing the risk of dying (odds ratios for exercise vs. anticoagulants, 0.09; and for exercise vs. antiplatelets, 0.10). However, there was considerable uncertainty in these findings, owing to a small number of events in the exercise trials, the investigators noted.

For heart failure, on the other hand, fewer deaths occurred with diuretics and beta-blockers, compared with control (OR, 0.19 and 0.71, respectively), and diuretics were more effective than exercise, angiotensin converting enzyme inhibitors, beta-blockers, and angiotensin receptor blockers (OR, 0.24, 0.21, 0.27, 0.21, respectively). For prediabetes, neither exercise nor drug interventions were clearly effective for reducing mortality.

"In secondary analyses comparing exercise with the drug interventions pooled together, there was no definitive difference between drug and exercise intervention in coronary heart disease, heart failure, and prediabetes, but effect sizes had modestly substantial uncertainty for heart failure and prediabetes," the investigators noted

The study "highlights the near absence of evidence on the comparative effectiveness of exercise and drug interventions on mortality outcomes. Existing evidence on the mortality benefits of physical activity is limited to the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes," they said, adding that the amount of evidence on the mortality benefit of exercise is dwarfed by that of drug interventions, and there is a clear lack of exercise and drug comparisons.

"Albeit this considerable asymmetry in the evidence base, our analysis suggests that exercise potentially had similar effectiveness to drug interventions with two exceptions," they said, noting that exercise appeared more effective for stroke rehabilitation and that diuretics outperformed all comparators for heart failure.

But when the drug interventions were considered together in sensitivity analyses, exercise and drug interventions did not differ in terms of mortality benefit "in all conditions except for stroke rehabilitation, where exercise interventions were associated with a reduction in the odds of mortality more than drug interventions," they said.

The findings highlight a "blind spot" in available scientific evidence resulting from an apparent bias against testing exercise interventions – an observation that highlights "the changing landscape of medical research, which seems to increasingly favor drug interventions over strategies to modify lifestyle," they added, noting that this "lopsided nature of modern medical research" may prohibit detection of the most effective interventions for a given condition if that intervention does not involve a prescription drug.

Nevertheless, the current findings suggest that exercise interventions should be considered as a viable alternative to – or alongside – drug therapy, they said, adding that a more nuanced consideration of the effectiveness of different types of physical activity is warranted.

The findings also point to a need for additional randomized trials on the comparative effectiveness of exercise and drug interventions. Given the scarcity of financial resources to fund such trials, the investigators proposed requiring that pharmaceutical sponsors of new drugs include exercise intervention as an active comparator arm in drug trials.

"In cases where drug options provide only modest benefit, patients deserve to understand the relative impact that physical activity might have on their condition," they concluded.

The investigators reported having no disclosures.

Exercise may be at least as effective as many drug interventions with respect to mortality outcomes for secondary prevention of coronary heart disease.

A "meta-epidemiological" study of 12 drug-related meta-analyses, 4 exercise-related meta-analyses, and 3 recent exercise trials, – including over 339,000 subjects from 305 trials – demonstrated no statistically detectable difference in mortality between exercise and drug interventions for the secondary prevention of coronary heart disease and primary prevention of diabetes and demonstrated a slight increase in the efficacy of physical activity over drug treatment for patients with stroke, judging from findings of a Cochrane review.

In coronary heart disease the risk of dying were reduced with the use of statins (odds ratio, 0.82), beta-blockers (OR, 0.85), angiotensin converting enzyme inhibitors (OR, 0.83), and antiplatelets (OR, 0.83), compared with control, and the credible intervals for these drugs ranged from 0.72 to 0.96. Exercise interventions, however, had similar point estimates but wider credible intervals that extended on both sides of 1.00 (OR, 0.89; 95% confidence interval, 0.76-1.04), Huseyin Naci, a doctoral candidate and research fellow at the London School of Economic and Political Science, and Dr. John P.A. Ioannidis, professor of medicine and director of the prevention research center at Stanford (Calif.) University, reported online Oct. 1 in BMJ.

"When compared head to head in network meta-analyses, all interventions were not different beyond chance: there were no statistically detectable differences among any of the exercise and drug intervention in terms of the effects on mortality outcomes," the investigators said (BMJ 2013 Oct. 1 [doi: 10.1136/bmj.f5577]).

Additionally, with respect to stroke, exercise was significantly more effective than drug interventions were for reducing the risk of dying (odds ratios for exercise vs. anticoagulants, 0.09; and for exercise vs. antiplatelets, 0.10). However, there was considerable uncertainty in these findings, owing to a small number of events in the exercise trials, the investigators noted.

For heart failure, on the other hand, fewer deaths occurred with diuretics and beta-blockers, compared with control (OR, 0.19 and 0.71, respectively), and diuretics were more effective than exercise, angiotensin converting enzyme inhibitors, beta-blockers, and angiotensin receptor blockers (OR, 0.24, 0.21, 0.27, 0.21, respectively). For prediabetes, neither exercise nor drug interventions were clearly effective for reducing mortality.

"In secondary analyses comparing exercise with the drug interventions pooled together, there was no definitive difference between drug and exercise intervention in coronary heart disease, heart failure, and prediabetes, but effect sizes had modestly substantial uncertainty for heart failure and prediabetes," the investigators noted

The study "highlights the near absence of evidence on the comparative effectiveness of exercise and drug interventions on mortality outcomes. Existing evidence on the mortality benefits of physical activity is limited to the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes," they said, adding that the amount of evidence on the mortality benefit of exercise is dwarfed by that of drug interventions, and there is a clear lack of exercise and drug comparisons.

"Albeit this considerable asymmetry in the evidence base, our analysis suggests that exercise potentially had similar effectiveness to drug interventions with two exceptions," they said, noting that exercise appeared more effective for stroke rehabilitation and that diuretics outperformed all comparators for heart failure.

But when the drug interventions were considered together in sensitivity analyses, exercise and drug interventions did not differ in terms of mortality benefit "in all conditions except for stroke rehabilitation, where exercise interventions were associated with a reduction in the odds of mortality more than drug interventions," they said.

The findings highlight a "blind spot" in available scientific evidence resulting from an apparent bias against testing exercise interventions – an observation that highlights "the changing landscape of medical research, which seems to increasingly favor drug interventions over strategies to modify lifestyle," they added, noting that this "lopsided nature of modern medical research" may prohibit detection of the most effective interventions for a given condition if that intervention does not involve a prescription drug.

Nevertheless, the current findings suggest that exercise interventions should be considered as a viable alternative to – or alongside – drug therapy, they said, adding that a more nuanced consideration of the effectiveness of different types of physical activity is warranted.

The findings also point to a need for additional randomized trials on the comparative effectiveness of exercise and drug interventions. Given the scarcity of financial resources to fund such trials, the investigators proposed requiring that pharmaceutical sponsors of new drugs include exercise intervention as an active comparator arm in drug trials.

"In cases where drug options provide only modest benefit, patients deserve to understand the relative impact that physical activity might have on their condition," they concluded.

The investigators reported having no disclosures.

Exercise may be at least as effective as many drug interventions with respect to mortality outcomes for secondary prevention of coronary heart disease.

A "meta-epidemiological" study of 12 drug-related meta-analyses, 4 exercise-related meta-analyses, and 3 recent exercise trials, – including over 339,000 subjects from 305 trials – demonstrated no statistically detectable difference in mortality between exercise and drug interventions for the secondary prevention of coronary heart disease and primary prevention of diabetes and demonstrated a slight increase in the efficacy of physical activity over drug treatment for patients with stroke, judging from findings of a Cochrane review.

In coronary heart disease the risk of dying were reduced with the use of statins (odds ratio, 0.82), beta-blockers (OR, 0.85), angiotensin converting enzyme inhibitors (OR, 0.83), and antiplatelets (OR, 0.83), compared with control, and the credible intervals for these drugs ranged from 0.72 to 0.96. Exercise interventions, however, had similar point estimates but wider credible intervals that extended on both sides of 1.00 (OR, 0.89; 95% confidence interval, 0.76-1.04), Huseyin Naci, a doctoral candidate and research fellow at the London School of Economic and Political Science, and Dr. John P.A. Ioannidis, professor of medicine and director of the prevention research center at Stanford (Calif.) University, reported online Oct. 1 in BMJ.

© Dave/Fotolia.com

"When compared head to head in network meta-analyses, all interventions were not different beyond chance: there were no statistically detectable differences among any of the exercise and drug intervention in terms of the effects on mortality outcomes," the investigators said (BMJ 2013 Oct. 1 [doi: 10.1136/bmj.f5577]).

Additionally, with respect to stroke, exercise was significantly more effective than drug interventions were for reducing the risk of dying (odds ratios for exercise vs. anticoagulants, 0.09; and for exercise vs. antiplatelets, 0.10). However, there was considerable uncertainty in these findings, owing to a small number of events in the exercise trials, the investigators noted.

For heart failure, on the other hand, fewer deaths occurred with diuretics and beta-blockers, compared with control (OR, 0.19 and 0.71, respectively), and diuretics were more effective than exercise, angiotensin converting enzyme inhibitors, beta-blockers, and angiotensin receptor blockers (OR, 0.24, 0.21, 0.27, 0.21, respectively). For prediabetes, neither exercise nor drug interventions were clearly effective for reducing mortality.

"In secondary analyses comparing exercise with the drug interventions pooled together, there was no definitive difference between drug and exercise intervention in coronary heart disease, heart failure, and prediabetes, but effect sizes had modestly substantial uncertainty for heart failure and prediabetes," the investigators noted

The study "highlights the near absence of evidence on the comparative effectiveness of exercise and drug interventions on mortality outcomes. Existing evidence on the mortality benefits of physical activity is limited to the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes," they said, adding that the amount of evidence on the mortality benefit of exercise is dwarfed by that of drug interventions, and there is a clear lack of exercise and drug comparisons.

"Albeit this considerable asymmetry in the evidence base, our analysis suggests that exercise potentially had similar effectiveness to drug interventions with two exceptions," they said, noting that exercise appeared more effective for stroke rehabilitation and that diuretics outperformed all comparators for heart failure.

But when the drug interventions were considered together in sensitivity analyses, exercise and drug interventions did not differ in terms of mortality benefit "in all conditions except for stroke rehabilitation, where exercise interventions were associated with a reduction in the odds of mortality more than drug interventions," they said.

The findings highlight a "blind spot" in available scientific evidence resulting from an apparent bias against testing exercise interventions – an observation that highlights "the changing landscape of medical research, which seems to increasingly favor drug interventions over strategies to modify lifestyle," they added, noting that this "lopsided nature of modern medical research" may prohibit detection of the most effective interventions for a given condition if that intervention does not involve a prescription drug.

Nevertheless, the current findings suggest that exercise interventions should be considered as a viable alternative to – or alongside – drug therapy, they said, adding that a more nuanced consideration of the effectiveness of different types of physical activity is warranted.

The findings also point to a need for additional randomized trials on the comparative effectiveness of exercise and drug interventions. Given the scarcity of financial resources to fund such trials, the investigators proposed requiring that pharmaceutical sponsors of new drugs include exercise intervention as an active comparator arm in drug trials.

"In cases where drug options provide only modest benefit, patients deserve to understand the relative impact that physical activity might have on their condition," they concluded.

The investigators reported having no disclosures.

Exercise may be at least as effective as many drug interventions with respect to mortality outcomes for secondary prevention of coronary heart disease.

A "meta-epidemiological" study of 12 drug-related meta-analyses, 4 exercise-related meta-analyses, and 3 recent exercise trials, – including over 339,000 subjects from 305 trials – demonstrated no statistically detectable difference in mortality between exercise and drug interventions for the secondary prevention of coronary heart disease and primary prevention of diabetes and demonstrated a slight increase in the efficacy of physical activity over drug treatment for patients with stroke, judging from findings of a Cochrane review.

In coronary heart disease the risk of dying were reduced with the use of statins (odds ratio, 0.82), beta-blockers (OR, 0.85), angiotensin converting enzyme inhibitors (OR, 0.83), and antiplatelets (OR, 0.83), compared with control, and the credible intervals for these drugs ranged from 0.72 to 0.96. Exercise interventions, however, had similar point estimates but wider credible intervals that extended on both sides of 1.00 (OR, 0.89; 95% confidence interval, 0.76-1.04), Huseyin Naci, a doctoral candidate and research fellow at the London School of Economic and Political Science, and Dr. John P.A. Ioannidis, professor of medicine and director of the prevention research center at Stanford (Calif.) University, reported online Oct. 1 in BMJ.

© Dave/Fotolia.com

"When compared head to head in network meta-analyses, all interventions were not different beyond chance: there were no statistically detectable differences among any of the exercise and drug intervention in terms of the effects on mortality outcomes," the investigators said (BMJ 2013 Oct. 1 [doi: 10.1136/bmj.f5577]).

Additionally, with respect to stroke, exercise was significantly more effective than drug interventions were for reducing the risk of dying (odds ratios for exercise vs. anticoagulants, 0.09; and for exercise vs. antiplatelets, 0.10). However, there was considerable uncertainty in these findings, owing to a small number of events in the exercise trials, the investigators noted.

For heart failure, on the other hand, fewer deaths occurred with diuretics and beta-blockers, compared with control (OR, 0.19 and 0.71, respectively), and diuretics were more effective than exercise, angiotensin converting enzyme inhibitors, beta-blockers, and angiotensin receptor blockers (OR, 0.24, 0.21, 0.27, 0.21, respectively). For prediabetes, neither exercise nor drug interventions were clearly effective for reducing mortality.

"In secondary analyses comparing exercise with the drug interventions pooled together, there was no definitive difference between drug and exercise intervention in coronary heart disease, heart failure, and prediabetes, but effect sizes had modestly substantial uncertainty for heart failure and prediabetes," the investigators noted

The study "highlights the near absence of evidence on the comparative effectiveness of exercise and drug interventions on mortality outcomes. Existing evidence on the mortality benefits of physical activity is limited to the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes," they said, adding that the amount of evidence on the mortality benefit of exercise is dwarfed by that of drug interventions, and there is a clear lack of exercise and drug comparisons.

"Albeit this considerable asymmetry in the evidence base, our analysis suggests that exercise potentially had similar effectiveness to drug interventions with two exceptions," they said, noting that exercise appeared more effective for stroke rehabilitation and that diuretics outperformed all comparators for heart failure.

But when the drug interventions were considered together in sensitivity analyses, exercise and drug interventions did not differ in terms of mortality benefit "in all conditions except for stroke rehabilitation, where exercise interventions were associated with a reduction in the odds of mortality more than drug interventions," they said.

The findings highlight a "blind spot" in available scientific evidence resulting from an apparent bias against testing exercise interventions – an observation that highlights "the changing landscape of medical research, which seems to increasingly favor drug interventions over strategies to modify lifestyle," they added, noting that this "lopsided nature of modern medical research" may prohibit detection of the most effective interventions for a given condition if that intervention does not involve a prescription drug.

Nevertheless, the current findings suggest that exercise interventions should be considered as a viable alternative to – or alongside – drug therapy, they said, adding that a more nuanced consideration of the effectiveness of different types of physical activity is warranted.

