With the Hospital Readmissions Reduction Program (HRRP) in its 5th year, what has been the impact on hospitals and on hospitalists?

First of all, a lot of penalties have been paid by hospitals. According to an analysis by Kaiser Health News,¹ the Centers for Medicare and Medicaid Services will withhold $528 million from 2,597 hospitals in the current fiscal year, Oct. 1, 2016 to Sept. 30, 2017, for readmissions for six diagnoses that occurred between July 2012 and June 2015. The number of penalized hospitals is down slightly from 2,665 the year before, but the total annual withhold will go up by $108 million.

HRRP exacts Medicare payment penalties from hospitals that have rates of readmissions – within 30 days of discharge – that are higher than expected, based on national rates and the health of their patient population. The maximum penalty is now up to 3% of a hospital’s Medicare reimbursement. Hospitals are being penalized an average of 0.73% of their annual Medicare reimbursement, and cumulative HRRP penalties will reach nearly $1.9 billion by the end of the fiscal year, Kaiser Health News reports.²

What have we learned about readmissions in 5 years?

A lot of recently published research about readmissions has documented modest decreases in overall readmissions nationally, from over 21% to under 18% between 2007 and 2014, although most of the reduction occurred in the first couple of years after HRRP was announced and it has since largely leveled off.

Other research has tried to explore the relationship between readmissions rates and other outcomes that might matter more to patients or that might be better proxies for the quality of the hospital experience. Is readmission rate a true measure of quality, or just a utilization measure? Research has also tried to document what works: what are the best strategies for preventing avoidable readmissions by improving the discharge process, care transitions, and the coordination of care postdischarge in the community – although no silver bullet has yet been identified.

A recent effort to inject more equity into the penalties program, contained in the wide-ranging 21st Century Cures Act signed into law by President Obama in December 2016, requires Medicare to account for patients’ socio-economic backgrounds when it calculates reductions in its payments to hospitals under HRRP. The law directs the government to change the way pay for performance is applied to safety net hospitals by setting different penalty thresholds for hospitals based on the proportion of their patients who are dually eligible for Medicare and Medicaid.

It remains to be seen how this will be implemented and with what impact. But some critics have continued to question whether hospitals should be held accountable for readmissions, whether 30 days is the correct time frame for that accountability, and whether some hospitals might be simply taking the penalty hit rather than investing in the hard work of care transitions.
 

Impact on working hospitalists

One expert, Ashish Jha, MD, MPH, director of Harvard’s Global Health Institute, wants to see hospitalists get more engaged in the conversation about how to improve hospital care overall.

Readmissions at the front lines

Preetham Talari, MD, FACP, FHM, hospitalist at University of Kentucky HealthCare in Lexington, has an interest in health care safety, quality improvement, and value. He has led the university’s site participation in Project BOOST, the Society of Hospital Medicine’s national mentored quality improvement initiative for care transitions. Dr. Talari also led a quality initiative at the university called the Interprofessional Teamwork Innovation Model to systematize teamwork, first piloted on a 30-bed hospitalist unit where he is medical director.

Better interventions, better infrastructure

Leora Horwitz, MD, MHS, director of the Center for Healthcare Innovation and Delivery Science at New York University School of Public Health, says the biggest change she has seen resulting from readmissions penalties is that transitions of care are now understood to be both important and the responsibility of front line hospitalists. “That was not true 5 or 10 years ago. We used to spend hours admitting patients to the hospital and then 5 minutes on their discharge.”

Recent research on readmissions penalties

A survey by Yale researchers, published in JAMA in December 2016, found that hospitals financially penalized under HRRP reduced their readmissions rates at a higher rate than nonpenalized hospitals, “which implies that penalties can improve quality and readmission performance for hospitals with the most room for improvement,” coauthor Kumar Dharmarajan, MD, MBA, said in a statement.⁴ The hospitals responded to external pressures – in other words, financial penalties worked. But most of the reduction happened in the 2 years before actual penalties went into effect, which suggests that further improvement will not be easy, the authors note.

A survey of the attitudes of hospital leaders on the HRRP found that it has had a major impact on their efforts to reduce readmissions rates, although the failure to take sociodemographic factors into account was a major complaint for these leaders.⁵ Most said the penalties were too large, but 42.5% believed HRRP was likely to improve quality.

Some have questioned whether readmissions penalties were just encouraging hospitals to reduce their rates by keeping returning patients in observation units rather than formally readmitting them. Zuckerman et al. in the New England Journal of Medicine found no evidence that changes in observation unit stays accounted for the documented decrease in readmissions.⁶

But according to Papanicolas et al. in Health Affairs, patient hospital experience has improved only modestly under hospital value-based purchasing for U.S. hospitals, with no evidence that the program has had a beneficial effect on overall patient experience.⁷ Another study from Harvard by Figueroa et al. found that evidence is lacking that hospital value-based purchasing leads to lower mortality rates.⁸

References

1. Rau J. Medicare’s Readmission Penalties Hit New High. Kaiser Health News. 2016 Aug 2.

2. Boccuti C, Casillas G. Aiming for Fewer Hospital U-turns: The Medicare Hospital Readmission Reduction Program. Kaiser Health News, 2016 Sep 30.

3. Keenan PS, Normand SLT, Lin Z, et al. An administrative claims measure suitable for profiling hospital performance on the basis of 30-day all-cause readmission rates among patients with heart failure. Circ Cardiovasc Qual Outcomes. 2008;1:29-37.

4. Desai NR, Ross JS, Kwon JY, et al. Association between hospital penalty status under the Hospital Readmission Reduction Program and readmission rates for target and nontarget conditions. JAMA. 2016 Dec 27;316(24):2647-56.

5. Joynt KE, Figueroa JF, Orav EJ, Jha AK. Opinions on the Hospital Readmissions Reduction Program: Results of a national survey of hospital leaders. Am J Manag Care. 2016 Aug 1;222(8):e287-94.

6. Zuckerman RB, Sheingold SH, Orav EJ, et al. Readmissions, observation, and the Hospital Readmissions Reduction Program. N Engl J Med. 2016 Apr 21;374(16):1543-51.

7. Papanicolas I, Figueroa JF, Orav EJ, Jha AK. Patient hospital experience improved modestly, but no evidence Medicare incentives promoted meaningful gain. Health Aff (Millwood). 2017 Jan;36(1):133-40.

8. Figueroa JF, Tsugawa Y, Zheng J, et al. Association between the value-based purchasing pay for performance program and patient mortality in US hospitals: observational study. BMJ. 2016;353:i2214.

With the Hospital Readmissions Reduction Program (HRRP) in its 5th year, what has been the impact on hospitals and on hospitalists?

First of all, a lot of penalties have been paid by hospitals. According to an analysis by Kaiser Health News,¹ the Centers for Medicare and Medicaid Services will withhold $528 million from 2,597 hospitals in the current fiscal year, Oct. 1, 2016 to Sept. 30, 2017, for readmissions for six diagnoses that occurred between July 2012 and June 2015. The number of penalized hospitals is down slightly from 2,665 the year before, but the total annual withhold will go up by $108 million.

HRRP exacts Medicare payment penalties from hospitals that have rates of readmissions – within 30 days of discharge – that are higher than expected, based on national rates and the health of their patient population. The maximum penalty is now up to 3% of a hospital’s Medicare reimbursement. Hospitals are being penalized an average of 0.73% of their annual Medicare reimbursement, and cumulative HRRP penalties will reach nearly $1.9 billion by the end of the fiscal year, Kaiser Health News reports.²

What have we learned about readmissions in 5 years?

A lot of recently published research about readmissions has documented modest decreases in overall readmissions nationally, from over 21% to under 18% between 2007 and 2014, although most of the reduction occurred in the first couple of years after HRRP was announced and it has since largely leveled off.

Other research has tried to explore the relationship between readmissions rates and other outcomes that might matter more to patients or that might be better proxies for the quality of the hospital experience. Is readmission rate a true measure of quality, or just a utilization measure? Research has also tried to document what works: what are the best strategies for preventing avoidable readmissions by improving the discharge process, care transitions, and the coordination of care postdischarge in the community – although no silver bullet has yet been identified.

A recent effort to inject more equity into the penalties program, contained in the wide-ranging 21st Century Cures Act signed into law by President Obama in December 2016, requires Medicare to account for patients’ socio-economic backgrounds when it calculates reductions in its payments to hospitals under HRRP. The law directs the government to change the way pay for performance is applied to safety net hospitals by setting different penalty thresholds for hospitals based on the proportion of their patients who are dually eligible for Medicare and Medicaid.

It remains to be seen how this will be implemented and with what impact. But some critics have continued to question whether hospitals should be held accountable for readmissions, whether 30 days is the correct time frame for that accountability, and whether some hospitals might be simply taking the penalty hit rather than investing in the hard work of care transitions.
 

Impact on working hospitalists

One expert, Ashish Jha, MD, MPH, director of Harvard’s Global Health Institute, wants to see hospitalists get more engaged in the conversation about how to improve hospital care overall.

Readmissions at the front lines

Preetham Talari, MD, FACP, FHM, hospitalist at University of Kentucky HealthCare in Lexington, has an interest in health care safety, quality improvement, and value. He has led the university’s site participation in Project BOOST, the Society of Hospital Medicine’s national mentored quality improvement initiative for care transitions. Dr. Talari also led a quality initiative at the university called the Interprofessional Teamwork Innovation Model to systematize teamwork, first piloted on a 30-bed hospitalist unit where he is medical director.

Better interventions, better infrastructure

Leora Horwitz, MD, MHS, director of the Center for Healthcare Innovation and Delivery Science at New York University School of Public Health, says the biggest change she has seen resulting from readmissions penalties is that transitions of care are now understood to be both important and the responsibility of front line hospitalists. “That was not true 5 or 10 years ago. We used to spend hours admitting patients to the hospital and then 5 minutes on their discharge.”

Recent research on readmissions penalties

A survey by Yale researchers, published in JAMA in December 2016, found that hospitals financially penalized under HRRP reduced their readmissions rates at a higher rate than nonpenalized hospitals, “which implies that penalties can improve quality and readmission performance for hospitals with the most room for improvement,” coauthor Kumar Dharmarajan, MD, MBA, said in a statement.⁴ The hospitals responded to external pressures – in other words, financial penalties worked. But most of the reduction happened in the 2 years before actual penalties went into effect, which suggests that further improvement will not be easy, the authors note.

A survey of the attitudes of hospital leaders on the HRRP found that it has had a major impact on their efforts to reduce readmissions rates, although the failure to take sociodemographic factors into account was a major complaint for these leaders.⁵ Most said the penalties were too large, but 42.5% believed HRRP was likely to improve quality.

Some have questioned whether readmissions penalties were just encouraging hospitals to reduce their rates by keeping returning patients in observation units rather than formally readmitting them. Zuckerman et al. in the New England Journal of Medicine found no evidence that changes in observation unit stays accounted for the documented decrease in readmissions.⁶

But according to Papanicolas et al. in Health Affairs, patient hospital experience has improved only modestly under hospital value-based purchasing for U.S. hospitals, with no evidence that the program has had a beneficial effect on overall patient experience.⁷ Another study from Harvard by Figueroa et al. found that evidence is lacking that hospital value-based purchasing leads to lower mortality rates.⁸

References

1. Rau J. Medicare’s Readmission Penalties Hit New High. Kaiser Health News. 2016 Aug 2.

2. Boccuti C, Casillas G. Aiming for Fewer Hospital U-turns: The Medicare Hospital Readmission Reduction Program. Kaiser Health News, 2016 Sep 30.

3. Keenan PS, Normand SLT, Lin Z, et al. An administrative claims measure suitable for profiling hospital performance on the basis of 30-day all-cause readmission rates among patients with heart failure. Circ Cardiovasc Qual Outcomes. 2008;1:29-37.

4. Desai NR, Ross JS, Kwon JY, et al. Association between hospital penalty status under the Hospital Readmission Reduction Program and readmission rates for target and nontarget conditions. JAMA. 2016 Dec 27;316(24):2647-56.

5. Joynt KE, Figueroa JF, Orav EJ, Jha AK. Opinions on the Hospital Readmissions Reduction Program: Results of a national survey of hospital leaders. Am J Manag Care. 2016 Aug 1;222(8):e287-94.

6. Zuckerman RB, Sheingold SH, Orav EJ, et al. Readmissions, observation, and the Hospital Readmissions Reduction Program. N Engl J Med. 2016 Apr 21;374(16):1543-51.

7. Papanicolas I, Figueroa JF, Orav EJ, Jha AK. Patient hospital experience improved modestly, but no evidence Medicare incentives promoted meaningful gain. Health Aff (Millwood). 2017 Jan;36(1):133-40.

8. Figueroa JF, Tsugawa Y, Zheng J, et al. Association between the value-based purchasing pay for performance program and patient mortality in US hospitals: observational study. BMJ. 2016;353:i2214.

With the Hospital Readmissions Reduction Program (HRRP) in its 5th year, what has been the impact on hospitals and on hospitalists?

First of all, a lot of penalties have been paid by hospitals. According to an analysis by Kaiser Health News,¹ the Centers for Medicare and Medicaid Services will withhold $528 million from 2,597 hospitals in the current fiscal year, Oct. 1, 2016 to Sept. 30, 2017, for readmissions for six diagnoses that occurred between July 2012 and June 2015. The number of penalized hospitals is down slightly from 2,665 the year before, but the total annual withhold will go up by $108 million.

HRRP exacts Medicare payment penalties from hospitals that have rates of readmissions – within 30 days of discharge – that are higher than expected, based on national rates and the health of their patient population. The maximum penalty is now up to 3% of a hospital’s Medicare reimbursement. Hospitals are being penalized an average of 0.73% of their annual Medicare reimbursement, and cumulative HRRP penalties will reach nearly $1.9 billion by the end of the fiscal year, Kaiser Health News reports.²

What have we learned about readmissions in 5 years?

A lot of recently published research about readmissions has documented modest decreases in overall readmissions nationally, from over 21% to under 18% between 2007 and 2014, although most of the reduction occurred in the first couple of years after HRRP was announced and it has since largely leveled off.

Other research has tried to explore the relationship between readmissions rates and other outcomes that might matter more to patients or that might be better proxies for the quality of the hospital experience. Is readmission rate a true measure of quality, or just a utilization measure? Research has also tried to document what works: what are the best strategies for preventing avoidable readmissions by improving the discharge process, care transitions, and the coordination of care postdischarge in the community – although no silver bullet has yet been identified.