The findings also point to a need for additional randomized trials on the comparative effectiveness of exercise and drug interventions. Given the scarcity of financial resources to fund such trials, the investigators proposed requiring that pharmaceutical sponsors of new drugs include exercise intervention as an active comparator arm in drug trials.

"In cases where drug options provide only modest benefit, patients deserve to understand the relative impact that physical activity might have on their condition," they concluded.

The investigators reported having no disclosures.

Exercise may be at least as effective as many drug interventions with respect to mortality outcomes for secondary prevention of coronary heart disease.

A "meta-epidemiological" study of 12 drug-related meta-analyses, 4 exercise-related meta-analyses, and 3 recent exercise trials, – including over 339,000 subjects from 305 trials – demonstrated no statistically detectable difference in mortality between exercise and drug interventions for the secondary prevention of coronary heart disease and primary prevention of diabetes and demonstrated a slight increase in the efficacy of physical activity over drug treatment for patients with stroke, judging from findings of a Cochrane review.

In coronary heart disease the risk of dying were reduced with the use of statins (odds ratio, 0.82), beta-blockers (OR, 0.85), angiotensin converting enzyme inhibitors (OR, 0.83), and antiplatelets (OR, 0.83), compared with control, and the credible intervals for these drugs ranged from 0.72 to 0.96. Exercise interventions, however, had similar point estimates but wider credible intervals that extended on both sides of 1.00 (OR, 0.89; 95% confidence interval, 0.76-1.04), Huseyin Naci, a doctoral candidate and research fellow at the London School of Economic and Political Science, and Dr. John P.A. Ioannidis, professor of medicine and director of the prevention research center at Stanford (Calif.) University, reported online Oct. 1 in BMJ.

© Dave/Fotolia.com

"When compared head to head in network meta-analyses, all interventions were not different beyond chance: there were no statistically detectable differences among any of the exercise and drug intervention in terms of the effects on mortality outcomes," the investigators said (BMJ 2013 Oct. 1 [doi: 10.1136/bmj.f5577]).

Additionally, with respect to stroke, exercise was significantly more effective than drug interventions were for reducing the risk of dying (odds ratios for exercise vs. anticoagulants, 0.09; and for exercise vs. antiplatelets, 0.10). However, there was considerable uncertainty in these findings, owing to a small number of events in the exercise trials, the investigators noted.

For heart failure, on the other hand, fewer deaths occurred with diuretics and beta-blockers, compared with control (OR, 0.19 and 0.71, respectively), and diuretics were more effective than exercise, angiotensin converting enzyme inhibitors, beta-blockers, and angiotensin receptor blockers (OR, 0.24, 0.21, 0.27, 0.21, respectively). For prediabetes, neither exercise nor drug interventions were clearly effective for reducing mortality.

"In secondary analyses comparing exercise with the drug interventions pooled together, there was no definitive difference between drug and exercise intervention in coronary heart disease, heart failure, and prediabetes, but effect sizes had modestly substantial uncertainty for heart failure and prediabetes," the investigators noted

The study "highlights the near absence of evidence on the comparative effectiveness of exercise and drug interventions on mortality outcomes. Existing evidence on the mortality benefits of physical activity is limited to the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes," they said, adding that the amount of evidence on the mortality benefit of exercise is dwarfed by that of drug interventions, and there is a clear lack of exercise and drug comparisons.

"Albeit this considerable asymmetry in the evidence base, our analysis suggests that exercise potentially had similar effectiveness to drug interventions with two exceptions," they said, noting that exercise appeared more effective for stroke rehabilitation and that diuretics outperformed all comparators for heart failure.

But when the drug interventions were considered together in sensitivity analyses, exercise and drug interventions did not differ in terms of mortality benefit "in all conditions except for stroke rehabilitation, where exercise interventions were associated with a reduction in the odds of mortality more than drug interventions," they said.

The findings highlight a "blind spot" in available scientific evidence resulting from an apparent bias against testing exercise interventions – an observation that highlights "the changing landscape of medical research, which seems to increasingly favor drug interventions over strategies to modify lifestyle," they added, noting that this "lopsided nature of modern medical research" may prohibit detection of the most effective interventions for a given condition if that intervention does not involve a prescription drug.

Nevertheless, the current findings suggest that exercise interventions should be considered as a viable alternative to – or alongside – drug therapy, they said, adding that a more nuanced consideration of the effectiveness of different types of physical activity is warranted.

The findings also point to a need for additional randomized trials on the comparative effectiveness of exercise and drug interventions. Given the scarcity of financial resources to fund such trials, the investigators proposed requiring that pharmaceutical sponsors of new drugs include exercise intervention as an active comparator arm in drug trials.

"In cases where drug options provide only modest benefit, patients deserve to understand the relative impact that physical activity might have on their condition," they concluded.

The investigators reported having no disclosures.

While black and Hispanic race were associated with an increase in infant bed sharing between 1993 and 2010, those whose physicians did not agree with the practice were less likely to engage in bed sharing, according to findings from the National Infant Sleep Position study.

Of 18,986 participants who took part in the annual telephone survey, 11.2% reported infant bed sharing as a usual practice, with the percentage increasing from 6.5% in 1993 to 13.5% in 2010, Dr. Eve R. Colson of Yale University, New Haven, Conn., and her colleagues reported Sept. 30 in JAMA Pediatrics.

©michaeljung/thinkstockphotos

Based on findings from 2006-2010, when questions about physician communication were added to the survey, less than half (46%) of participants reported talking with a physician about bed sharing; and most (72.6%) said their physician was against bed sharing, while 21.3% reported that their physician was neutral and 6.1% reported their physician was supportive of the practice.

Survey respondents with a physician who had a negative attitude about bed sharing were less likely to engage in the practice (odds ratio, 0.66), while a neutral attitude on the part of the physician was associated with increased bed sharing (OR, 1.38), the investigators noted. No significant association was seen between positive physician attitude toward the practice and bed sharing.

This finding could have particular implications for changing behavior, as the results suggest there needs to be more consistent physician advice in line with AAP recommendations – infants should share a room with parents without sharing a bed when sleeping – might reduce bed sharing, the investigators noted.

Among white respondents, the percentage reporting bed sharing increased significantly from 1993 to 2000, but not from 2001 to 2010. For black and Hispanic respondents, the percentage increased progressively across the study period.

After the researchers adjusted for changes in bed sharing over time, black and Hispanic maternal race was significantly associated with bed sharing (OR, 3.47 and 1.33, respectively), as was "other" maternal race (OR, 2.46), the investigators reported (JAMA Pediatr. 2013 Sept. 30 [doi:10.1001/jamapediatrics.2013.2560]).

Significant associations were seen between bed sharing and maternal educational level less than high school, compared with college or greater (OR, 1.42); household income of less than $20,000 and $20,000-$50,000, compared with income greater than $50,000 (OR, 1.69 and 1.29, respectively); living in the West, South, or mid-Atlantic, compared with the Midwest (OR, 1.61, 1.47, and 0.77, respectively); infant age younger than 8 weeks and infant age 8-15 weeks, compared with age 16 weeks or older (OR, 1.45 and 1.31, respectively); and preterm birth, compared with full-term birth (OR, 1.41).

The National Infant Sleep Position study is a cross-sectional study that tracks infant care practices through annual telephone surveys. About 1,000 nighttime caregivers of infants born within 7 months of the survey administration participated; the respondent was the infant’s mother in 84% of cases.

The findings are important because of the strong association between infant bed sharing, sudden infant death syndrome, and unintentional sleep-related infant death. While quilt and comforter use – another risk factor for sleep-related infant death declined over time, it is also strongly associated with bed sharing.

Though limited by a number of factors – such as survey responses may not reflect actual practice; there was a declining response rate in the later years of the study; and the sample was not nationally representative when compared with nationally collected vital statistics – the findings provide valuable information about trends associated with bed sharing, the investigators noted. "The data may be useful in evaluating the impact of any broad intervention to change behavior."

This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors reported having no disclosures.

While black and Hispanic race were associated with an increase in infant bed sharing between 1993 and 2010, those whose physicians did not agree with the practice were less likely to engage in bed sharing, according to findings from the National Infant Sleep Position study.

Of 18,986 participants who took part in the annual telephone survey, 11.2% reported infant bed sharing as a usual practice, with the percentage increasing from 6.5% in 1993 to 13.5% in 2010, Dr. Eve R. Colson of Yale University, New Haven, Conn., and her colleagues reported Sept. 30 in JAMA Pediatrics.

©michaeljung/thinkstockphotos

Based on findings from 2006-2010, when questions about physician communication were added to the survey, less than half (46%) of participants reported talking with a physician about bed sharing; and most (72.6%) said their physician was against bed sharing, while 21.3% reported that their physician was neutral and 6.1% reported their physician was supportive of the practice.

Survey respondents with a physician who had a negative attitude about bed sharing were less likely to engage in the practice (odds ratio, 0.66), while a neutral attitude on the part of the physician was associated with increased bed sharing (OR, 1.38), the investigators noted. No significant association was seen between positive physician attitude toward the practice and bed sharing.

This finding could have particular implications for changing behavior, as the results suggest there needs to be more consistent physician advice in line with AAP recommendations – infants should share a room with parents without sharing a bed when sleeping – might reduce bed sharing, the investigators noted.

Among white respondents, the percentage reporting bed sharing increased significantly from 1993 to 2000, but not from 2001 to 2010. For black and Hispanic respondents, the percentage increased progressively across the study period.

After the researchers adjusted for changes in bed sharing over time, black and Hispanic maternal race was significantly associated with bed sharing (OR, 3.47 and 1.33, respectively), as was "other" maternal race (OR, 2.46), the investigators reported (JAMA Pediatr. 2013 Sept. 30 [doi:10.1001/jamapediatrics.2013.2560]).

Significant associations were seen between bed sharing and maternal educational level less than high school, compared with college or greater (OR, 1.42); household income of less than $20,000 and $20,000-$50,000, compared with income greater than $50,000 (OR, 1.69 and 1.29, respectively); living in the West, South, or mid-Atlantic, compared with the Midwest (OR, 1.61, 1.47, and 0.77, respectively); infant age younger than 8 weeks and infant age 8-15 weeks, compared with age 16 weeks or older (OR, 1.45 and 1.31, respectively); and preterm birth, compared with full-term birth (OR, 1.41).

The National Infant Sleep Position study is a cross-sectional study that tracks infant care practices through annual telephone surveys. About 1,000 nighttime caregivers of infants born within 7 months of the survey administration participated; the respondent was the infant’s mother in 84% of cases.

The findings are important because of the strong association between infant bed sharing, sudden infant death syndrome, and unintentional sleep-related infant death. While quilt and comforter use – another risk factor for sleep-related infant death declined over time, it is also strongly associated with bed sharing.

Though limited by a number of factors – such as survey responses may not reflect actual practice; there was a declining response rate in the later years of the study; and the sample was not nationally representative when compared with nationally collected vital statistics – the findings provide valuable information about trends associated with bed sharing, the investigators noted. "The data may be useful in evaluating the impact of any broad intervention to change behavior."

This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors reported having no disclosures.

While black and Hispanic race were associated with an increase in infant bed sharing between 1993 and 2010, those whose physicians did not agree with the practice were less likely to engage in bed sharing, according to findings from the National Infant Sleep Position study.

Of 18,986 participants who took part in the annual telephone survey, 11.2% reported infant bed sharing as a usual practice, with the percentage increasing from 6.5% in 1993 to 13.5% in 2010, Dr. Eve R. Colson of Yale University, New Haven, Conn., and her colleagues reported Sept. 30 in JAMA Pediatrics.

©michaeljung/thinkstockphotos

Based on findings from 2006-2010, when questions about physician communication were added to the survey, less than half (46%) of participants reported talking with a physician about bed sharing; and most (72.6%) said their physician was against bed sharing, while 21.3% reported that their physician was neutral and 6.1% reported their physician was supportive of the practice.

Survey respondents with a physician who had a negative attitude about bed sharing were less likely to engage in the practice (odds ratio, 0.66), while a neutral attitude on the part of the physician was associated with increased bed sharing (OR, 1.38), the investigators noted. No significant association was seen between positive physician attitude toward the practice and bed sharing.

This finding could have particular implications for changing behavior, as the results suggest there needs to be more consistent physician advice in line with AAP recommendations – infants should share a room with parents without sharing a bed when sleeping – might reduce bed sharing, the investigators noted.

Among white respondents, the percentage reporting bed sharing increased significantly from 1993 to 2000, but not from 2001 to 2010. For black and Hispanic respondents, the percentage increased progressively across the study period.

After the researchers adjusted for changes in bed sharing over time, black and Hispanic maternal race was significantly associated with bed sharing (OR, 3.47 and 1.33, respectively), as was "other" maternal race (OR, 2.46), the investigators reported (JAMA Pediatr. 2013 Sept. 30 [doi:10.1001/jamapediatrics.2013.2560]).

Significant associations were seen between bed sharing and maternal educational level less than high school, compared with college or greater (OR, 1.42); household income of less than $20,000 and $20,000-$50,000, compared with income greater than $50,000 (OR, 1.69 and 1.29, respectively); living in the West, South, or mid-Atlantic, compared with the Midwest (OR, 1.61, 1.47, and 0.77, respectively); infant age younger than 8 weeks and infant age 8-15 weeks, compared with age 16 weeks or older (OR, 1.45 and 1.31, respectively); and preterm birth, compared with full-term birth (OR, 1.41).

The National Infant Sleep Position study is a cross-sectional study that tracks infant care practices through annual telephone surveys. About 1,000 nighttime caregivers of infants born within 7 months of the survey administration participated; the respondent was the infant’s mother in 84% of cases.

The findings are important because of the strong association between infant bed sharing, sudden infant death syndrome, and unintentional sleep-related infant death. While quilt and comforter use – another risk factor for sleep-related infant death declined over time, it is also strongly associated with bed sharing.

Though limited by a number of factors – such as survey responses may not reflect actual practice; there was a declining response rate in the later years of the study; and the sample was not nationally representative when compared with nationally collected vital statistics – the findings provide valuable information about trends associated with bed sharing, the investigators noted. "The data may be useful in evaluating the impact of any broad intervention to change behavior."

This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors reported having no disclosures.

LAS VEGAS – The future looks bright for lupus treatment given the extensive list of drugs and targets currently undergoing evaluation, but for now treatment remains largely an art, according to Dr. Richard Furie.

"We try to integrate science, but it really is an art – these patients are very difficult," he said at the meeting.

That’s because of the heterogeneity of the disease, and the need to balance the benefits of treatment against the potential harms, which are extensive with currently available drugs, he explained.

Success is best achieved by "getting back to basics," he added.

First, as simple as it sounds, "do good" by controlling disease activity, preventing damage from disease, and preventing flares – as even one flare can cause damage – and "do no harm," which requires preventing damage from treatment and avoiding the treatment of damage with agents intended for active disease, he said.

"This is difficult, but the last thing we want to do is bombard a patient with potentially toxic medication when they are not going to reverse damage. ... We have a lot of potentially harmful medications. ... The name of the game is to minimize damage over time," said Dr. Furie, chief of the division of rheumatology at North Shore–LIJ Health System and professor of medicine at Hofstra North Shore–LIJ School of Medicine in Hempstead, N.Y.

Dr. Furie outlined his principles for treatment design:

• Identify disease manifestations.

• Distinguish activity from chronicity. For example, it is important to determine if a rash represents active disease or a scar, and whether proteinuria represents active nephritis or previous damage.

• Prioritize active disease manifestations.

• View disease activity as a continuum.

• Treat with the least toxic medicine and the lowest dose needed to address the most concerning disease manifestation. This will hopefully bring other manifestations under control as well, but treating too aggressively can lead to unnecessary damage, he said.

As for currently available treatments, "we’ve come a long way and patients are doing better," he said.

But the number of medications remains limited, and a great deal more work must be done, particularly with respect to lupus nephritis.

"At best, we do a good job with treatment in about 30%-40% of [patients with lupus nephritis], so in more than half we’re not doing well," he said.

More efficacious therapies are also needed for severe extrarenal lupus, flare prevention, and remission induction, he said, noting that treatments that are safer than steroids and cyclophosphamide also are needed.

Among currently used treatments, rituximab, while promising in open-label studies and off-label experience, has had disappointing results in randomized, controlled clinical trials. It nonetheless remains "in the toolbox," Dr. Furie said, noting that interest remains high in studying the agent for nephritis.

Mycophenolate mofetil also has been disappointing, in that it failed to show superiority to cyclophosphamide in the Aspreva Lupus Management Study (ALMS). However, Dr. Furie classified this drug as a "successful failure," because ALMS demonstrated what many had already believed – that mycophenolate mofetil is a good drug for lupus nephritis (J. Am. Soc. Nephrol. 2009;20:1103-12) .

Another agent, belimumab, on the other hand, represents a success story – and a history-making success story at that, he said.

Belimumab was the first drug approved for SLE via a randomized controlled trial, he explained, noting that it has favorable effects on steroid tapering to under 7.5 mg/day, 36-Item Short Form Health Survey (SF-36) fatigue scores, flare rates, and DNA antibody and complement levels – all with a favorable safety profile.

Unfortunately, the failures outweigh the successes with respect to the "humbling process" of drug development, but many drugs and targets are currently being investigated, he said.

In fact, there are more studies than there are patients, he said, adding, "but it still strikes me how many companies want to go forward in lupus, and I think it’s great for the field."

"There are a lot of interesting drugs on the horizon. ... We will someday have biomarkers, personalized therapy, and better outcomes," he said at the meeting, held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

Dr. Furie reported receiving research support and/or serving as a consultant or investigator for several companies, including AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Merck, and Novartis. He also has received research support from the National Institute of Allergy and Infectious Diseases.

LAS VEGAS – The future looks bright for lupus treatment given the extensive list of drugs and targets currently undergoing evaluation, but for now treatment remains largely an art, according to Dr. Richard Furie.

"We try to integrate science, but it really is an art – these patients are very difficult," he said at the meeting.

That’s because of the heterogeneity of the disease, and the need to balance the benefits of treatment against the potential harms, which are extensive with currently available drugs, he explained.

Success is best achieved by "getting back to basics," he added.

First, as simple as it sounds, "do good" by controlling disease activity, preventing damage from disease, and preventing flares – as even one flare can cause damage – and "do no harm," which requires preventing damage from treatment and avoiding the treatment of damage with agents intended for active disease, he said.

"This is difficult, but the last thing we want to do is bombard a patient with potentially toxic medication when they are not going to reverse damage. ... We have a lot of potentially harmful medications. ... The name of the game is to minimize damage over time," said Dr. Furie, chief of the division of rheumatology at North Shore–LIJ Health System and professor of medicine at Hofstra North Shore–LIJ School of Medicine in Hempstead, N.Y.

Dr. Furie outlined his principles for treatment design:

• Identify disease manifestations.

• Distinguish activity from chronicity. For example, it is important to determine if a rash represents active disease or a scar, and whether proteinuria represents active nephritis or previous damage.

• Prioritize active disease manifestations.

• View disease activity as a continuum.

• Treat with the least toxic medicine and the lowest dose needed to address the most concerning disease manifestation. This will hopefully bring other manifestations under control as well, but treating too aggressively can lead to unnecessary damage, he said.

As for currently available treatments, "we’ve come a long way and patients are doing better," he said.

But the number of medications remains limited, and a great deal more work must be done, particularly with respect to lupus nephritis.

"At best, we do a good job with treatment in about 30%-40% of [patients with lupus nephritis], so in more than half we’re not doing well," he said.

More efficacious therapies are also needed for severe extrarenal lupus, flare prevention, and remission induction, he said, noting that treatments that are safer than steroids and cyclophosphamide also are needed.

Among currently used treatments, rituximab, while promising in open-label studies and off-label experience, has had disappointing results in randomized, controlled clinical trials. It nonetheless remains "in the toolbox," Dr. Furie said, noting that interest remains high in studying the agent for nephritis.

Mycophenolate mofetil also has been disappointing, in that it failed to show superiority to cyclophosphamide in the Aspreva Lupus Management Study (ALMS). However, Dr. Furie classified this drug as a "successful failure," because ALMS demonstrated what many had already believed – that mycophenolate mofetil is a good drug for lupus nephritis (J. Am. Soc. Nephrol. 2009;20:1103-12) .

Another agent, belimumab, on the other hand, represents a success story – and a history-making success story at that, he said.

Belimumab was the first drug approved for SLE via a randomized controlled trial, he explained, noting that it has favorable effects on steroid tapering to under 7.5 mg/day, 36-Item Short Form Health Survey (SF-36) fatigue scores, flare rates, and DNA antibody and complement levels – all with a favorable safety profile.

Unfortunately, the failures outweigh the successes with respect to the "humbling process" of drug development, but many drugs and targets are currently being investigated, he said.

In fact, there are more studies than there are patients, he said, adding, "but it still strikes me how many companies want to go forward in lupus, and I think it’s great for the field."

"There are a lot of interesting drugs on the horizon. ... We will someday have biomarkers, personalized therapy, and better outcomes," he said at the meeting, held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

Dr. Furie reported receiving research support and/or serving as a consultant or investigator for several companies, including AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Merck, and Novartis. He also has received research support from the National Institute of Allergy and Infectious Diseases.

LAS VEGAS – The future looks bright for lupus treatment given the extensive list of drugs and targets currently undergoing evaluation, but for now treatment remains largely an art, according to Dr. Richard Furie.

"We try to integrate science, but it really is an art – these patients are very difficult," he said at the meeting.

That’s because of the heterogeneity of the disease, and the need to balance the benefits of treatment against the potential harms, which are extensive with currently available drugs, he explained.

Success is best achieved by "getting back to basics," he added.

First, as simple as it sounds, "do good" by controlling disease activity, preventing damage from disease, and preventing flares – as even one flare can cause damage – and "do no harm," which requires preventing damage from treatment and avoiding the treatment of damage with agents intended for active disease, he said.

"This is difficult, but the last thing we want to do is bombard a patient with potentially toxic medication when they are not going to reverse damage. ... We have a lot of potentially harmful medications. ... The name of the game is to minimize damage over time," said Dr. Furie, chief of the division of rheumatology at North Shore–LIJ Health System and professor of medicine at Hofstra North Shore–LIJ School of Medicine in Hempstead, N.Y.

Dr. Furie outlined his principles for treatment design:

• Identify disease manifestations.

• Distinguish activity from chronicity. For example, it is important to determine if a rash represents active disease or a scar, and whether proteinuria represents active nephritis or previous damage.

• Prioritize active disease manifestations.

• View disease activity as a continuum.

• Treat with the least toxic medicine and the lowest dose needed to address the most concerning disease manifestation. This will hopefully bring other manifestations under control as well, but treating too aggressively can lead to unnecessary damage, he said.

As for currently available treatments, "we’ve come a long way and patients are doing better," he said.

But the number of medications remains limited, and a great deal more work must be done, particularly with respect to lupus nephritis.

"At best, we do a good job with treatment in about 30%-40% of [patients with lupus nephritis], so in more than half we’re not doing well," he said.

More efficacious therapies are also needed for severe extrarenal lupus, flare prevention, and remission induction, he said, noting that treatments that are safer than steroids and cyclophosphamide also are needed.

Among currently used treatments, rituximab, while promising in open-label studies and off-label experience, has had disappointing results in randomized, controlled clinical trials. It nonetheless remains "in the toolbox," Dr. Furie said, noting that interest remains high in studying the agent for nephritis.

Mycophenolate mofetil also has been disappointing, in that it failed to show superiority to cyclophosphamide in the Aspreva Lupus Management Study (ALMS). However, Dr. Furie classified this drug as a "successful failure," because ALMS demonstrated what many had already believed – that mycophenolate mofetil is a good drug for lupus nephritis (J. Am. Soc. Nephrol. 2009;20:1103-12) .

Another agent, belimumab, on the other hand, represents a success story – and a history-making success story at that, he said.

Belimumab was the first drug approved for SLE via a randomized controlled trial, he explained, noting that it has favorable effects on steroid tapering to under 7.5 mg/day, 36-Item Short Form Health Survey (SF-36) fatigue scores, flare rates, and DNA antibody and complement levels – all with a favorable safety profile.

Unfortunately, the failures outweigh the successes with respect to the "humbling process" of drug development, but many drugs and targets are currently being investigated, he said.

In fact, there are more studies than there are patients, he said, adding, "but it still strikes me how many companies want to go forward in lupus, and I think it’s great for the field."

"There are a lot of interesting drugs on the horizon. ... We will someday have biomarkers, personalized therapy, and better outcomes," he said at the meeting, held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

Dr. Furie reported receiving research support and/or serving as a consultant or investigator for several companies, including AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Merck, and Novartis. He also has received research support from the National Institute of Allergy and Infectious Diseases.

LAS VEGAS – A coalition working to address dual-energy X-ray absorptiometry access issues is developing draft legislation that would establish a geographically adjusted national minimum payment for DXA, according to Dr. Michael Schweitz.

Under the draft legislation – a response to a series of reimbursement cuts over the past several years – DXA CPT codes 77080 and 77082 would be paid at $98 and $35, respectively, and a bundled code or bundled payment for bone density and vertebral fracture assessment studies would result in a national minimum payment of $133, Dr. Schweitz, president of the Coalition of State Rheumatology Organizations, said at Perspectives in Rheumatic Diseases 2013 during an update on federal legislative and regulatory issues facing rheumatologists.

Restoring reimbursement is an issue on the "front burner," he said, noting that studies have demonstrated an increase in hip fracture rates in the wake of declining reimbursement as some practices have abandoned DXA.

The DXA draft legislation is just one of a number of current legislative initiatives and issues that should be on rheumatologists’ radar, Dr. Schweitz said.

Sequestration

Under sequestration – a "heavy hammer" proposed as a way to push for agreement on a deficit-reduction plan and implemented when that agreement didn’t materialize – Medicare provider reductions are limited to 2% per year. Claims are reduced by 2% after beneficiary coinsurance or deductible. H.R. 1416, the Cancer Patient Protection Act of 2013, would terminate sequester cuts for all part B drugs, not just cancer drugs.

Medicare physician payment

Based on the formula for the Medicare sustainable growth rate, or SGR, physician payments will be cut by 24.4% if Congress does not intervene by Jan. 1, 2014. The latest cost estimate by the Congressional Budget Office for repeal of the SGR is $176 billion – far less than previous estimates and far less than the combined cost of prior short-term patches. President Barack Obama’s 2014 budget, as well as Congressional budgets and recent federal rulemakings, all assume that Congress will fix the SGR this year. Draft legislation released in July based on a replacement proposal from the bipartisan House Energy & Commerce Committee calls for a two-phase approach. Phase I would repeal the SGR entirely and replace it with a 5-year period of stable payments, including a 0.5% increase across-the-board, and phase II would involve implementation of an enhanced "PQRS-like Update Incentive Program." This would maintain fee-for-service as an option, allow providers to move into other models at any time, and would involve physician-driven quality measurement.

"This is something all of us should be aware of ... you can be sure that this whole system of reimbursement for what we do is going to change in the future," said Dr. Schweitz, who has a private practice in West Palm Beach, Fla.

How the changes would be paid for has not been defined, but there is a proposal from the House Ways & Means Committee that involves entitlement reform with increased part B/D deductibles and an increased age for eligibility.

Part B drug payments

A new bill (H.R. 800) that would affect physicians who provide in-office drug infusion excludes prompt pay discounts from manufacturers to wholesalers from the average sales price (ASP) calculation for part B drugs. This would improve payment for physicians who do not receive the discounts. However, the president’s 2014 budget assumes part B drugs are overpaid and proposes reducing Medicare payment from ASP plus 6% to ASP plus 3%.

This would require legislation to enact. The House and Senate budgets do not include any assumption regarding ASP.

"There’s very little chance, I think, that either side is going to be successful with this," Dr. Schweitz said.

The Independent Payment Advisory Board

The IPAB, a 15-member board created as part of the Affordable Care Act to make recommendations to cut spending when costs exceed growth targets, has been a contentious issue.

"There is a huge outcry in Congress against this IPAB," Dr. Schweitz said, explaining that there is a sense that the IPAB represents a usurping of the authority of Congress in controlling this part of Medicare activity.

A bipartisan repeal effort is underway in the form of H.R. 351/S. 351, the Protecting Seniors’ Access to Medicare Act. This has a chance of moving forward, but opposition in the Senate could hold it back, Dr. Schweitz said.

Of note, the president’s 2014 budget would lower the target rate that triggers IPAB recommendations from gross domestic product plus 1% to GDP plus 0.5%. Also, House Speaker John Boehner (R-Ohio) and Senate Minority Leader Mitch McConnell (R-Ky.) are on record saying that they will not nominate members to the IPAB, he said.

Private contracting

Private contracting is permitted under current law, but physicians who engage in it must opt out of Medicare for 2 years; patients who sign a private contract must pay out of pocket, even for services covered by Medicare. Under S. 236/H.R. 1310 – the Medicare Patient Empowerment Act – the 2-year opt-out requirement would be eliminated and beneficiaries could use their benefits to offset a portion of the fee set by their physician. This would protect low-income patients, "dual-eligibles," and patients with certain emergent or urgent health conditions. It is opposed by the Democratic Party and AARP, who see it as a cost-shifting mechanism; others feel it is a way to help reduce Medicare spending, he noted.

Medical liability reform

There’s been "a lot of noise but not much action" when it comes to medical liability reform, Dr. Schweitz said.

A House bill that would have included a $250,000 cap on noneconomic damages was paired with the IPAB repeal bill in the 112th Congress but did not make it to the Senate.

"There’s no such bill active in this [113th] Congress, but there are other kinds of liability reform acts that are more focused," he said.

These include H.R. 36/S. 961, the Health Care Safety Net Enhancement Act of 2013, which would extend Federal Tort Claims Act liability protections to on-call specialty physicians; H.R. 1733, the Good Samaritan Health Professionals Act of 2013, which would limit liability of health care professionals who volunteer to provide health care in response to a declared natural disaster; and H.R. 1473, the Standard of Care Protection Act, which would protect physicians from the use of quality measures for reimbursement issues in other federal health care laws to be used as standards of care in liability lawsuits.