A recent effort to inject more equity into the penalties program, contained in the wide-ranging 21st Century Cures Act signed into law by President Obama in December 2016, requires Medicare to account for patients’ socio-economic backgrounds when it calculates reductions in its payments to hospitals under HRRP. The law directs the government to change the way pay for performance is applied to safety net hospitals by setting different penalty thresholds for hospitals based on the proportion of their patients who are dually eligible for Medicare and Medicaid.

It remains to be seen how this will be implemented and with what impact. But some critics have continued to question whether hospitals should be held accountable for readmissions, whether 30 days is the correct time frame for that accountability, and whether some hospitals might be simply taking the penalty hit rather than investing in the hard work of care transitions.
 

Impact on working hospitalists

One expert, Ashish Jha, MD, MPH, director of Harvard’s Global Health Institute, wants to see hospitalists get more engaged in the conversation about how to improve hospital care overall.

Readmissions at the front lines

Preetham Talari, MD, FACP, FHM, hospitalist at University of Kentucky HealthCare in Lexington, has an interest in health care safety, quality improvement, and value. He has led the university’s site participation in Project BOOST, the Society of Hospital Medicine’s national mentored quality improvement initiative for care transitions. Dr. Talari also led a quality initiative at the university called the Interprofessional Teamwork Innovation Model to systematize teamwork, first piloted on a 30-bed hospitalist unit where he is medical director.

Better interventions, better infrastructure

Leora Horwitz, MD, MHS, director of the Center for Healthcare Innovation and Delivery Science at New York University School of Public Health, says the biggest change she has seen resulting from readmissions penalties is that transitions of care are now understood to be both important and the responsibility of front line hospitalists. “That was not true 5 or 10 years ago. We used to spend hours admitting patients to the hospital and then 5 minutes on their discharge.”

Recent research on readmissions penalties

A survey by Yale researchers, published in JAMA in December 2016, found that hospitals financially penalized under HRRP reduced their readmissions rates at a higher rate than nonpenalized hospitals, “which implies that penalties can improve quality and readmission performance for hospitals with the most room for improvement,” coauthor Kumar Dharmarajan, MD, MBA, said in a statement.⁴ The hospitals responded to external pressures – in other words, financial penalties worked. But most of the reduction happened in the 2 years before actual penalties went into effect, which suggests that further improvement will not be easy, the authors note.

A survey of the attitudes of hospital leaders on the HRRP found that it has had a major impact on their efforts to reduce readmissions rates, although the failure to take sociodemographic factors into account was a major complaint for these leaders.⁵ Most said the penalties were too large, but 42.5% believed HRRP was likely to improve quality.

Some have questioned whether readmissions penalties were just encouraging hospitals to reduce their rates by keeping returning patients in observation units rather than formally readmitting them. Zuckerman et al. in the New England Journal of Medicine found no evidence that changes in observation unit stays accounted for the documented decrease in readmissions.⁶

But according to Papanicolas et al. in Health Affairs, patient hospital experience has improved only modestly under hospital value-based purchasing for U.S. hospitals, with no evidence that the program has had a beneficial effect on overall patient experience.⁷ Another study from Harvard by Figueroa et al. found that evidence is lacking that hospital value-based purchasing leads to lower mortality rates.⁸

References

1. Rau J. Medicare’s Readmission Penalties Hit New High. Kaiser Health News. 2016 Aug 2.

2. Boccuti C, Casillas G. Aiming for Fewer Hospital U-turns: The Medicare Hospital Readmission Reduction Program. Kaiser Health News, 2016 Sep 30.

3. Keenan PS, Normand SLT, Lin Z, et al. An administrative claims measure suitable for profiling hospital performance on the basis of 30-day all-cause readmission rates among patients with heart failure. Circ Cardiovasc Qual Outcomes. 2008;1:29-37.

4. Desai NR, Ross JS, Kwon JY, et al. Association between hospital penalty status under the Hospital Readmission Reduction Program and readmission rates for target and nontarget conditions. JAMA. 2016 Dec 27;316(24):2647-56.

5. Joynt KE, Figueroa JF, Orav EJ, Jha AK. Opinions on the Hospital Readmissions Reduction Program: Results of a national survey of hospital leaders. Am J Manag Care. 2016 Aug 1;222(8):e287-94.

6. Zuckerman RB, Sheingold SH, Orav EJ, et al. Readmissions, observation, and the Hospital Readmissions Reduction Program. N Engl J Med. 2016 Apr 21;374(16):1543-51.

7. Papanicolas I, Figueroa JF, Orav EJ, Jha AK. Patient hospital experience improved modestly, but no evidence Medicare incentives promoted meaningful gain. Health Aff (Millwood). 2017 Jan;36(1):133-40.

8. Figueroa JF, Tsugawa Y, Zheng J, et al. Association between the value-based purchasing pay for performance program and patient mortality in US hospitals: observational study. BMJ. 2016;353:i2214.

Research Hospital

Life-long hematopoiesis relies on hundreds more blood progenitors than previously reported, according to preclinical research published in Nature Cell Biology.

Previous studies linked life-long mammalian blood production to just a handful of precursor cells that emerge during prenatal development.

In the current study, researchers found that, in mice, roughly 600 to 700 developmental precursors contribute to life-long hematopoiesis.

The number of precursor cells in humans is likely at least 10 times greater, according to researchers.

“All previous studies had reported that very few precursor cells are involved in establishing the blood system,” said study author Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“But data in this study show that, actually, hundreds of cells are involved and that the developing blood system is more complex and may be shaped, in part, by regulatory bottlenecks that occur late in development and serve to restrict the number of blood-forming stem cells.”

For this study, Miguel Ganuza, PhD, a fellow in Dr McKinney-Freeman’s lab, adapted a system used to study the cellular makeup of solid tumors. The multi-colored labeling system is activated by genes expressed during specific windows of development.

Dr Ganuza used the system to label and track the fate of precursor cells from various developmental stages in mice.

“We wanted to understand what was happening with different progenitor cells at different stages of development when we knew important decisions on the fate of cells occurred,” Dr Ganuza said.

David Finkelstein, PhD, of the St. Jude Department of Computational Biology, then used mathematical modeling to work backward from peripheral blood in adult mice to track the contribution of precursor cells from the early, middle, and late stages of prenatal development.

The results showed that far more precursor cells than expected contribute to life-long hematopoiesis in adult mice.

The researchers found about 719 Flk1⁺ mesodermal precursors emerged at embryonic days 7 to 8.5, 633 VE-cadherin⁺ endothelial precursors emerged at embryonic days 8.5 to 11.5, and 545 Vav1⁺ nascent hematopoietic stem and progenitor cells emerged at embryonic days 11.5 to 14.5.

The team also said specification of hemogenic endothelial cells begins at embryonic day 8.5 and ends by embryonic day 10.5. After that, it cannot be reactivated.

Finally, the researchers found that intra-aortic hematopoietic clusters are polyclonal in origin.

The team said these findings raised questions about the role of the fetal liver in hematopoiesis.

“For decades, the fetal liver was thought to be where the number of blood stem cells expanded dramatically,” Dr McKinney-Freeman said.

“The results in this study raise questions about that model and even suggest the presence of developmental bottlenecks in the fetal liver or at later stages of development that restrict the blood stem cell population. This is when science is most interesting, when you see things you didn’t expect.”

While unexpected, the newly revealed size and complexity of the emerging blood system make sense developmentally, Dr McKinney-Freeman said.

“Producing hundreds of progenitor cells during different developmental stages means the organism has greater flexibility to adapt to issues and problems that might emerge as development progresses,” she noted.

The findings also have clinical implications, according to Dr McKinney-Freeman.

“Understanding how the blood system emerges, including the number and complexity of the progenitor cells involved, will help us unravel the origins of disease and identify cells that might be susceptible to disease-causing mutations,” she concluded.

Research Hospital

Life-long hematopoiesis relies on hundreds more blood progenitors than previously reported, according to preclinical research published in Nature Cell Biology.

Previous studies linked life-long mammalian blood production to just a handful of precursor cells that emerge during prenatal development.

In the current study, researchers found that, in mice, roughly 600 to 700 developmental precursors contribute to life-long hematopoiesis.

The number of precursor cells in humans is likely at least 10 times greater, according to researchers.

“All previous studies had reported that very few precursor cells are involved in establishing the blood system,” said study author Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“But data in this study show that, actually, hundreds of cells are involved and that the developing blood system is more complex and may be shaped, in part, by regulatory bottlenecks that occur late in development and serve to restrict the number of blood-forming stem cells.”

For this study, Miguel Ganuza, PhD, a fellow in Dr McKinney-Freeman’s lab, adapted a system used to study the cellular makeup of solid tumors. The multi-colored labeling system is activated by genes expressed during specific windows of development.

Dr Ganuza used the system to label and track the fate of precursor cells from various developmental stages in mice.

“We wanted to understand what was happening with different progenitor cells at different stages of development when we knew important decisions on the fate of cells occurred,” Dr Ganuza said.

David Finkelstein, PhD, of the St. Jude Department of Computational Biology, then used mathematical modeling to work backward from peripheral blood in adult mice to track the contribution of precursor cells from the early, middle, and late stages of prenatal development.

The results showed that far more precursor cells than expected contribute to life-long hematopoiesis in adult mice.

The researchers found about 719 Flk1⁺ mesodermal precursors emerged at embryonic days 7 to 8.5, 633 VE-cadherin⁺ endothelial precursors emerged at embryonic days 8.5 to 11.5, and 545 Vav1⁺ nascent hematopoietic stem and progenitor cells emerged at embryonic days 11.5 to 14.5.

The team also said specification of hemogenic endothelial cells begins at embryonic day 8.5 and ends by embryonic day 10.5. After that, it cannot be reactivated.

Finally, the researchers found that intra-aortic hematopoietic clusters are polyclonal in origin.

The team said these findings raised questions about the role of the fetal liver in hematopoiesis.

“For decades, the fetal liver was thought to be where the number of blood stem cells expanded dramatically,” Dr McKinney-Freeman said.

“The results in this study raise questions about that model and even suggest the presence of developmental bottlenecks in the fetal liver or at later stages of development that restrict the blood stem cell population. This is when science is most interesting, when you see things you didn’t expect.”

While unexpected, the newly revealed size and complexity of the emerging blood system make sense developmentally, Dr McKinney-Freeman said.

“Producing hundreds of progenitor cells during different developmental stages means the organism has greater flexibility to adapt to issues and problems that might emerge as development progresses,” she noted.

The findings also have clinical implications, according to Dr McKinney-Freeman.

“Understanding how the blood system emerges, including the number and complexity of the progenitor cells involved, will help us unravel the origins of disease and identify cells that might be susceptible to disease-causing mutations,” she concluded.

Research Hospital

Life-long hematopoiesis relies on hundreds more blood progenitors than previously reported, according to preclinical research published in Nature Cell Biology.

Previous studies linked life-long mammalian blood production to just a handful of precursor cells that emerge during prenatal development.

In the current study, researchers found that, in mice, roughly 600 to 700 developmental precursors contribute to life-long hematopoiesis.

The number of precursor cells in humans is likely at least 10 times greater, according to researchers.

“All previous studies had reported that very few precursor cells are involved in establishing the blood system,” said study author Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“But data in this study show that, actually, hundreds of cells are involved and that the developing blood system is more complex and may be shaped, in part, by regulatory bottlenecks that occur late in development and serve to restrict the number of blood-forming stem cells.”

For this study, Miguel Ganuza, PhD, a fellow in Dr McKinney-Freeman’s lab, adapted a system used to study the cellular makeup of solid tumors. The multi-colored labeling system is activated by genes expressed during specific windows of development.

Dr Ganuza used the system to label and track the fate of precursor cells from various developmental stages in mice.

“We wanted to understand what was happening with different progenitor cells at different stages of development when we knew important decisions on the fate of cells occurred,” Dr Ganuza said.

David Finkelstein, PhD, of the St. Jude Department of Computational Biology, then used mathematical modeling to work backward from peripheral blood in adult mice to track the contribution of precursor cells from the early, middle, and late stages of prenatal development.

The results showed that far more precursor cells than expected contribute to life-long hematopoiesis in adult mice.

The researchers found about 719 Flk1⁺ mesodermal precursors emerged at embryonic days 7 to 8.5, 633 VE-cadherin⁺ endothelial precursors emerged at embryonic days 8.5 to 11.5, and 545 Vav1⁺ nascent hematopoietic stem and progenitor cells emerged at embryonic days 11.5 to 14.5.

The team also said specification of hemogenic endothelial cells begins at embryonic day 8.5 and ends by embryonic day 10.5. After that, it cannot be reactivated.

Finally, the researchers found that intra-aortic hematopoietic clusters are polyclonal in origin.

The team said these findings raised questions about the role of the fetal liver in hematopoiesis.

“For decades, the fetal liver was thought to be where the number of blood stem cells expanded dramatically,” Dr McKinney-Freeman said.

“The results in this study raise questions about that model and even suggest the presence of developmental bottlenecks in the fetal liver or at later stages of development that restrict the blood stem cell population. This is when science is most interesting, when you see things you didn’t expect.”

While unexpected, the newly revealed size and complexity of the emerging blood system make sense developmentally, Dr McKinney-Freeman said.

“Producing hundreds of progenitor cells during different developmental stages means the organism has greater flexibility to adapt to issues and problems that might emerge as development progresses,” she noted.

The findings also have clinical implications, according to Dr McKinney-Freeman.

“Understanding how the blood system emerges, including the number and complexity of the progenitor cells involved, will help us unravel the origins of disease and identify cells that might be susceptible to disease-causing mutations,” she concluded.

Photo from Genentech

Roche has announced a partial clinical hold on 2 trials of the anti-PD-L1 antibody atezolizumab (Tecentriq).

One is a phase 1b/2 study (NCT02631577) in which researchers are evaluating atezolizumab in combination with obinutuzumab plus lenalidomide in patients with relapsed or refractory follicular lymphoma.

The other is a phase 1b study (NCT02431208) of atezolizumab alone or in combination with an immunomodulatory drug and/or daratumumab in patients with multiple myeloma (MM).