Biosimilars

The president’s 2014 budget proposes to reduce the exclusivity for brand names from 12 years to 7 years beginning in 2014 and to prohibit "evergreening" – the securing of additional periods of exclusivity for brand biologics because of minor changes in product formulations.

Additionally, the Coalition of State Rheumatology Organizations is lobbying state legislatures to ensure that biosimilars legislation includes appropriate patient protections, such as physician notification of any substitution, appropriate record keeping, and "dispense as written" requirements. To date, five such bills have passed, with North Dakota, Utah, Virginia, and Oregon including all of these measures and Florida including all but notification.

Graduate medical education

Workforce shortages aren’t just a primary care issue. They also affect multiple specialties, including rheumatology. Though not unique in this regard, rheumatology is representative of an aging specialty, with more physicians reaching the end of their careers than young physicians entering the field. Coupled with the aging population, this raises concerns. The coalition and the Alliance of Specialty Medicine Policy Roundtable on Workforce sought cosponsors for H.R. 1180 and S. 577, the Resident Physician Shortage Reduction Act of 2013, and H.R. 1201, the Training Tomorrow’s Doctor Today Act. These legislative initiatives seek to address the problem of residency-slot shortages.

Dr. Schweitz reported having no disclosures.

rhnews@frontlinemedcom.com

LAS VEGAS – A coalition working to address dual-energy X-ray absorptiometry access issues is developing draft legislation that would establish a geographically adjusted national minimum payment for DXA, according to Dr. Michael Schweitz.

Under the draft legislation – a response to a series of reimbursement cuts over the past several years – DXA CPT codes 77080 and 77082 would be paid at $98 and $35, respectively, and a bundled code or bundled payment for bone density and vertebral fracture assessment studies would result in a national minimum payment of $133, Dr. Schweitz, president of the Coalition of State Rheumatology Organizations, said at Perspectives in Rheumatic Diseases 2013 during an update on federal legislative and regulatory issues facing rheumatologists.

Restoring reimbursement is an issue on the "front burner," he said, noting that studies have demonstrated an increase in hip fracture rates in the wake of declining reimbursement as some practices have abandoned DXA.

The DXA draft legislation is just one of a number of current legislative initiatives and issues that should be on rheumatologists’ radar, Dr. Schweitz said.

Sequestration

Under sequestration – a "heavy hammer" proposed as a way to push for agreement on a deficit-reduction plan and implemented when that agreement didn’t materialize – Medicare provider reductions are limited to 2% per year. Claims are reduced by 2% after beneficiary coinsurance or deductible. H.R. 1416, the Cancer Patient Protection Act of 2013, would terminate sequester cuts for all part B drugs, not just cancer drugs.

Medicare physician payment

Based on the formula for the Medicare sustainable growth rate, or SGR, physician payments will be cut by 24.4% if Congress does not intervene by Jan. 1, 2014. The latest cost estimate by the Congressional Budget Office for repeal of the SGR is $176 billion – far less than previous estimates and far less than the combined cost of prior short-term patches. President Barack Obama’s 2014 budget, as well as Congressional budgets and recent federal rulemakings, all assume that Congress will fix the SGR this year. Draft legislation released in July based on a replacement proposal from the bipartisan House Energy & Commerce Committee calls for a two-phase approach. Phase I would repeal the SGR entirely and replace it with a 5-year period of stable payments, including a 0.5% increase across-the-board, and phase II would involve implementation of an enhanced "PQRS-like Update Incentive Program." This would maintain fee-for-service as an option, allow providers to move into other models at any time, and would involve physician-driven quality measurement.

"This is something all of us should be aware of ... you can be sure that this whole system of reimbursement for what we do is going to change in the future," said Dr. Schweitz, who has a private practice in West Palm Beach, Fla.

How the changes would be paid for has not been defined, but there is a proposal from the House Ways & Means Committee that involves entitlement reform with increased part B/D deductibles and an increased age for eligibility.

Part B drug payments

A new bill (H.R. 800) that would affect physicians who provide in-office drug infusion excludes prompt pay discounts from manufacturers to wholesalers from the average sales price (ASP) calculation for part B drugs. This would improve payment for physicians who do not receive the discounts. However, the president’s 2014 budget assumes part B drugs are overpaid and proposes reducing Medicare payment from ASP plus 6% to ASP plus 3%.

This would require legislation to enact. The House and Senate budgets do not include any assumption regarding ASP.

"There’s very little chance, I think, that either side is going to be successful with this," Dr. Schweitz said.

The Independent Payment Advisory Board

The IPAB, a 15-member board created as part of the Affordable Care Act to make recommendations to cut spending when costs exceed growth targets, has been a contentious issue.

"There is a huge outcry in Congress against this IPAB," Dr. Schweitz said, explaining that there is a sense that the IPAB represents a usurping of the authority of Congress in controlling this part of Medicare activity.

A bipartisan repeal effort is underway in the form of H.R. 351/S. 351, the Protecting Seniors’ Access to Medicare Act. This has a chance of moving forward, but opposition in the Senate could hold it back, Dr. Schweitz said.

Of note, the president’s 2014 budget would lower the target rate that triggers IPAB recommendations from gross domestic product plus 1% to GDP plus 0.5%. Also, House Speaker John Boehner (R-Ohio) and Senate Minority Leader Mitch McConnell (R-Ky.) are on record saying that they will not nominate members to the IPAB, he said.

Private contracting

Private contracting is permitted under current law, but physicians who engage in it must opt out of Medicare for 2 years; patients who sign a private contract must pay out of pocket, even for services covered by Medicare. Under S. 236/H.R. 1310 – the Medicare Patient Empowerment Act – the 2-year opt-out requirement would be eliminated and beneficiaries could use their benefits to offset a portion of the fee set by their physician. This would protect low-income patients, "dual-eligibles," and patients with certain emergent or urgent health conditions. It is opposed by the Democratic Party and AARP, who see it as a cost-shifting mechanism; others feel it is a way to help reduce Medicare spending, he noted.

Medical liability reform

There’s been "a lot of noise but not much action" when it comes to medical liability reform, Dr. Schweitz said.

A House bill that would have included a $250,000 cap on noneconomic damages was paired with the IPAB repeal bill in the 112th Congress but did not make it to the Senate.

"There’s no such bill active in this [113th] Congress, but there are other kinds of liability reform acts that are more focused," he said.

These include H.R. 36/S. 961, the Health Care Safety Net Enhancement Act of 2013, which would extend Federal Tort Claims Act liability protections to on-call specialty physicians; H.R. 1733, the Good Samaritan Health Professionals Act of 2013, which would limit liability of health care professionals who volunteer to provide health care in response to a declared natural disaster; and H.R. 1473, the Standard of Care Protection Act, which would protect physicians from the use of quality measures for reimbursement issues in other federal health care laws to be used as standards of care in liability lawsuits.

Biosimilars

The president’s 2014 budget proposes to reduce the exclusivity for brand names from 12 years to 7 years beginning in 2014 and to prohibit "evergreening" – the securing of additional periods of exclusivity for brand biologics because of minor changes in product formulations.

Additionally, the Coalition of State Rheumatology Organizations is lobbying state legislatures to ensure that biosimilars legislation includes appropriate patient protections, such as physician notification of any substitution, appropriate record keeping, and "dispense as written" requirements. To date, five such bills have passed, with North Dakota, Utah, Virginia, and Oregon including all of these measures and Florida including all but notification.

Graduate medical education

Workforce shortages aren’t just a primary care issue. They also affect multiple specialties, including rheumatology. Though not unique in this regard, rheumatology is representative of an aging specialty, with more physicians reaching the end of their careers than young physicians entering the field. Coupled with the aging population, this raises concerns. The coalition and the Alliance of Specialty Medicine Policy Roundtable on Workforce sought cosponsors for H.R. 1180 and S. 577, the Resident Physician Shortage Reduction Act of 2013, and H.R. 1201, the Training Tomorrow’s Doctor Today Act. These legislative initiatives seek to address the problem of residency-slot shortages.

Dr. Schweitz reported having no disclosures.

rhnews@frontlinemedcom.com

LAS VEGAS – A coalition working to address dual-energy X-ray absorptiometry access issues is developing draft legislation that would establish a geographically adjusted national minimum payment for DXA, according to Dr. Michael Schweitz.

Under the draft legislation – a response to a series of reimbursement cuts over the past several years – DXA CPT codes 77080 and 77082 would be paid at $98 and $35, respectively, and a bundled code or bundled payment for bone density and vertebral fracture assessment studies would result in a national minimum payment of $133, Dr. Schweitz, president of the Coalition of State Rheumatology Organizations, said at Perspectives in Rheumatic Diseases 2013 during an update on federal legislative and regulatory issues facing rheumatologists.

Restoring reimbursement is an issue on the "front burner," he said, noting that studies have demonstrated an increase in hip fracture rates in the wake of declining reimbursement as some practices have abandoned DXA.

The DXA draft legislation is just one of a number of current legislative initiatives and issues that should be on rheumatologists’ radar, Dr. Schweitz said.

Sequestration

Under sequestration – a "heavy hammer" proposed as a way to push for agreement on a deficit-reduction plan and implemented when that agreement didn’t materialize – Medicare provider reductions are limited to 2% per year. Claims are reduced by 2% after beneficiary coinsurance or deductible. H.R. 1416, the Cancer Patient Protection Act of 2013, would terminate sequester cuts for all part B drugs, not just cancer drugs.

Medicare physician payment

Based on the formula for the Medicare sustainable growth rate, or SGR, physician payments will be cut by 24.4% if Congress does not intervene by Jan. 1, 2014. The latest cost estimate by the Congressional Budget Office for repeal of the SGR is $176 billion – far less than previous estimates and far less than the combined cost of prior short-term patches. President Barack Obama’s 2014 budget, as well as Congressional budgets and recent federal rulemakings, all assume that Congress will fix the SGR this year. Draft legislation released in July based on a replacement proposal from the bipartisan House Energy & Commerce Committee calls for a two-phase approach. Phase I would repeal the SGR entirely and replace it with a 5-year period of stable payments, including a 0.5% increase across-the-board, and phase II would involve implementation of an enhanced "PQRS-like Update Incentive Program." This would maintain fee-for-service as an option, allow providers to move into other models at any time, and would involve physician-driven quality measurement.

"This is something all of us should be aware of ... you can be sure that this whole system of reimbursement for what we do is going to change in the future," said Dr. Schweitz, who has a private practice in West Palm Beach, Fla.

How the changes would be paid for has not been defined, but there is a proposal from the House Ways & Means Committee that involves entitlement reform with increased part B/D deductibles and an increased age for eligibility.

Part B drug payments

A new bill (H.R. 800) that would affect physicians who provide in-office drug infusion excludes prompt pay discounts from manufacturers to wholesalers from the average sales price (ASP) calculation for part B drugs. This would improve payment for physicians who do not receive the discounts. However, the president’s 2014 budget assumes part B drugs are overpaid and proposes reducing Medicare payment from ASP plus 6% to ASP plus 3%.

This would require legislation to enact. The House and Senate budgets do not include any assumption regarding ASP.

"There’s very little chance, I think, that either side is going to be successful with this," Dr. Schweitz said.

The Independent Payment Advisory Board

The IPAB, a 15-member board created as part of the Affordable Care Act to make recommendations to cut spending when costs exceed growth targets, has been a contentious issue.

"There is a huge outcry in Congress against this IPAB," Dr. Schweitz said, explaining that there is a sense that the IPAB represents a usurping of the authority of Congress in controlling this part of Medicare activity.

A bipartisan repeal effort is underway in the form of H.R. 351/S. 351, the Protecting Seniors’ Access to Medicare Act. This has a chance of moving forward, but opposition in the Senate could hold it back, Dr. Schweitz said.

Of note, the president’s 2014 budget would lower the target rate that triggers IPAB recommendations from gross domestic product plus 1% to GDP plus 0.5%. Also, House Speaker John Boehner (R-Ohio) and Senate Minority Leader Mitch McConnell (R-Ky.) are on record saying that they will not nominate members to the IPAB, he said.

Private contracting

Private contracting is permitted under current law, but physicians who engage in it must opt out of Medicare for 2 years; patients who sign a private contract must pay out of pocket, even for services covered by Medicare. Under S. 236/H.R. 1310 – the Medicare Patient Empowerment Act – the 2-year opt-out requirement would be eliminated and beneficiaries could use their benefits to offset a portion of the fee set by their physician. This would protect low-income patients, "dual-eligibles," and patients with certain emergent or urgent health conditions. It is opposed by the Democratic Party and AARP, who see it as a cost-shifting mechanism; others feel it is a way to help reduce Medicare spending, he noted.

Medical liability reform

There’s been "a lot of noise but not much action" when it comes to medical liability reform, Dr. Schweitz said.

A House bill that would have included a $250,000 cap on noneconomic damages was paired with the IPAB repeal bill in the 112th Congress but did not make it to the Senate.

"There’s no such bill active in this [113th] Congress, but there are other kinds of liability reform acts that are more focused," he said.

These include H.R. 36/S. 961, the Health Care Safety Net Enhancement Act of 2013, which would extend Federal Tort Claims Act liability protections to on-call specialty physicians; H.R. 1733, the Good Samaritan Health Professionals Act of 2013, which would limit liability of health care professionals who volunteer to provide health care in response to a declared natural disaster; and H.R. 1473, the Standard of Care Protection Act, which would protect physicians from the use of quality measures for reimbursement issues in other federal health care laws to be used as standards of care in liability lawsuits.

Biosimilars

The president’s 2014 budget proposes to reduce the exclusivity for brand names from 12 years to 7 years beginning in 2014 and to prohibit "evergreening" – the securing of additional periods of exclusivity for brand biologics because of minor changes in product formulations.

Additionally, the Coalition of State Rheumatology Organizations is lobbying state legislatures to ensure that biosimilars legislation includes appropriate patient protections, such as physician notification of any substitution, appropriate record keeping, and "dispense as written" requirements. To date, five such bills have passed, with North Dakota, Utah, Virginia, and Oregon including all of these measures and Florida including all but notification.

Graduate medical education

Workforce shortages aren’t just a primary care issue. They also affect multiple specialties, including rheumatology. Though not unique in this regard, rheumatology is representative of an aging specialty, with more physicians reaching the end of their careers than young physicians entering the field. Coupled with the aging population, this raises concerns. The coalition and the Alliance of Specialty Medicine Policy Roundtable on Workforce sought cosponsors for H.R. 1180 and S. 577, the Resident Physician Shortage Reduction Act of 2013, and H.R. 1201, the Training Tomorrow’s Doctor Today Act. These legislative initiatives seek to address the problem of residency-slot shortages.

Dr. Schweitz reported having no disclosures.

rhnews@frontlinemedcom.com

LAS VEGAS – Corticosteroids remain the initial treatment of choice for myositis and myositis-associated interstitial lung disease, but immunosuppressive agents, intravenous immunoglobulin, and biologics can also play a role in the treatment of one or both of these conditions, according to Dr. Chester V. Oddis.