The partial clinical hold on these trials means patients who are currently enrolled and are deriving clinical benefit may continue to receive treatment, but no additional patients will be enrolled.

The decision to place these trials on hold is related to risks identified in 2 trials of the anti-PD-1 agent pembrolizumab. Results from these trials showed that combining pembrolizumab with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) increases the risk of death in patients with MM.

The results led to clinical holds on these trials (and a third trial of pembrolizumab) as well as an investigation by the US Food and Drug Administration (FDA).

The FDA has stressed its belief that the benefits of taking pembrolizumab and other PD-1/PD-L1 inhibitors for their approved uses continue to outweigh the risks.

However, the agency also thinks there may be an unfavorable risk-benefit ratio for patients receiving PD-1/PD-L1 treatment alone or in other combinations in unapproved indications.

Therefore, the FDA is investigating trials of PD-1/PD-L1 inhibitors being studied in combination with immunomodulatory agents or other classes of drugs in patients with hematologic malignancies.

In the course of this investigation, the FDA has placed holds on trials of nivolumab and durvalumab as well as atezolizumab.

According to Roche, there is no evidence of an increased risk of death or serious events with the use of atezolizumab in combination with immunomodulatory agents.

Photo from Genentech

Roche has announced a partial clinical hold on 2 trials of the anti-PD-L1 antibody atezolizumab (Tecentriq).

One is a phase 1b/2 study (NCT02631577) in which researchers are evaluating atezolizumab in combination with obinutuzumab plus lenalidomide in patients with relapsed or refractory follicular lymphoma.

The other is a phase 1b study (NCT02431208) of atezolizumab alone or in combination with an immunomodulatory drug and/or daratumumab in patients with multiple myeloma (MM).

The partial clinical hold on these trials means patients who are currently enrolled and are deriving clinical benefit may continue to receive treatment, but no additional patients will be enrolled.

The decision to place these trials on hold is related to risks identified in 2 trials of the anti-PD-1 agent pembrolizumab. Results from these trials showed that combining pembrolizumab with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) increases the risk of death in patients with MM.

The results led to clinical holds on these trials (and a third trial of pembrolizumab) as well as an investigation by the US Food and Drug Administration (FDA).

The FDA has stressed its belief that the benefits of taking pembrolizumab and other PD-1/PD-L1 inhibitors for their approved uses continue to outweigh the risks.

However, the agency also thinks there may be an unfavorable risk-benefit ratio for patients receiving PD-1/PD-L1 treatment alone or in other combinations in unapproved indications.

Therefore, the FDA is investigating trials of PD-1/PD-L1 inhibitors being studied in combination with immunomodulatory agents or other classes of drugs in patients with hematologic malignancies.

In the course of this investigation, the FDA has placed holds on trials of nivolumab and durvalumab as well as atezolizumab.

According to Roche, there is no evidence of an increased risk of death or serious events with the use of atezolizumab in combination with immunomodulatory agents.

Photo from Genentech

Roche has announced a partial clinical hold on 2 trials of the anti-PD-L1 antibody atezolizumab (Tecentriq).

One is a phase 1b/2 study (NCT02631577) in which researchers are evaluating atezolizumab in combination with obinutuzumab plus lenalidomide in patients with relapsed or refractory follicular lymphoma.

The other is a phase 1b study (NCT02431208) of atezolizumab alone or in combination with an immunomodulatory drug and/or daratumumab in patients with multiple myeloma (MM).

The partial clinical hold on these trials means patients who are currently enrolled and are deriving clinical benefit may continue to receive treatment, but no additional patients will be enrolled.

The decision to place these trials on hold is related to risks identified in 2 trials of the anti-PD-1 agent pembrolizumab. Results from these trials showed that combining pembrolizumab with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) increases the risk of death in patients with MM.

The results led to clinical holds on these trials (and a third trial of pembrolizumab) as well as an investigation by the US Food and Drug Administration (FDA).

The FDA has stressed its belief that the benefits of taking pembrolizumab and other PD-1/PD-L1 inhibitors for their approved uses continue to outweigh the risks.

However, the agency also thinks there may be an unfavorable risk-benefit ratio for patients receiving PD-1/PD-L1 treatment alone or in other combinations in unapproved indications.

Therefore, the FDA is investigating trials of PD-1/PD-L1 inhibitors being studied in combination with immunomodulatory agents or other classes of drugs in patients with hematologic malignancies.

In the course of this investigation, the FDA has placed holds on trials of nivolumab and durvalumab as well as atezolizumab.

According to Roche, there is no evidence of an increased risk of death or serious events with the use of atezolizumab in combination with immunomodulatory agents.

Antihemophilic factor

The European Medicines Agency (EMA) has concluded there is “no clear and consistent evidence” of a difference in inhibitor development between the 2 classes of factor VIII (FVIII) products.

A review of data from several studies has suggested that hemophilia A patients are no more likely to develop inhibitors if they receive a recombinant FVIII product rather than a plasma-derived FVIII product.

The review began after publication of the SIPPET study¹, which suggested that patients who received plasma-derived FVIII had a lower incidence of inhibitors than patients treated with recombinant FVIII.

To test this conclusion, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) reviewed data on all FVIII products authorized for use in the European Union. This includes products containing the active substances human coagulation FVIII, efmoroctocog alfa, moroctocog alfa, octocog alfa, simoctocog alfa, susoctocog alfa, and turoctocog alfa.

The PRAC examined data from the SIPPET study and additional clinical trials and observational studies.^2-5

The data did not show any statistically significant or clinically meaningful difference in inhibitor risk between FVIII classes.

The PRAC said results of the SIPPET study cannot be extrapolated to individual products, as the study only included a small number of FVIII products.

The PRAC’s conclusion was sent to the EMA’s Committee for Medicinal Products for Human Use (CHMP) for adoption of the EMA’s final opinion. And the CHMP has adopted the opinion that there is “no clear and consistent evidence” of a difference in inhibitor development.

The CHMP’s opinion will be forwarded to the European Commission, which will issue a final, legally binding decision applicable in all European Union member states. The European Commission typically adheres to the CHMP’s recommendations.

The EMA said prescribing information for FVIII products will be updated as appropriate to add inhibitor development as a very common side effect in previously untreated patients and as uncommon in previously treated patients.

The warning on inhibitor development will be amended to state that low titers of inhibitors pose less risk of insufficient response than high titers.

1. Peyvandi F, Mannucci PM, Garagiola I et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med (2016), 374:2054-64.

2. Gouw SC et al. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood (2007), 109:4648-54.

3. Gouw SC et al. PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med (2013), 368:231-9.

4. Iorio A et al. Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series. Haemophilia (2017), 23:255-63.

5. Fischer K et al. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost (2015) 113:968-75.

Antihemophilic factor

The European Medicines Agency (EMA) has concluded there is “no clear and consistent evidence” of a difference in inhibitor development between the 2 classes of factor VIII (FVIII) products.

A review of data from several studies has suggested that hemophilia A patients are no more likely to develop inhibitors if they receive a recombinant FVIII product rather than a plasma-derived FVIII product.

The review began after publication of the SIPPET study¹, which suggested that patients who received plasma-derived FVIII had a lower incidence of inhibitors than patients treated with recombinant FVIII.