For myositis in general, Dr. Oddis, professor of medicine and associate director of the rheumatology fellowship training program at the University of Pittsburgh, recommends an initial divided dose of 30 mg of prednisone twice daily, continued until serum creatine kinase (CK) levels fall to normal. At that time, the total daily prednisone dose can be consolidated into a single morning dose, he said at Perspectives in Rheumatic Diseases 2013.

The prednisone can then be tapered by 25% every 3-4 weeks down to a 5- to 10-mg daily maintenance dose that is continued until active disease is suppressed for 12 months. This is a general guideline that helps prevent disease flares, he noted.

Keep in mind that improvement in strength generally lags behind improvement in CK levels, he added.

Nonsteroidal immunosuppressives

Not all patients will need an additional immunosuppressive agent, but for those who do, methotrexate is a good option, Dr. Oddis said, noting that methotrexate is the drug he is most comfortable using in those cases.

The literature also supports the combined use of methotrexate and azathioprine, which when given together have been shown to be effective in treatment-resistant myositis and in those who failed either of the drugs alone.

"So that’s a regimen you might want to think about," he said.

Another immunosuppressive option is mycophenolate mofetil (MMF), which has been shown in several small studies and case series to be of benefit. In one study, 6 of 10 patients with dermatomyositis successfully tapered corticosteroids with MMF, and 10 of 12 in another study experienced improvement in cutaneous features of the disease.

The use of intravenous immunoglobulin (IVIg) as add-on therapy with MMF was effective in severe refractory patients, including four with polymyositis and three with dermatomyositis. In a retrospective review of 50 patients with juvenile dermatomyositis, MMF for 12 months was well tolerated, improved skin and muscle, and proved to be steroid-sparing, Dr. Oddis said.

Cyclosporine, tacrolimus, and cyclophosphamide are other immunosuppressive options.

While cyclophosphamide is more often used for myositis-associated interstitial lung disease (ILD), it can be of benefit for refractory skin disease, and can be useful in non-ILD myositis cases that involve severe skin disease.

The only available controlled data for IVIg alone are from a study published more than 20 years ago, but that randomized, double-blind, placebo-controlled study showed that treatment was safe, effective, and steroid sparing in 15 patients with dermatomyositis, he said.

Biologics

As for biologics, anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy and B-cell therapy have both been considered. Anti-TNF-alpha therapy makes sense because TNF-alpha and other proinflammatory cytokines are increased in muscle tissue of myositis patients; TNF-alpha is toxic to myofibers and prevents their regeneration; and TNF-alpha enhances other inflammatory cytokines in both dermatomyositis and polymyositis, but data are lacking on whether targeting TNF-alpha is worthwhile.

B cell therapy, on the other hand, is showing promise. In one open-label pilot study, rituximab was effective in seven patients with refractory dermatomyositis, and in others it was effective in anti-synthetase syndrome. Rituximab also was effective in two studies for refractory myositis and dermatomyositis rash, and it induced longstanding remission in some of the patients. In another study, however, rituximab was not effective for dermatomyositis rash.

The multicenter Rituximab in Myositis (RIM) study, the largest ever done in myositis, evaluated rituximab for the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis patients.

Although the primary and secondary endpoints of the RIM study were not achieved, 83% of refractory adult and juvenile myositis patients met the definition of improvement, there was a significant corticosteroid sparing effect between the baseline dose and the dose at study conclusion, and treatment was generally well tolerated, he said.

Other targets that are being explored include interleukin-6 and type 1 IFN genes. Findings suggest that coordinated dysregulation of type 1 IFN signaling and IL-6 production are contributors to dermatomyositis pathogenesis, he explained.

Treating myositis patients with ILD

The treatment approach to these patients is somewhat similar to those without ILD, with corticosteroids as initial treatment, Dr. Oddis said.

Cyclophosphamide and azathioprine have been used early on, and also in corticosteroid resistant cases, but with variable results. Cyclophosphamide can be given orally or by IV for 3-6 months.

MMF has been used with success in connective tissue disease–associated ILD, and based on small studies it appears to be effective in myositis-associated ILD as well.

Cyclosporine and tacrolimus have been used in both adult and pediatric patients with promising, steroid-sparing results, he said, noting that the use of anti-T-cell therapy in myositis-associated ILD makes sense, because findings from multiple studies have implicated activated CD8-positive T-cells in myositis-associated ILD.

"It’s an exciting time for therapeutic interventions in myositis, but even though we have all these therapeutic options, we have to temper our enthusiasm with what they do long term," he said.

Dr. Oddis has served on an advisory board for Questcor.

The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

LAS VEGAS – Corticosteroids remain the initial treatment of choice for myositis and myositis-associated interstitial lung disease, but immunosuppressive agents, intravenous immunoglobulin, and biologics can also play a role in the treatment of one or both of these conditions, according to Dr. Chester V. Oddis.

For myositis in general, Dr. Oddis, professor of medicine and associate director of the rheumatology fellowship training program at the University of Pittsburgh, recommends an initial divided dose of 30 mg of prednisone twice daily, continued until serum creatine kinase (CK) levels fall to normal. At that time, the total daily prednisone dose can be consolidated into a single morning dose, he said at Perspectives in Rheumatic Diseases 2013.

The prednisone can then be tapered by 25% every 3-4 weeks down to a 5- to 10-mg daily maintenance dose that is continued until active disease is suppressed for 12 months. This is a general guideline that helps prevent disease flares, he noted.

Keep in mind that improvement in strength generally lags behind improvement in CK levels, he added.

Nonsteroidal immunosuppressives

Not all patients will need an additional immunosuppressive agent, but for those who do, methotrexate is a good option, Dr. Oddis said, noting that methotrexate is the drug he is most comfortable using in those cases.

The literature also supports the combined use of methotrexate and azathioprine, which when given together have been shown to be effective in treatment-resistant myositis and in those who failed either of the drugs alone.

"So that’s a regimen you might want to think about," he said.

Another immunosuppressive option is mycophenolate mofetil (MMF), which has been shown in several small studies and case series to be of benefit. In one study, 6 of 10 patients with dermatomyositis successfully tapered corticosteroids with MMF, and 10 of 12 in another study experienced improvement in cutaneous features of the disease.

The use of intravenous immunoglobulin (IVIg) as add-on therapy with MMF was effective in severe refractory patients, including four with polymyositis and three with dermatomyositis. In a retrospective review of 50 patients with juvenile dermatomyositis, MMF for 12 months was well tolerated, improved skin and muscle, and proved to be steroid-sparing, Dr. Oddis said.

Cyclosporine, tacrolimus, and cyclophosphamide are other immunosuppressive options.

While cyclophosphamide is more often used for myositis-associated interstitial lung disease (ILD), it can be of benefit for refractory skin disease, and can be useful in non-ILD myositis cases that involve severe skin disease.

The only available controlled data for IVIg alone are from a study published more than 20 years ago, but that randomized, double-blind, placebo-controlled study showed that treatment was safe, effective, and steroid sparing in 15 patients with dermatomyositis, he said.

Biologics

As for biologics, anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy and B-cell therapy have both been considered. Anti-TNF-alpha therapy makes sense because TNF-alpha and other proinflammatory cytokines are increased in muscle tissue of myositis patients; TNF-alpha is toxic to myofibers and prevents their regeneration; and TNF-alpha enhances other inflammatory cytokines in both dermatomyositis and polymyositis, but data are lacking on whether targeting TNF-alpha is worthwhile.

B cell therapy, on the other hand, is showing promise. In one open-label pilot study, rituximab was effective in seven patients with refractory dermatomyositis, and in others it was effective in anti-synthetase syndrome. Rituximab also was effective in two studies for refractory myositis and dermatomyositis rash, and it induced longstanding remission in some of the patients. In another study, however, rituximab was not effective for dermatomyositis rash.

The multicenter Rituximab in Myositis (RIM) study, the largest ever done in myositis, evaluated rituximab for the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis patients.

Although the primary and secondary endpoints of the RIM study were not achieved, 83% of refractory adult and juvenile myositis patients met the definition of improvement, there was a significant corticosteroid sparing effect between the baseline dose and the dose at study conclusion, and treatment was generally well tolerated, he said.

Other targets that are being explored include interleukin-6 and type 1 IFN genes. Findings suggest that coordinated dysregulation of type 1 IFN signaling and IL-6 production are contributors to dermatomyositis pathogenesis, he explained.

Treating myositis patients with ILD

The treatment approach to these patients is somewhat similar to those without ILD, with corticosteroids as initial treatment, Dr. Oddis said.

Cyclophosphamide and azathioprine have been used early on, and also in corticosteroid resistant cases, but with variable results. Cyclophosphamide can be given orally or by IV for 3-6 months.

MMF has been used with success in connective tissue disease–associated ILD, and based on small studies it appears to be effective in myositis-associated ILD as well.

Cyclosporine and tacrolimus have been used in both adult and pediatric patients with promising, steroid-sparing results, he said, noting that the use of anti-T-cell therapy in myositis-associated ILD makes sense, because findings from multiple studies have implicated activated CD8-positive T-cells in myositis-associated ILD.

"It’s an exciting time for therapeutic interventions in myositis, but even though we have all these therapeutic options, we have to temper our enthusiasm with what they do long term," he said.

Dr. Oddis has served on an advisory board for Questcor.

The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

LAS VEGAS – Corticosteroids remain the initial treatment of choice for myositis and myositis-associated interstitial lung disease, but immunosuppressive agents, intravenous immunoglobulin, and biologics can also play a role in the treatment of one or both of these conditions, according to Dr. Chester V. Oddis.

For myositis in general, Dr. Oddis, professor of medicine and associate director of the rheumatology fellowship training program at the University of Pittsburgh, recommends an initial divided dose of 30 mg of prednisone twice daily, continued until serum creatine kinase (CK) levels fall to normal. At that time, the total daily prednisone dose can be consolidated into a single morning dose, he said at Perspectives in Rheumatic Diseases 2013.

The prednisone can then be tapered by 25% every 3-4 weeks down to a 5- to 10-mg daily maintenance dose that is continued until active disease is suppressed for 12 months. This is a general guideline that helps prevent disease flares, he noted.

Keep in mind that improvement in strength generally lags behind improvement in CK levels, he added.

Nonsteroidal immunosuppressives

Not all patients will need an additional immunosuppressive agent, but for those who do, methotrexate is a good option, Dr. Oddis said, noting that methotrexate is the drug he is most comfortable using in those cases.

The literature also supports the combined use of methotrexate and azathioprine, which when given together have been shown to be effective in treatment-resistant myositis and in those who failed either of the drugs alone.

"So that’s a regimen you might want to think about," he said.

Another immunosuppressive option is mycophenolate mofetil (MMF), which has been shown in several small studies and case series to be of benefit. In one study, 6 of 10 patients with dermatomyositis successfully tapered corticosteroids with MMF, and 10 of 12 in another study experienced improvement in cutaneous features of the disease.

The use of intravenous immunoglobulin (IVIg) as add-on therapy with MMF was effective in severe refractory patients, including four with polymyositis and three with dermatomyositis. In a retrospective review of 50 patients with juvenile dermatomyositis, MMF for 12 months was well tolerated, improved skin and muscle, and proved to be steroid-sparing, Dr. Oddis said.

Cyclosporine, tacrolimus, and cyclophosphamide are other immunosuppressive options.

While cyclophosphamide is more often used for myositis-associated interstitial lung disease (ILD), it can be of benefit for refractory skin disease, and can be useful in non-ILD myositis cases that involve severe skin disease.

The only available controlled data for IVIg alone are from a study published more than 20 years ago, but that randomized, double-blind, placebo-controlled study showed that treatment was safe, effective, and steroid sparing in 15 patients with dermatomyositis, he said.

Biologics

As for biologics, anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy and B-cell therapy have both been considered. Anti-TNF-alpha therapy makes sense because TNF-alpha and other proinflammatory cytokines are increased in muscle tissue of myositis patients; TNF-alpha is toxic to myofibers and prevents their regeneration; and TNF-alpha enhances other inflammatory cytokines in both dermatomyositis and polymyositis, but data are lacking on whether targeting TNF-alpha is worthwhile.

B cell therapy, on the other hand, is showing promise. In one open-label pilot study, rituximab was effective in seven patients with refractory dermatomyositis, and in others it was effective in anti-synthetase syndrome. Rituximab also was effective in two studies for refractory myositis and dermatomyositis rash, and it induced longstanding remission in some of the patients. In another study, however, rituximab was not effective for dermatomyositis rash.

The multicenter Rituximab in Myositis (RIM) study, the largest ever done in myositis, evaluated rituximab for the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis patients.

Although the primary and secondary endpoints of the RIM study were not achieved, 83% of refractory adult and juvenile myositis patients met the definition of improvement, there was a significant corticosteroid sparing effect between the baseline dose and the dose at study conclusion, and treatment was generally well tolerated, he said.

Other targets that are being explored include interleukin-6 and type 1 IFN genes. Findings suggest that coordinated dysregulation of type 1 IFN signaling and IL-6 production are contributors to dermatomyositis pathogenesis, he explained.

Treating myositis patients with ILD

The treatment approach to these patients is somewhat similar to those without ILD, with corticosteroids as initial treatment, Dr. Oddis said.

Cyclophosphamide and azathioprine have been used early on, and also in corticosteroid resistant cases, but with variable results. Cyclophosphamide can be given orally or by IV for 3-6 months.

MMF has been used with success in connective tissue disease–associated ILD, and based on small studies it appears to be effective in myositis-associated ILD as well.

Cyclosporine and tacrolimus have been used in both adult and pediatric patients with promising, steroid-sparing results, he said, noting that the use of anti-T-cell therapy in myositis-associated ILD makes sense, because findings from multiple studies have implicated activated CD8-positive T-cells in myositis-associated ILD.

"It’s an exciting time for therapeutic interventions in myositis, but even though we have all these therapeutic options, we have to temper our enthusiasm with what they do long term," he said.

Dr. Oddis has served on an advisory board for Questcor.

The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

Noninvasive prenatal testing is moving from bench to bedside at a dizzying pace, and while this rapid integration into clinical practice is raising important clinical and ethical questions, it also is creating exciting new opportunities – such as the potential for antenatal treatment of Down syndrome.

In an editorial in Prenatal Diagnosis, Dr. Lyn S. Chitty and Dr. Diana W. Bianchi note that "we are in the midst of a paradigm shift in the way that prenatal screening and diagnosis are performed around the world."

The shift is occurring at a pace unprecedented in the history of prenatal care, and the available tests, which measure cell free fetal DNA (cfDNA) in the maternal blood and currently are used to detect trisomy 21, 18, and 13, as well as sex chromosome aneuploidies, provide a "readily accessible and generally safer option for prenatal testing than can be offered from 10 until 40 weeks of gestation," wrote Dr. Chitty of Great Ormond Street and University College London hospitals and Dr. Bianchi, the Natalie V. Zucker Professor of Pediatrics, Obstetrics, and Gynecology of Tufts University, Boston (Prenatal Diagnosis 2013;33:511-13).

October will mark 2 years since the commercial debut of the first noninvasive prenatal test (NIPT) for aneuploidy in the United States – MaterniT21 (Sequenom, San Diego), a laboratory-developed test that detects increases in the amount of chromosomal 21, 18, and 13 material in maternal blood.

"This was followed by multiple publications, several professional society recommendations, and a logarithmic uptake in the number of tests ordered. The reason why noninvasive prenatal testing (NIPT) represents a paradigm shift is that it changes the algorithm of screening followed by invasive testing that has been in practice worldwide for the last 30 years," they said.

Rather than undergoing combined ultrasound screening and serum screening (the "combined test"), followed by more invasive chorionic villus sampling or amniocentesis to rule out aneuploidy for a positive combined test, more women now have the option of a simple blood test. The negative predictive value of NIPT is high, so fewer women are subjected to the invasive procedures, which increase the risk for miscarriage and other adverse outcomes.

The NIPT options are expanding quickly; since MaterniT21 became available, three other companies launched similar tests: Harmony (Ariosa Diagnostics, San Jose, Calif.), verifi (Verinata Health, Redwood City, Calif.), and – most recently – Panorama (Natera, San Carlos, Calif.).

None are approved by the Food and Drug Administration, but all are performed in Clinical Laboratory Improvement Amendments (CLIA)–approved laboratories as laboratory-developed tests.

The tests are typically administered any time after 10 weeks’. gestation because that is generally when an adequate amount of fetal DNA is present in the maternal serum, Dr. Bianchi, also a geneticist and executive director of the Mother Infant Research Institute at Tufts, explained during an NIPT symposium at the annual meeting of the American College of Obstetricians and Gynecologists in New Orleans.

Some of the tests use massively parallel sequencing, which can be used to "look at everything," including sex chromosome aneuploidies, although most laboratories use software that masks all but the results of interest. Other tests use more targeted sequencing to focus on the chromosomes of interest.

Studies suggest that NIPT is at least 99% accurate for detecting trisomy 21 and trisomy 18, and between 79% and 92% accurate for trisomy 13, with a false positive rate of less than 1% for each, according to a 2012 fact sheet developed by the National Coalition for Health Professional Education in Genetics and the National Society of Genetic Counselors.

Serum screening, by comparison, has an 80%-95% detection rate for trisomy 21 and trisomy 18, with false-positive rates of 3% -5%. The rates for trisomy 13 are uncertain, according to the fact sheet.

Most studies to date have included mainly women with singleton pregnancies at high risk of trisomy 21 due to advanced maternal age, an abnormal serum screen, a personal or family history of aneuploidy, or an abnormal ultrasound, and as a result most current recommendations support screening only in this population.

A December 2012 opinion from the American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine Publications Committee, for example, notes that NIPT "offers tremendous potential as a screening tool for fetal aneuploidy," but that it should be offered, after pretest counseling, only to women with high-risk singleton pregnancies. Cell-free fetal DNA testing has not been sufficiently evaluated in those at low risk or with multiple gestations, the committee said (Obstet. Gynecol. 2012;120:1532-4).

In January 2013, the National Society of Genetic Counselors released a similar position statement (J. Genet. Counsel. 2013 [doi: 10.1007/s10897-012-9564-0]).

New evidence, however, suggests that NIPT also is feasible in low-risk pregnancies.

For example, two studies in the July issue of Ultrasound in Obstetrics and Gynecology indicate that both routine and contingent implementation of NIPT for first trimester trisomy screening are feasible.

In one of the studies, Dr. M.M. Gil of King’s College Hospital, London, and his colleagues demonstrated that in 1,005 singleton pregnancies, routine NIPT for trisomies 21, 18, and 13 at 10 weeks’ gestation had a lower false positive rate than did the combined test performed at 12 weeks (0.1% vs. 3.4%), although abnormal results required confirmation using invasive testing.

"This study has shown that routine screening for trisomies by cfDNA testing at 10 weeks is feasible, allowing diagnosis of aneuploidies and the option of pregnancy termination within the first trimester," the investigators concluded (Ultrasound Obstet. Gynecol. 2013;42:34-40).

In the second study, which involved women with singleton pregnancies who underwent screening between March 2006 and May 2012, Dr. K.H. Nicolaides, also of King’s College Hospital, London, and his colleagues demonstrated that effective first trimester screening for Down syndrome can be achieved – with a 98% detection rate and an invasive testing rate below 0.5% – using contingent screening (Ultrasound Obstet. Gynecol. 2013;42:41-50).

"The results demonstrate that in contingent screening, a detection rate of 98% in fetuses with trisomy 21, at an overall invasive testing rate less than 0.5%, could be achieved by offering the cfDNA test to about 36%, 21%, and 11% of cases identified by first-line screening using the combined test alone, using the combined test with the addition of serum placental growth factor and alpha-fetoprotein, and using the combined test with the addition of placental growth factor, alpha-fetoprotein, and ductus venosus pulsatility index for veins, respectively," they said. "Screening for trisomy 21 by cfDNA testing contingent on the results of an expanded combined test would retain the advantages of the current method of screening, but with a simultaneous major increase in detection rate and decrease in the rate of invasive testing," they concluded.

Data also suggest that NIPT can be used successfully in twin pregnancies, albeit with the caveat that deeper sequencing may be necessary in these pregnancies, Dr. Bianchi noted.

These findings suggest that even wider implementation of NIPT is likely, she said, adding that there are major concerns about such implementation – not the least of which is fitting adequate pre- and posttest counseling into busy practices.

"It is not straightforward – there are multiple issues that need to be discussed," she said.

Questions also remain about the performance of the tests in normal- vs. high-risk pregnancies, she said.

Recently, a Blue Cross Blue Shield Technology Evaluation Center report concluded that NIPT meets the company’s criteria for both normal- and high-risk pregnancies, Dr. Bianchi noted.

"We’ll be hearing more about this in the coming year. Everyone is looking for more data," she said.

The results thus far – with more than 100,000 tests performed – undoubtedly have been encouraging. Since the integration of these tests into clinical practice began, many medical centers already are witnessing significant declines in the number of invasive procedures being performed for aneuploidy, Dr. Bianchi said, noting that such procedures have decreased by 34% in the first year at Tufts Medical Center, where NIPT is routinely offered as an option to high-risk women, and as an alternative to invasive procedures in average-risk women who test positive on traditional screening. Invasive procedures are strongly encouraged in those with aneuploidy detected on NIPT.

As a result of these outcomes, every aspect of the current standard of care is being questioned, Dr. Chitty and Dr. Bianchi wrote in their editorial. "For example, do we still need to measure maternal serum biomarkers, and what is the place of nuchal translucency measurement?" they asked.

The use of NIPT and the rapid advances taking place in the field, also raise important ethical questions.

Even before Sequenom introduced the MaterniT21 test to the market, the ethical implications of NIPT were being weighed. In a 2009 paper, Dr. Antina de Jong of Maastricht (the Netherlands) University and colleagues noted that although the introduction of NIPT would have some "ethically favorable consequences," such as the absence of iatrogenic miscarriage resulting from a test, earlier reassurance of a healthy fetus, a longer period for decision-making and the possibility of an early abortion, "which may be physically and psychologically less burdening and ethically less problematic because of presumed lower mortal fetal status," the possibility that NIPT would eventually include testing for a broader scope of abnormalities complicates the ethical issues.

Notwithstanding the potential benefits with respect to earlier decision making, one concern is the "normalization and trivialization of early selective abortion," they said, adding that "more generalized use of noninvasive testing could facilitate selective terminations of pregnancy in a range of conditions hitherto not diagnosed prenatally and where the arguments for and against termination may not have received sufficient scrutiny."

Also, testing for a broader scope of abnormalities has important implications regarding informed consent, they said (Eur. J. Hum. Genet. 2009 [doi:10.1038/ejhg.2009.203]).

"Informed consent will become far more challenging – if attainable at all. Moreover, should [NIPT] testing become available for a wider range of disorders including late-onset disease, this may lead to the same ethical difficulties as with regard to wide range testing of newborns, in which the dominant view is that the child’s right not to know should be respected," the authors wrote. "It is difficult to see how this respect can be upheld when, after broadening prenatal testing, children will be born with a positive test result for a serious late-onset disease."

Another facet of NIPT that is rife with ethical implications is noninvasive fetal whole genome sequencing, which was shown in a recent proof-of-concept study to be possible using only parental DNA samples and plasma. That study is revisited from a clinical standpoint in an article published in the same issue of Prenatal Diagnosis along with the editorial by Dr. Chitty and Dr. Bianchi and a number of other related articles and studies. (To give readers an overview of "this rapidly changing field," both the June and July issues of the journal are dedicated to NIPT, said Dr. Bianchi, the journal’s editor-in-chief).

"If noninvasive determination of the entire fetal genomic sequence becomes clinically available, there will be a significant increase in the number of ethical issues that arise," Dr. Chitty and Dr. Bianchi noted.

"You can imagine, it’s hard enough now to counsel about serum screening results for Down syndrome. Imagine if you had to deal with the entire human genome. But it’s coming – it’s coming, so we have to figure out ... what’s to be communicated to expectant couples," Dr. Bianchi said, adding that she hopes much of the groundwork for dealing with these issues will be laid in adult and pediatric populations before they have to be considered for fetuses.

While these advances bring with them ethical concerns, they also open doors to exciting opportunities, she said.

"The challenge now is to translate this technology into practice that is accessible to all pregnant women and in an ethical way that preserves informed parental choice, while not increasing overall costs to the health care system," Dr. Chitty and Dr. Bianchi said.

Dr. Bianchi is chair of the clinical advisory board for Verinata Health Inc., and has received honorarium and research funding from the company. She is editor-in-chief of the Journal of Prenatal Diagnosis, and has received honorarium from the company. Dr. Nicolaides’ and Dr. Gil’s studies were funded by grants from the Fetal Medicine Foundation. Dr. de Jong’s research was supported by the Centre for Society and Genomics in the Netherlands, funded by the Netherlands Genomics Initiative, and the Netherlands Organisation for Scientific Research Zonmw Prevention Fund.

Noninvasive prenatal testing is moving from bench to bedside at a dizzying pace, and while this rapid integration into clinical practice is raising important clinical and ethical questions, it also is creating exciting new opportunities – such as the potential for antenatal treatment of Down syndrome.

In an editorial in Prenatal Diagnosis, Dr. Lyn S. Chitty and Dr. Diana W. Bianchi note that "we are in the midst of a paradigm shift in the way that prenatal screening and diagnosis are performed around the world."

The shift is occurring at a pace unprecedented in the history of prenatal care, and the available tests, which measure cell free fetal DNA (cfDNA) in the maternal blood and currently are used to detect trisomy 21, 18, and 13, as well as sex chromosome aneuploidies, provide a "readily accessible and generally safer option for prenatal testing than can be offered from 10 until 40 weeks of gestation," wrote Dr. Chitty of Great Ormond Street and University College London hospitals and Dr. Bianchi, the Natalie V. Zucker Professor of Pediatrics, Obstetrics, and Gynecology of Tufts University, Boston (Prenatal Diagnosis 2013;33:511-13).

October will mark 2 years since the commercial debut of the first noninvasive prenatal test (NIPT) for aneuploidy in the United States – MaterniT21 (Sequenom, San Diego), a laboratory-developed test that detects increases in the amount of chromosomal 21, 18, and 13 material in maternal blood.

"This was followed by multiple publications, several professional society recommendations, and a logarithmic uptake in the number of tests ordered. The reason why noninvasive prenatal testing (NIPT) represents a paradigm shift is that it changes the algorithm of screening followed by invasive testing that has been in practice worldwide for the last 30 years," they said.

Rather than undergoing combined ultrasound screening and serum screening (the "combined test"), followed by more invasive chorionic villus sampling or amniocentesis to rule out aneuploidy for a positive combined test, more women now have the option of a simple blood test. The negative predictive value of NIPT is high, so fewer women are subjected to the invasive procedures, which increase the risk for miscarriage and other adverse outcomes.

The NIPT options are expanding quickly; since MaterniT21 became available, three other companies launched similar tests: Harmony (Ariosa Diagnostics, San Jose, Calif.), verifi (Verinata Health, Redwood City, Calif.), and – most recently – Panorama (Natera, San Carlos, Calif.).

None are approved by the Food and Drug Administration, but all are performed in Clinical Laboratory Improvement Amendments (CLIA)–approved laboratories as laboratory-developed tests.

The tests are typically administered any time after 10 weeks’. gestation because that is generally when an adequate amount of fetal DNA is present in the maternal serum, Dr. Bianchi, also a geneticist and executive director of the Mother Infant Research Institute at Tufts, explained during an NIPT symposium at the annual meeting of the American College of Obstetricians and Gynecologists in New Orleans.

Some of the tests use massively parallel sequencing, which can be used to "look at everything," including sex chromosome aneuploidies, although most laboratories use software that masks all but the results of interest. Other tests use more targeted sequencing to focus on the chromosomes of interest.

Studies suggest that NIPT is at least 99% accurate for detecting trisomy 21 and trisomy 18, and between 79% and 92% accurate for trisomy 13, with a false positive rate of less than 1% for each, according to a 2012 fact sheet developed by the National Coalition for Health Professional Education in Genetics and the National Society of Genetic Counselors.

Serum screening, by comparison, has an 80%-95% detection rate for trisomy 21 and trisomy 18, with false-positive rates of 3% -5%. The rates for trisomy 13 are uncertain, according to the fact sheet.

Most studies to date have included mainly women with singleton pregnancies at high risk of trisomy 21 due to advanced maternal age, an abnormal serum screen, a personal or family history of aneuploidy, or an abnormal ultrasound, and as a result most current recommendations support screening only in this population.

A December 2012 opinion from the American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine Publications Committee, for example, notes that NIPT "offers tremendous potential as a screening tool for fetal aneuploidy," but that it should be offered, after pretest counseling, only to women with high-risk singleton pregnancies. Cell-free fetal DNA testing has not been sufficiently evaluated in those at low risk or with multiple gestations, the committee said (Obstet. Gynecol. 2012;120:1532-4).

In January 2013, the National Society of Genetic Counselors released a similar position statement (J. Genet. Counsel. 2013 [doi: 10.1007/s10897-012-9564-0]).

New evidence, however, suggests that NIPT also is feasible in low-risk pregnancies.

For example, two studies in the July issue of Ultrasound in Obstetrics and Gynecology indicate that both routine and contingent implementation of NIPT for first trimester trisomy screening are feasible.

In one of the studies, Dr. M.M. Gil of King’s College Hospital, London, and his colleagues demonstrated that in 1,005 singleton pregnancies, routine NIPT for trisomies 21, 18, and 13 at 10 weeks’ gestation had a lower false positive rate than did the combined test performed at 12 weeks (0.1% vs. 3.4%), although abnormal results required confirmation using invasive testing.

"This study has shown that routine screening for trisomies by cfDNA testing at 10 weeks is feasible, allowing diagnosis of aneuploidies and the option of pregnancy termination within the first trimester," the investigators concluded (Ultrasound Obstet. Gynecol. 2013;42:34-40).