To test this conclusion, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) reviewed data on all FVIII products authorized for use in the European Union. This includes products containing the active substances human coagulation FVIII, efmoroctocog alfa, moroctocog alfa, octocog alfa, simoctocog alfa, susoctocog alfa, and turoctocog alfa.

The PRAC examined data from the SIPPET study and additional clinical trials and observational studies.^2-5

The data did not show any statistically significant or clinically meaningful difference in inhibitor risk between FVIII classes.

The PRAC said results of the SIPPET study cannot be extrapolated to individual products, as the study only included a small number of FVIII products.

The PRAC’s conclusion was sent to the EMA’s Committee for Medicinal Products for Human Use (CHMP) for adoption of the EMA’s final opinion. And the CHMP has adopted the opinion that there is “no clear and consistent evidence” of a difference in inhibitor development.

The CHMP’s opinion will be forwarded to the European Commission, which will issue a final, legally binding decision applicable in all European Union member states. The European Commission typically adheres to the CHMP’s recommendations.

The EMA said prescribing information for FVIII products will be updated as appropriate to add inhibitor development as a very common side effect in previously untreated patients and as uncommon in previously treated patients.

The warning on inhibitor development will be amended to state that low titers of inhibitors pose less risk of insufficient response than high titers.

1. Peyvandi F, Mannucci PM, Garagiola I et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med (2016), 374:2054-64.

2. Gouw SC et al. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood (2007), 109:4648-54.

3. Gouw SC et al. PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med (2013), 368:231-9.

4. Iorio A et al. Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series. Haemophilia (2017), 23:255-63.

5. Fischer K et al. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost (2015) 113:968-75.

Antihemophilic factor

The European Medicines Agency (EMA) has concluded there is “no clear and consistent evidence” of a difference in inhibitor development between the 2 classes of factor VIII (FVIII) products.

A review of data from several studies has suggested that hemophilia A patients are no more likely to develop inhibitors if they receive a recombinant FVIII product rather than a plasma-derived FVIII product.

The review began after publication of the SIPPET study¹, which suggested that patients who received plasma-derived FVIII had a lower incidence of inhibitors than patients treated with recombinant FVIII.

To test this conclusion, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) reviewed data on all FVIII products authorized for use in the European Union. This includes products containing the active substances human coagulation FVIII, efmoroctocog alfa, moroctocog alfa, octocog alfa, simoctocog alfa, susoctocog alfa, and turoctocog alfa.

The PRAC examined data from the SIPPET study and additional clinical trials and observational studies.^2-5

The data did not show any statistically significant or clinically meaningful difference in inhibitor risk between FVIII classes.

The PRAC said results of the SIPPET study cannot be extrapolated to individual products, as the study only included a small number of FVIII products.

The PRAC’s conclusion was sent to the EMA’s Committee for Medicinal Products for Human Use (CHMP) for adoption of the EMA’s final opinion. And the CHMP has adopted the opinion that there is “no clear and consistent evidence” of a difference in inhibitor development.

The CHMP’s opinion will be forwarded to the European Commission, which will issue a final, legally binding decision applicable in all European Union member states. The European Commission typically adheres to the CHMP’s recommendations.

The EMA said prescribing information for FVIII products will be updated as appropriate to add inhibitor development as a very common side effect in previously untreated patients and as uncommon in previously treated patients.

The warning on inhibitor development will be amended to state that low titers of inhibitors pose less risk of insufficient response than high titers.

1. Peyvandi F, Mannucci PM, Garagiola I et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med (2016), 374:2054-64.

2. Gouw SC et al. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood (2007), 109:4648-54.

3. Gouw SC et al. PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med (2013), 368:231-9.

4. Iorio A et al. Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series. Haemophilia (2017), 23:255-63.

5. Fischer K et al. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost (2015) 113:968-75.

Switching to riociguat may be an effective strategy for pulmonary arterial hypertension (PAH) patients who respond inadequately to phosphodiesterase-5 inhibitors, results from a small open-label study demonstrated.

“This study represents an important step towards determining if this new treatment strategy is an effective approach to the management of patients with PAH, although additional data from larger, randomised, controlled studies are needed to further establish the safety and efficacy of this approach,” researchers led by Marius M. Hoeper, MD, wrote in a study published online Sept. 9, 2017, in the European Respiratory Journal.

Current clinical data indicate that many patients with PAH who receive phosphodiesterase-5 inhibitors do not reach treatment goals. “For example, in the AMBITION study, 73% of patients with PAH receiving tadalafil monotherapy and 61% of those receiving tadalafil in combination with ambrisentan did not achieve a satisfactory clinical response at week 24 of the study (N Engl J Med. 2015;373:834-44),” Dr. Hoeper of the Clinic for Respiratory Medicine at Hannover Medical School Germany and his associates wrote. “Furthermore, in the SERAPHIN study, event-free survival of patients receiving [phosphodiesterase-5 inhibitors] monotherapy was approximately 50% at 3 years (N Engl J Med. 2013;369:809-18).”

For the current trial, known as RESPITE, investigators from nine countries in Europe and North America enrolled 61 PAH patients in a 24-week, open-label uncontrolled analysis to investigate the safety, feasibility, and benefit of switching them from phosphodiesterase-5 inhibitors to riociguat. The patients underwent 1-3 days free of phosphodiesterase-5 inhibitors before receiving riociguat in a maximum dose of up to 2.5 mg t.i.d. Most patients (74%) were female, and 92% were Caucasian. In all, 51 patients (84%) completed all 24 weeks of treatment, while the remaining 10 discontinued treatment, 4 of whom due to adverse events.

Among those who completed all 24 weeks of the trial, their mean 6-minute walking distance had increased by a mean of 31 meters and their N-terminal pro b-type natriuretic peptide level decreased by a mean of 347 pg/mL^. Additionally, 54% of the patients studied experienced an improvement in their the World Health Organization Functional Class. However, 32 patients (52%) experienced study drug–related adverse events and 10 (16%) experienced serious adverse events, two of which were related to the drug being studied. Six patients (10%) experienced clinical worsening, including death in two, though the deaths were deemed to be unrelated to the drug being studied.

“Although not mechanistically studied, the findings of RESPITE support the hypothesis that a defective [nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate] pathway might explain why some patients have no sufficient or sustained response to [phosphodiesterase-5 inhibitors] therapy,” the researchers noted. “In such patients, direct stimulation of [soluble guanylate cyclase] may be more effective than inhibition of [phosphodiesterase-5], but this hypothesis is still unproven.”

They acknowledged certain limitations of the study, including its prospective design and the relatively homogenous patient population. “Other limitations include the lack of a long-term continuation phase, and the absence of mechanistic data allowing identification of patients likely to respond or not respond to switching,” they wrote. “Two deaths were observed in this study, which might raise concerns, although neither of the deaths (one due to pneumonia and one due to subdural haematoma) was considered by the investigators to be study drug-related or due to worsening PAH. Given the lack of a control group and the rate of study withdrawals and clinical worsening events, further evaluation to clarify the safety of switching is required.”

The study was funded by Bayer AG, Berlin. Dr. Hoeper and his coauthors disclosed having financial ties to numerous pharmaceutical companies, including Bayer, which makes riociguat.

[email protected]

PRIMARY SOURCE: Eur Respir J. 2017 Sep 9. doi: 10.1183/13993003.02425-2016.