In the second study, which involved women with singleton pregnancies who underwent screening between March 2006 and May 2012, Dr. K.H. Nicolaides, also of King’s College Hospital, London, and his colleagues demonstrated that effective first trimester screening for Down syndrome can be achieved – with a 98% detection rate and an invasive testing rate below 0.5% – using contingent screening (Ultrasound Obstet. Gynecol. 2013;42:41-50).

"The results demonstrate that in contingent screening, a detection rate of 98% in fetuses with trisomy 21, at an overall invasive testing rate less than 0.5%, could be achieved by offering the cfDNA test to about 36%, 21%, and 11% of cases identified by first-line screening using the combined test alone, using the combined test with the addition of serum placental growth factor and alpha-fetoprotein, and using the combined test with the addition of placental growth factor, alpha-fetoprotein, and ductus venosus pulsatility index for veins, respectively," they said. "Screening for trisomy 21 by cfDNA testing contingent on the results of an expanded combined test would retain the advantages of the current method of screening, but with a simultaneous major increase in detection rate and decrease in the rate of invasive testing," they concluded.

Data also suggest that NIPT can be used successfully in twin pregnancies, albeit with the caveat that deeper sequencing may be necessary in these pregnancies, Dr. Bianchi noted.

These findings suggest that even wider implementation of NIPT is likely, she said, adding that there are major concerns about such implementation – not the least of which is fitting adequate pre- and posttest counseling into busy practices.

"It is not straightforward – there are multiple issues that need to be discussed," she said.

Questions also remain about the performance of the tests in normal- vs. high-risk pregnancies, she said.

Recently, a Blue Cross Blue Shield Technology Evaluation Center report concluded that NIPT meets the company’s criteria for both normal- and high-risk pregnancies, Dr. Bianchi noted.

"We’ll be hearing more about this in the coming year. Everyone is looking for more data," she said.

The results thus far – with more than 100,000 tests performed – undoubtedly have been encouraging. Since the integration of these tests into clinical practice began, many medical centers already are witnessing significant declines in the number of invasive procedures being performed for aneuploidy, Dr. Bianchi said, noting that such procedures have decreased by 34% in the first year at Tufts Medical Center, where NIPT is routinely offered as an option to high-risk women, and as an alternative to invasive procedures in average-risk women who test positive on traditional screening. Invasive procedures are strongly encouraged in those with aneuploidy detected on NIPT.

As a result of these outcomes, every aspect of the current standard of care is being questioned, Dr. Chitty and Dr. Bianchi wrote in their editorial. "For example, do we still need to measure maternal serum biomarkers, and what is the place of nuchal translucency measurement?" they asked.

The use of NIPT and the rapid advances taking place in the field, also raise important ethical questions.

Even before Sequenom introduced the MaterniT21 test to the market, the ethical implications of NIPT were being weighed. In a 2009 paper, Dr. Antina de Jong of Maastricht (the Netherlands) University and colleagues noted that although the introduction of NIPT would have some "ethically favorable consequences," such as the absence of iatrogenic miscarriage resulting from a test, earlier reassurance of a healthy fetus, a longer period for decision-making and the possibility of an early abortion, "which may be physically and psychologically less burdening and ethically less problematic because of presumed lower mortal fetal status," the possibility that NIPT would eventually include testing for a broader scope of abnormalities complicates the ethical issues.

Notwithstanding the potential benefits with respect to earlier decision making, one concern is the "normalization and trivialization of early selective abortion," they said, adding that "more generalized use of noninvasive testing could facilitate selective terminations of pregnancy in a range of conditions hitherto not diagnosed prenatally and where the arguments for and against termination may not have received sufficient scrutiny."

Also, testing for a broader scope of abnormalities has important implications regarding informed consent, they said (Eur. J. Hum. Genet. 2009 [doi:10.1038/ejhg.2009.203]).

"Informed consent will become far more challenging – if attainable at all. Moreover, should [NIPT] testing become available for a wider range of disorders including late-onset disease, this may lead to the same ethical difficulties as with regard to wide range testing of newborns, in which the dominant view is that the child’s right not to know should be respected," the authors wrote. "It is difficult to see how this respect can be upheld when, after broadening prenatal testing, children will be born with a positive test result for a serious late-onset disease."

Another facet of NIPT that is rife with ethical implications is noninvasive fetal whole genome sequencing, which was shown in a recent proof-of-concept study to be possible using only parental DNA samples and plasma. That study is revisited from a clinical standpoint in an article published in the same issue of Prenatal Diagnosis along with the editorial by Dr. Chitty and Dr. Bianchi and a number of other related articles and studies. (To give readers an overview of "this rapidly changing field," both the June and July issues of the journal are dedicated to NIPT, said Dr. Bianchi, the journal’s editor-in-chief).

"If noninvasive determination of the entire fetal genomic sequence becomes clinically available, there will be a significant increase in the number of ethical issues that arise," Dr. Chitty and Dr. Bianchi noted.

"You can imagine, it’s hard enough now to counsel about serum screening results for Down syndrome. Imagine if you had to deal with the entire human genome. But it’s coming – it’s coming, so we have to figure out ... what’s to be communicated to expectant couples," Dr. Bianchi said, adding that she hopes much of the groundwork for dealing with these issues will be laid in adult and pediatric populations before they have to be considered for fetuses.

While these advances bring with them ethical concerns, they also open doors to exciting opportunities, she said.

"The challenge now is to translate this technology into practice that is accessible to all pregnant women and in an ethical way that preserves informed parental choice, while not increasing overall costs to the health care system," Dr. Chitty and Dr. Bianchi said.

Dr. Bianchi is chair of the clinical advisory board for Verinata Health Inc., and has received honorarium and research funding from the company. She is editor-in-chief of the Journal of Prenatal Diagnosis, and has received honorarium from the company. Dr. Nicolaides’ and Dr. Gil’s studies were funded by grants from the Fetal Medicine Foundation. Dr. de Jong’s research was supported by the Centre for Society and Genomics in the Netherlands, funded by the Netherlands Genomics Initiative, and the Netherlands Organisation for Scientific Research Zonmw Prevention Fund.

Noninvasive prenatal testing is moving from bench to bedside at a dizzying pace, and while this rapid integration into clinical practice is raising important clinical and ethical questions, it also is creating exciting new opportunities – such as the potential for antenatal treatment of Down syndrome.

In an editorial in Prenatal Diagnosis, Dr. Lyn S. Chitty and Dr. Diana W. Bianchi note that "we are in the midst of a paradigm shift in the way that prenatal screening and diagnosis are performed around the world."

The shift is occurring at a pace unprecedented in the history of prenatal care, and the available tests, which measure cell free fetal DNA (cfDNA) in the maternal blood and currently are used to detect trisomy 21, 18, and 13, as well as sex chromosome aneuploidies, provide a "readily accessible and generally safer option for prenatal testing than can be offered from 10 until 40 weeks of gestation," wrote Dr. Chitty of Great Ormond Street and University College London hospitals and Dr. Bianchi, the Natalie V. Zucker Professor of Pediatrics, Obstetrics, and Gynecology of Tufts University, Boston (Prenatal Diagnosis 2013;33:511-13).

October will mark 2 years since the commercial debut of the first noninvasive prenatal test (NIPT) for aneuploidy in the United States – MaterniT21 (Sequenom, San Diego), a laboratory-developed test that detects increases in the amount of chromosomal 21, 18, and 13 material in maternal blood.

"This was followed by multiple publications, several professional society recommendations, and a logarithmic uptake in the number of tests ordered. The reason why noninvasive prenatal testing (NIPT) represents a paradigm shift is that it changes the algorithm of screening followed by invasive testing that has been in practice worldwide for the last 30 years," they said.

Rather than undergoing combined ultrasound screening and serum screening (the "combined test"), followed by more invasive chorionic villus sampling or amniocentesis to rule out aneuploidy for a positive combined test, more women now have the option of a simple blood test. The negative predictive value of NIPT is high, so fewer women are subjected to the invasive procedures, which increase the risk for miscarriage and other adverse outcomes.

The NIPT options are expanding quickly; since MaterniT21 became available, three other companies launched similar tests: Harmony (Ariosa Diagnostics, San Jose, Calif.), verifi (Verinata Health, Redwood City, Calif.), and – most recently – Panorama (Natera, San Carlos, Calif.).

None are approved by the Food and Drug Administration, but all are performed in Clinical Laboratory Improvement Amendments (CLIA)–approved laboratories as laboratory-developed tests.

The tests are typically administered any time after 10 weeks’. gestation because that is generally when an adequate amount of fetal DNA is present in the maternal serum, Dr. Bianchi, also a geneticist and executive director of the Mother Infant Research Institute at Tufts, explained during an NIPT symposium at the annual meeting of the American College of Obstetricians and Gynecologists in New Orleans.

Some of the tests use massively parallel sequencing, which can be used to "look at everything," including sex chromosome aneuploidies, although most laboratories use software that masks all but the results of interest. Other tests use more targeted sequencing to focus on the chromosomes of interest.

Studies suggest that NIPT is at least 99% accurate for detecting trisomy 21 and trisomy 18, and between 79% and 92% accurate for trisomy 13, with a false positive rate of less than 1% for each, according to a 2012 fact sheet developed by the National Coalition for Health Professional Education in Genetics and the National Society of Genetic Counselors.

Serum screening, by comparison, has an 80%-95% detection rate for trisomy 21 and trisomy 18, with false-positive rates of 3% -5%. The rates for trisomy 13 are uncertain, according to the fact sheet.

Most studies to date have included mainly women with singleton pregnancies at high risk of trisomy 21 due to advanced maternal age, an abnormal serum screen, a personal or family history of aneuploidy, or an abnormal ultrasound, and as a result most current recommendations support screening only in this population.

A December 2012 opinion from the American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine Publications Committee, for example, notes that NIPT "offers tremendous potential as a screening tool for fetal aneuploidy," but that it should be offered, after pretest counseling, only to women with high-risk singleton pregnancies. Cell-free fetal DNA testing has not been sufficiently evaluated in those at low risk or with multiple gestations, the committee said (Obstet. Gynecol. 2012;120:1532-4).

In January 2013, the National Society of Genetic Counselors released a similar position statement (J. Genet. Counsel. 2013 [doi: 10.1007/s10897-012-9564-0]).

New evidence, however, suggests that NIPT also is feasible in low-risk pregnancies.

For example, two studies in the July issue of Ultrasound in Obstetrics and Gynecology indicate that both routine and contingent implementation of NIPT for first trimester trisomy screening are feasible.

In one of the studies, Dr. M.M. Gil of King’s College Hospital, London, and his colleagues demonstrated that in 1,005 singleton pregnancies, routine NIPT for trisomies 21, 18, and 13 at 10 weeks’ gestation had a lower false positive rate than did the combined test performed at 12 weeks (0.1% vs. 3.4%), although abnormal results required confirmation using invasive testing.

"This study has shown that routine screening for trisomies by cfDNA testing at 10 weeks is feasible, allowing diagnosis of aneuploidies and the option of pregnancy termination within the first trimester," the investigators concluded (Ultrasound Obstet. Gynecol. 2013;42:34-40).

In the second study, which involved women with singleton pregnancies who underwent screening between March 2006 and May 2012, Dr. K.H. Nicolaides, also of King’s College Hospital, London, and his colleagues demonstrated that effective first trimester screening for Down syndrome can be achieved – with a 98% detection rate and an invasive testing rate below 0.5% – using contingent screening (Ultrasound Obstet. Gynecol. 2013;42:41-50).

"The results demonstrate that in contingent screening, a detection rate of 98% in fetuses with trisomy 21, at an overall invasive testing rate less than 0.5%, could be achieved by offering the cfDNA test to about 36%, 21%, and 11% of cases identified by first-line screening using the combined test alone, using the combined test with the addition of serum placental growth factor and alpha-fetoprotein, and using the combined test with the addition of placental growth factor, alpha-fetoprotein, and ductus venosus pulsatility index for veins, respectively," they said. "Screening for trisomy 21 by cfDNA testing contingent on the results of an expanded combined test would retain the advantages of the current method of screening, but with a simultaneous major increase in detection rate and decrease in the rate of invasive testing," they concluded.

Data also suggest that NIPT can be used successfully in twin pregnancies, albeit with the caveat that deeper sequencing may be necessary in these pregnancies, Dr. Bianchi noted.

These findings suggest that even wider implementation of NIPT is likely, she said, adding that there are major concerns about such implementation – not the least of which is fitting adequate pre- and posttest counseling into busy practices.

"It is not straightforward – there are multiple issues that need to be discussed," she said.

Questions also remain about the performance of the tests in normal- vs. high-risk pregnancies, she said.

Recently, a Blue Cross Blue Shield Technology Evaluation Center report concluded that NIPT meets the company’s criteria for both normal- and high-risk pregnancies, Dr. Bianchi noted.

"We’ll be hearing more about this in the coming year. Everyone is looking for more data," she said.

The results thus far – with more than 100,000 tests performed – undoubtedly have been encouraging. Since the integration of these tests into clinical practice began, many medical centers already are witnessing significant declines in the number of invasive procedures being performed for aneuploidy, Dr. Bianchi said, noting that such procedures have decreased by 34% in the first year at Tufts Medical Center, where NIPT is routinely offered as an option to high-risk women, and as an alternative to invasive procedures in average-risk women who test positive on traditional screening. Invasive procedures are strongly encouraged in those with aneuploidy detected on NIPT.

As a result of these outcomes, every aspect of the current standard of care is being questioned, Dr. Chitty and Dr. Bianchi wrote in their editorial. "For example, do we still need to measure maternal serum biomarkers, and what is the place of nuchal translucency measurement?" they asked.

The use of NIPT and the rapid advances taking place in the field, also raise important ethical questions.

Even before Sequenom introduced the MaterniT21 test to the market, the ethical implications of NIPT were being weighed. In a 2009 paper, Dr. Antina de Jong of Maastricht (the Netherlands) University and colleagues noted that although the introduction of NIPT would have some "ethically favorable consequences," such as the absence of iatrogenic miscarriage resulting from a test, earlier reassurance of a healthy fetus, a longer period for decision-making and the possibility of an early abortion, "which may be physically and psychologically less burdening and ethically less problematic because of presumed lower mortal fetal status," the possibility that NIPT would eventually include testing for a broader scope of abnormalities complicates the ethical issues.

Notwithstanding the potential benefits with respect to earlier decision making, one concern is the "normalization and trivialization of early selective abortion," they said, adding that "more generalized use of noninvasive testing could facilitate selective terminations of pregnancy in a range of conditions hitherto not diagnosed prenatally and where the arguments for and against termination may not have received sufficient scrutiny."

Also, testing for a broader scope of abnormalities has important implications regarding informed consent, they said (Eur. J. Hum. Genet. 2009 [doi:10.1038/ejhg.2009.203]).

"Informed consent will become far more challenging – if attainable at all. Moreover, should [NIPT] testing become available for a wider range of disorders including late-onset disease, this may lead to the same ethical difficulties as with regard to wide range testing of newborns, in which the dominant view is that the child’s right not to know should be respected," the authors wrote. "It is difficult to see how this respect can be upheld when, after broadening prenatal testing, children will be born with a positive test result for a serious late-onset disease."

Another facet of NIPT that is rife with ethical implications is noninvasive fetal whole genome sequencing, which was shown in a recent proof-of-concept study to be possible using only parental DNA samples and plasma. That study is revisited from a clinical standpoint in an article published in the same issue of Prenatal Diagnosis along with the editorial by Dr. Chitty and Dr. Bianchi and a number of other related articles and studies. (To give readers an overview of "this rapidly changing field," both the June and July issues of the journal are dedicated to NIPT, said Dr. Bianchi, the journal’s editor-in-chief).

"If noninvasive determination of the entire fetal genomic sequence becomes clinically available, there will be a significant increase in the number of ethical issues that arise," Dr. Chitty and Dr. Bianchi noted.

"You can imagine, it’s hard enough now to counsel about serum screening results for Down syndrome. Imagine if you had to deal with the entire human genome. But it’s coming – it’s coming, so we have to figure out ... what’s to be communicated to expectant couples," Dr. Bianchi said, adding that she hopes much of the groundwork for dealing with these issues will be laid in adult and pediatric populations before they have to be considered for fetuses.

While these advances bring with them ethical concerns, they also open doors to exciting opportunities, she said.

"The challenge now is to translate this technology into practice that is accessible to all pregnant women and in an ethical way that preserves informed parental choice, while not increasing overall costs to the health care system," Dr. Chitty and Dr. Bianchi said.

Dr. Bianchi is chair of the clinical advisory board for Verinata Health Inc., and has received honorarium and research funding from the company. She is editor-in-chief of the Journal of Prenatal Diagnosis, and has received honorarium from the company. Dr. Nicolaides’ and Dr. Gil’s studies were funded by grants from the Fetal Medicine Foundation. Dr. de Jong’s research was supported by the Centre for Society and Genomics in the Netherlands, funded by the Netherlands Genomics Initiative, and the Netherlands Organisation for Scientific Research Zonmw Prevention Fund.

Varenicline successfully promoted durable smoking cessation without exacerbating depression or anxiety in a randomized, phase IV, industry-funded study of patients with stably treated major depressive disorder.

Smoking cessation, defined as carbon monoxide–confirmed continuous abstinence, was higher at weeks 9-12 among 256 subjects in the double-blind study who were randomized to receive varenicline, compared with 269 who received placebo (35.9% vs. 15.6%; odds ratio, 3.35), Dr. Robert M. Anthenelli of the University of California, San Diego, and his colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The differences between the groups were also significant for weeks 9-24 (20.3% vs. 10.4%; OR, 2.36) and for weeks 9-52 (25% vs. 12.3%; OR, 2.36), the investigators said (Ann. Intern. Med. 2013;159:390-400).*

© milosluz/istockphoto.com

No clinically relevant differences were seen between the groups in suicidal ideation or behavior as captured by the Columbia Suicide Severity Rating Scale. Furthermore, no overall worsening of depression or anxiety occurred in either group. In fact, trajectories of mood and anxiety rating trended slightly toward improvement in both groups, they said.

Participants in the multicenter study were adults aged 19-73 years who had no recent cardiovascular events, who smoked at least 10 cigarettes daily, and who had current or past stably treated unipolar major depressive disorder without psychotic features. They were recruited from 38 centers in 8 countries between March 2010 and June 2012. Randomization was stratified by antidepressant use at baseline (any vs. none) and by baseline depression score (Montgomery-Asberg Depression Rating Scale score 11 or less vs. greater than 11). Patients received either placebo or varenicline titrated to a dose of 1 mg twice daily for 12 weeks, with a 40-week nontreatment follow-up phase.

Treatment was relatively safe; although 72.3% and 66.9% of the treatment and placebo groups, respectively, experienced treatment-emergent adverse events, most were mild or moderate. The most frequent adverse events in the treatment vs. placebo groups were nausea (27.0% vs. 10.4%, respectively), headaches (16.8% vs. 11.2%), abnormal dreams (11.3% vs. 8.2%), irritability (10.9% vs. 8.2%), and insomnia (10.9% vs. 4.8%). Two patients in the treatment group died during the nontreatment phase, but neither death was considered to be related to treatment, the investigators said.

The findings suggest that varenicline, like other FDA-approved smoking cessation aids effective in non–psychiatrically ill smokers, are similarly effective in smokers with a history of depression – without increasing depressive symptoms; in the case of varenicline, as demonstrated in this study, this also applies to patients with depression who are using antidepressant medications.

"Varenicline is a partial agonist of brain alpha4beta 2 nicotinic acetylcholine receptors and is believed to alleviate nicotine withdrawal while simultaneously blocking its rewarding effects. Because depressed smokers are prone to more severe nicotine withdrawal than nonpsychiatric smokers, mitigating withdrawal symptoms may be important in this population," the investigators said. Depressed smokers who lapse into smoking while attempting to regulate mood may find cigarettes less reinforcing while taking varenicline, thus facilitating prolonged abstinence, they noted.

Although the findings may not extrapolate to untreated or actively depressed smokers and those with other psychiatric conditions, since only stably treated patients without psychotic features and other disorders frequently associated with major depressive disorder (such as bipolar disorder and current substance use disorders) were included, the findings nevertheless suggest an important role for varenicline in smokers with a history of stably treated depression.

"With 350 million individuals having the disease worldwide and because a large proportion of smokers that seeks treatment has a lifetime history of MDD, these results have the potential to reduce morbidity and mortality in many smokers," they concluded.

The researchers noted several study limitations, including their selection of "a population of smokers who were stably treated for or remitted from depression." Thus, they wrote, "our findings may not extrapolate to untreated or actively depressed smokers, whom many consider to be poor candidates for smoking cessation until their condition stabilizes." They also excluded individuals with "with psychotic features, bipolar disorder, current substance use disorders, and other conditions frequently associated with major depressive disorder; patients receiving medication for mania or psychosis were also excluded. Missing data resulting from attrition in both treatment groups may have affected the outcomes, the authors further noted.

This study was funded by Pfizer. Individual authors reported receiving support from the Department of Veterans Affairs; the National Institute on Alcohol Abuse and Alcoholism; the University of California, San Francisco; the Smoking Cessation Leadership Center; and/or the Colorado Department of Public Health and Environment. Detailed disclosures are available at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0777.

*CORRECTION, 10/10/13: An earlier version of this article misstated the citation for the journal article referenced in the story.

Varenicline successfully promoted durable smoking cessation without exacerbating depression or anxiety in a randomized, phase IV, industry-funded study of patients with stably treated major depressive disorder.

Smoking cessation, defined as carbon monoxide–confirmed continuous abstinence, was higher at weeks 9-12 among 256 subjects in the double-blind study who were randomized to receive varenicline, compared with 269 who received placebo (35.9% vs. 15.6%; odds ratio, 3.35), Dr. Robert M. Anthenelli of the University of California, San Diego, and his colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The differences between the groups were also significant for weeks 9-24 (20.3% vs. 10.4%; OR, 2.36) and for weeks 9-52 (25% vs. 12.3%; OR, 2.36), the investigators said (Ann. Intern. Med. 2013;159:390-400).*

© milosluz/istockphoto.com

No clinically relevant differences were seen between the groups in suicidal ideation or behavior as captured by the Columbia Suicide Severity Rating Scale. Furthermore, no overall worsening of depression or anxiety occurred in either group. In fact, trajectories of mood and anxiety rating trended slightly toward improvement in both groups, they said.

Participants in the multicenter study were adults aged 19-73 years who had no recent cardiovascular events, who smoked at least 10 cigarettes daily, and who had current or past stably treated unipolar major depressive disorder without psychotic features. They were recruited from 38 centers in 8 countries between March 2010 and June 2012. Randomization was stratified by antidepressant use at baseline (any vs. none) and by baseline depression score (Montgomery-Asberg Depression Rating Scale score 11 or less vs. greater than 11). Patients received either placebo or varenicline titrated to a dose of 1 mg twice daily for 12 weeks, with a 40-week nontreatment follow-up phase.

Treatment was relatively safe; although 72.3% and 66.9% of the treatment and placebo groups, respectively, experienced treatment-emergent adverse events, most were mild or moderate. The most frequent adverse events in the treatment vs. placebo groups were nausea (27.0% vs. 10.4%, respectively), headaches (16.8% vs. 11.2%), abnormal dreams (11.3% vs. 8.2%), irritability (10.9% vs. 8.2%), and insomnia (10.9% vs. 4.8%). Two patients in the treatment group died during the nontreatment phase, but neither death was considered to be related to treatment, the investigators said.

The findings suggest that varenicline, like other FDA-approved smoking cessation aids effective in non–psychiatrically ill smokers, are similarly effective in smokers with a history of depression – without increasing depressive symptoms; in the case of varenicline, as demonstrated in this study, this also applies to patients with depression who are using antidepressant medications.

"Varenicline is a partial agonist of brain alpha4beta 2 nicotinic acetylcholine receptors and is believed to alleviate nicotine withdrawal while simultaneously blocking its rewarding effects. Because depressed smokers are prone to more severe nicotine withdrawal than nonpsychiatric smokers, mitigating withdrawal symptoms may be important in this population," the investigators said. Depressed smokers who lapse into smoking while attempting to regulate mood may find cigarettes less reinforcing while taking varenicline, thus facilitating prolonged abstinence, they noted.

Although the findings may not extrapolate to untreated or actively depressed smokers and those with other psychiatric conditions, since only stably treated patients without psychotic features and other disorders frequently associated with major depressive disorder (such as bipolar disorder and current substance use disorders) were included, the findings nevertheless suggest an important role for varenicline in smokers with a history of stably treated depression.

"With 350 million individuals having the disease worldwide and because a large proportion of smokers that seeks treatment has a lifetime history of MDD, these results have the potential to reduce morbidity and mortality in many smokers," they concluded.

The researchers noted several study limitations, including their selection of "a population of smokers who were stably treated for or remitted from depression." Thus, they wrote, "our findings may not extrapolate to untreated or actively depressed smokers, whom many consider to be poor candidates for smoking cessation until their condition stabilizes." They also excluded individuals with "with psychotic features, bipolar disorder, current substance use disorders, and other conditions frequently associated with major depressive disorder; patients receiving medication for mania or psychosis were also excluded. Missing data resulting from attrition in both treatment groups may have affected the outcomes, the authors further noted.

This study was funded by Pfizer. Individual authors reported receiving support from the Department of Veterans Affairs; the National Institute on Alcohol Abuse and Alcoholism; the University of California, San Francisco; the Smoking Cessation Leadership Center; and/or the Colorado Department of Public Health and Environment. Detailed disclosures are available at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0777.

*CORRECTION, 10/10/13: An earlier version of this article misstated the citation for the journal article referenced in the story.

Varenicline successfully promoted durable smoking cessation without exacerbating depression or anxiety in a randomized, phase IV, industry-funded study of patients with stably treated major depressive disorder.

Smoking cessation, defined as carbon monoxide–confirmed continuous abstinence, was higher at weeks 9-12 among 256 subjects in the double-blind study who were randomized to receive varenicline, compared with 269 who received placebo (35.9% vs. 15.6%; odds ratio, 3.35), Dr. Robert M. Anthenelli of the University of California, San Diego, and his colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The differences between the groups were also significant for weeks 9-24 (20.3% vs. 10.4%; OR, 2.36) and for weeks 9-52 (25% vs. 12.3%; OR, 2.36), the investigators said (Ann. Intern. Med. 2013;159:390-400).*

© milosluz/istockphoto.com

No clinically relevant differences were seen between the groups in suicidal ideation or behavior as captured by the Columbia Suicide Severity Rating Scale. Furthermore, no overall worsening of depression or anxiety occurred in either group. In fact, trajectories of mood and anxiety rating trended slightly toward improvement in both groups, they said.

Participants in the multicenter study were adults aged 19-73 years who had no recent cardiovascular events, who smoked at least 10 cigarettes daily, and who had current or past stably treated unipolar major depressive disorder without psychotic features. They were recruited from 38 centers in 8 countries between March 2010 and June 2012. Randomization was stratified by antidepressant use at baseline (any vs. none) and by baseline depression score (Montgomery-Asberg Depression Rating Scale score 11 or less vs. greater than 11). Patients received either placebo or varenicline titrated to a dose of 1 mg twice daily for 12 weeks, with a 40-week nontreatment follow-up phase.

Treatment was relatively safe; although 72.3% and 66.9% of the treatment and placebo groups, respectively, experienced treatment-emergent adverse events, most were mild or moderate. The most frequent adverse events in the treatment vs. placebo groups were nausea (27.0% vs. 10.4%, respectively), headaches (16.8% vs. 11.2%), abnormal dreams (11.3% vs. 8.2%), irritability (10.9% vs. 8.2%), and insomnia (10.9% vs. 4.8%). Two patients in the treatment group died during the nontreatment phase, but neither death was considered to be related to treatment, the investigators said.

The findings suggest that varenicline, like other FDA-approved smoking cessation aids effective in non–psychiatrically ill smokers, are similarly effective in smokers with a history of depression – without increasing depressive symptoms; in the case of varenicline, as demonstrated in this study, this also applies to patients with depression who are using antidepressant medications.

"Varenicline is a partial agonist of brain alpha4beta 2 nicotinic acetylcholine receptors and is believed to alleviate nicotine withdrawal while simultaneously blocking its rewarding effects. Because depressed smokers are prone to more severe nicotine withdrawal than nonpsychiatric smokers, mitigating withdrawal symptoms may be important in this population," the investigators said. Depressed smokers who lapse into smoking while attempting to regulate mood may find cigarettes less reinforcing while taking varenicline, thus facilitating prolonged abstinence, they noted.

Although the findings may not extrapolate to untreated or actively depressed smokers and those with other psychiatric conditions, since only stably treated patients without psychotic features and other disorders frequently associated with major depressive disorder (such as bipolar disorder and current substance use disorders) were included, the findings nevertheless suggest an important role for varenicline in smokers with a history of stably treated depression.

"With 350 million individuals having the disease worldwide and because a large proportion of smokers that seeks treatment has a lifetime history of MDD, these results have the potential to reduce morbidity and mortality in many smokers," they concluded.

The researchers noted several study limitations, including their selection of "a population of smokers who were stably treated for or remitted from depression." Thus, they wrote, "our findings may not extrapolate to untreated or actively depressed smokers, whom many consider to be poor candidates for smoking cessation until their condition stabilizes." They also excluded individuals with "with psychotic features, bipolar disorder, current substance use disorders, and other conditions frequently associated with major depressive disorder; patients receiving medication for mania or psychosis were also excluded. Missing data resulting from attrition in both treatment groups may have affected the outcomes, the authors further noted.

This study was funded by Pfizer. Individual authors reported receiving support from the Department of Veterans Affairs; the National Institute on Alcohol Abuse and Alcoholism; the University of California, San Francisco; the Smoking Cessation Leadership Center; and/or the Colorado Department of Public Health and Environment. Detailed disclosures are available at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0777.

*CORRECTION, 10/10/13: An earlier version of this article misstated the citation for the journal article referenced in the story.