Switching to riociguat may be an effective strategy for pulmonary arterial hypertension (PAH) patients who respond inadequately to phosphodiesterase-5 inhibitors, results from a small open-label study demonstrated.

“This study represents an important step towards determining if this new treatment strategy is an effective approach to the management of patients with PAH, although additional data from larger, randomised, controlled studies are needed to further establish the safety and efficacy of this approach,” researchers led by Marius M. Hoeper, MD, wrote in a study published online Sept. 9, 2017, in the European Respiratory Journal.

Current clinical data indicate that many patients with PAH who receive phosphodiesterase-5 inhibitors do not reach treatment goals. “For example, in the AMBITION study, 73% of patients with PAH receiving tadalafil monotherapy and 61% of those receiving tadalafil in combination with ambrisentan did not achieve a satisfactory clinical response at week 24 of the study (N Engl J Med. 2015;373:834-44),” Dr. Hoeper of the Clinic for Respiratory Medicine at Hannover Medical School Germany and his associates wrote. “Furthermore, in the SERAPHIN study, event-free survival of patients receiving [phosphodiesterase-5 inhibitors] monotherapy was approximately 50% at 3 years (N Engl J Med. 2013;369:809-18).”

For the current trial, known as RESPITE, investigators from nine countries in Europe and North America enrolled 61 PAH patients in a 24-week, open-label uncontrolled analysis to investigate the safety, feasibility, and benefit of switching them from phosphodiesterase-5 inhibitors to riociguat. The patients underwent 1-3 days free of phosphodiesterase-5 inhibitors before receiving riociguat in a maximum dose of up to 2.5 mg t.i.d. Most patients (74%) were female, and 92% were Caucasian. In all, 51 patients (84%) completed all 24 weeks of treatment, while the remaining 10 discontinued treatment, 4 of whom due to adverse events.

Among those who completed all 24 weeks of the trial, their mean 6-minute walking distance had increased by a mean of 31 meters and their N-terminal pro b-type natriuretic peptide level decreased by a mean of 347 pg/mL^. Additionally, 54% of the patients studied experienced an improvement in their the World Health Organization Functional Class. However, 32 patients (52%) experienced study drug–related adverse events and 10 (16%) experienced serious adverse events, two of which were related to the drug being studied. Six patients (10%) experienced clinical worsening, including death in two, though the deaths were deemed to be unrelated to the drug being studied.

“Although not mechanistically studied, the findings of RESPITE support the hypothesis that a defective [nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate] pathway might explain why some patients have no sufficient or sustained response to [phosphodiesterase-5 inhibitors] therapy,” the researchers noted. “In such patients, direct stimulation of [soluble guanylate cyclase] may be more effective than inhibition of [phosphodiesterase-5], but this hypothesis is still unproven.”

They acknowledged certain limitations of the study, including its prospective design and the relatively homogenous patient population. “Other limitations include the lack of a long-term continuation phase, and the absence of mechanistic data allowing identification of patients likely to respond or not respond to switching,” they wrote. “Two deaths were observed in this study, which might raise concerns, although neither of the deaths (one due to pneumonia and one due to subdural haematoma) was considered by the investigators to be study drug-related or due to worsening PAH. Given the lack of a control group and the rate of study withdrawals and clinical worsening events, further evaluation to clarify the safety of switching is required.”

The study was funded by Bayer AG, Berlin. Dr. Hoeper and his coauthors disclosed having financial ties to numerous pharmaceutical companies, including Bayer, which makes riociguat.

[email protected]

PRIMARY SOURCE: Eur Respir J. 2017 Sep 9. doi: 10.1183/13993003.02425-2016.

Switching to riociguat may be an effective strategy for pulmonary arterial hypertension (PAH) patients who respond inadequately to phosphodiesterase-5 inhibitors, results from a small open-label study demonstrated.

“This study represents an important step towards determining if this new treatment strategy is an effective approach to the management of patients with PAH, although additional data from larger, randomised, controlled studies are needed to further establish the safety and efficacy of this approach,” researchers led by Marius M. Hoeper, MD, wrote in a study published online Sept. 9, 2017, in the European Respiratory Journal.

Current clinical data indicate that many patients with PAH who receive phosphodiesterase-5 inhibitors do not reach treatment goals. “For example, in the AMBITION study, 73% of patients with PAH receiving tadalafil monotherapy and 61% of those receiving tadalafil in combination with ambrisentan did not achieve a satisfactory clinical response at week 24 of the study (N Engl J Med. 2015;373:834-44),” Dr. Hoeper of the Clinic for Respiratory Medicine at Hannover Medical School Germany and his associates wrote. “Furthermore, in the SERAPHIN study, event-free survival of patients receiving [phosphodiesterase-5 inhibitors] monotherapy was approximately 50% at 3 years (N Engl J Med. 2013;369:809-18).”

For the current trial, known as RESPITE, investigators from nine countries in Europe and North America enrolled 61 PAH patients in a 24-week, open-label uncontrolled analysis to investigate the safety, feasibility, and benefit of switching them from phosphodiesterase-5 inhibitors to riociguat. The patients underwent 1-3 days free of phosphodiesterase-5 inhibitors before receiving riociguat in a maximum dose of up to 2.5 mg t.i.d. Most patients (74%) were female, and 92% were Caucasian. In all, 51 patients (84%) completed all 24 weeks of treatment, while the remaining 10 discontinued treatment, 4 of whom due to adverse events.

Among those who completed all 24 weeks of the trial, their mean 6-minute walking distance had increased by a mean of 31 meters and their N-terminal pro b-type natriuretic peptide level decreased by a mean of 347 pg/mL^. Additionally, 54% of the patients studied experienced an improvement in their the World Health Organization Functional Class. However, 32 patients (52%) experienced study drug–related adverse events and 10 (16%) experienced serious adverse events, two of which were related to the drug being studied. Six patients (10%) experienced clinical worsening, including death in two, though the deaths were deemed to be unrelated to the drug being studied.

“Although not mechanistically studied, the findings of RESPITE support the hypothesis that a defective [nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate] pathway might explain why some patients have no sufficient or sustained response to [phosphodiesterase-5 inhibitors] therapy,” the researchers noted. “In such patients, direct stimulation of [soluble guanylate cyclase] may be more effective than inhibition of [phosphodiesterase-5], but this hypothesis is still unproven.”

They acknowledged certain limitations of the study, including its prospective design and the relatively homogenous patient population. “Other limitations include the lack of a long-term continuation phase, and the absence of mechanistic data allowing identification of patients likely to respond or not respond to switching,” they wrote. “Two deaths were observed in this study, which might raise concerns, although neither of the deaths (one due to pneumonia and one due to subdural haematoma) was considered by the investigators to be study drug-related or due to worsening PAH. Given the lack of a control group and the rate of study withdrawals and clinical worsening events, further evaluation to clarify the safety of switching is required.”

The study was funded by Bayer AG, Berlin. Dr. Hoeper and his coauthors disclosed having financial ties to numerous pharmaceutical companies, including Bayer, which makes riociguat.

[email protected]

PRIMARY SOURCE: Eur Respir J. 2017 Sep 9. doi: 10.1183/13993003.02425-2016.

CHICAGO – The challenge of addressing marijuana use by children and teens is increasing with its wider availability; 29 states have now legalized cannabis for medical use, and 8 of them plus the District of Columbia have legalized recreational marijuana use.

“Past-month marijuana use is now higher than past-month use of cigarettes” based on teens’ responses to surveys from the National Institute on Drug Abuse (NIDA), Karen M. Wilson, MD, said at the annual meeting of the American Academy of Pediatrics.

CHICAGO – The challenge of addressing marijuana use by children and teens is increasing with its wider availability; 29 states have now legalized cannabis for medical use, and 8 of them plus the District of Columbia have legalized recreational marijuana use.

“Past-month marijuana use is now higher than past-month use of cigarettes” based on teens’ responses to surveys from the National Institute on Drug Abuse (NIDA), Karen M. Wilson, MD, said at the annual meeting of the American Academy of Pediatrics.

CHICAGO – The challenge of addressing marijuana use by children and teens is increasing with its wider availability; 29 states have now legalized cannabis for medical use, and 8 of them plus the District of Columbia have legalized recreational marijuana use.

“Past-month marijuana use is now higher than past-month use of cigarettes” based on teens’ responses to surveys from the National Institute on Drug Abuse (NIDA), Karen M. Wilson, MD, said at the annual meeting of the American Academy of Pediatrics.

The first single-dose, oral treatment for bacterial vaginosis will be available by prescription in early 2018, thanks to its approval by the Food and Drug Administration.

Symbiomix Therapeutics announced Sept. 18 that the FDA had granted approval to secnidazole (Solosec) 2 g oral granules for the treatment of bacterial vaginosis in adult women. Clinical trials of the 5-nitroimidazole antibiotic have shown it to be effective in a single dose, offering the potential for greater patient adherence to treatment over the common regimen of twice-a-day dosing for 7 days.

[email protected]

On Twitter @maryellenny

The first single-dose, oral treatment for bacterial vaginosis will be available by prescription in early 2018, thanks to its approval by the Food and Drug Administration.

Symbiomix Therapeutics announced Sept. 18 that the FDA had granted approval to secnidazole (Solosec) 2 g oral granules for the treatment of bacterial vaginosis in adult women. Clinical trials of the 5-nitroimidazole antibiotic have shown it to be effective in a single dose, offering the potential for greater patient adherence to treatment over the common regimen of twice-a-day dosing for 7 days.

[email protected]

On Twitter @maryellenny

The first single-dose, oral treatment for bacterial vaginosis will be available by prescription in early 2018, thanks to its approval by the Food and Drug Administration.

Symbiomix Therapeutics announced Sept. 18 that the FDA had granted approval to secnidazole (Solosec) 2 g oral granules for the treatment of bacterial vaginosis in adult women. Clinical trials of the 5-nitroimidazole antibiotic have shown it to be effective in a single dose, offering the potential for greater patient adherence to treatment over the common regimen of twice-a-day dosing for 7 days.

[email protected]

On Twitter @maryellenny

MADRID – Radioactive iodine treatment is associated with nearly twice the risk of developing acute myeloid leukemia (AML) in patients with well-differentiated thyroid cancer, based on data from the Surveillance Epidemiology and End Results (SEER) registry.

Up to 40% of patients in Europe and North America with well-differentiated thyroid cancer still receive radioactive iodine treatment “even though RAI has no proven benefit in this population,” Remco Molenaar, MD, PhD, of the University of Amsterdam reported at the European Society of Medical Oncology Congress.

Of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014, 55% had surgery only and 45% received surgery plus radioactive iodine treatment. After a median 4.3 years of follow-up, 44 patients developed AML. When cases in those exposed to RAI were cross-referenced to those who were not, the relative risk was increased more than fivefold. When the analysis controlled for an extensive list of potentially confounding variables, the hazard ratio of 1.79 remained statistically significant (P = .03).

“There is a nearly twofold increased risk even though radioactive iodine treatment is not indicated in this population,” Dr. Molenaar said. Moreover, AML following treatment for well-differentiated thyroid cancer was associated with a substantial reduction in expected overall survival, falling from a median 24.4 years to 7.5 years.

Compared with other AML patients, “those who develop AML after RAI also have a worse prognosis,” added Dr. Molenaar, noting the difference in overall survival is highly statistically significant (1.2 vs. 3.5 years; P = .004).

The ESMO-invited discussant, Tim Somervaille, MD, senior group leader of the Leukemia Biology Laboratory at the Cancer Research UK Manchester Institute, called this analysis “a more thorough and detailed study” than previous retrospective analyses, but he added a note of caution: Despite the almost twofold increase in risk, AML remains a rare iatrogenic event in thyroid cancer patients even if it is avoidable by withholding RAI therapy.

“These data do suggest that the risk is measurable and will further provide some downward pressure on the numbers of patients having unnecessary RAI therapy for well-differentiated thyroid cancer,” he said.

In the discussion that followed the presentation, one audience member suggested that telling patients they have a twofold increased risk of AML after RAI therapy is misleading. It was emphasized that a twofold increase of a very small number is still a very small number, but Dr. Molenaar suggested that this misses the point.

“I don’t think this is something that you need to discuss with patients, because you should not be giving RAI therapy to thyroid cancer patients with low- or intermediate-risk disease,” he said. Any AML case caused “by a therapy with no proven benefit is one too many,” especially since unnecessary RAI adds inconvenience and cost to treatment.

[email protected]

MADRID – Radioactive iodine treatment is associated with nearly twice the risk of developing acute myeloid leukemia (AML) in patients with well-differentiated thyroid cancer, based on data from the Surveillance Epidemiology and End Results (SEER) registry.

Up to 40% of patients in Europe and North America with well-differentiated thyroid cancer still receive radioactive iodine treatment “even though RAI has no proven benefit in this population,” Remco Molenaar, MD, PhD, of the University of Amsterdam reported at the European Society of Medical Oncology Congress.

Of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014, 55% had surgery only and 45% received surgery plus radioactive iodine treatment. After a median 4.3 years of follow-up, 44 patients developed AML. When cases in those exposed to RAI were cross-referenced to those who were not, the relative risk was increased more than fivefold. When the analysis controlled for an extensive list of potentially confounding variables, the hazard ratio of 1.79 remained statistically significant (P = .03).

“There is a nearly twofold increased risk even though radioactive iodine treatment is not indicated in this population,” Dr. Molenaar said. Moreover, AML following treatment for well-differentiated thyroid cancer was associated with a substantial reduction in expected overall survival, falling from a median 24.4 years to 7.5 years.

Compared with other AML patients, “those who develop AML after RAI also have a worse prognosis,” added Dr. Molenaar, noting the difference in overall survival is highly statistically significant (1.2 vs. 3.5 years; P = .004).

The ESMO-invited discussant, Tim Somervaille, MD, senior group leader of the Leukemia Biology Laboratory at the Cancer Research UK Manchester Institute, called this analysis “a more thorough and detailed study” than previous retrospective analyses, but he added a note of caution: Despite the almost twofold increase in risk, AML remains a rare iatrogenic event in thyroid cancer patients even if it is avoidable by withholding RAI therapy.

“These data do suggest that the risk is measurable and will further provide some downward pressure on the numbers of patients having unnecessary RAI therapy for well-differentiated thyroid cancer,” he said.

In the discussion that followed the presentation, one audience member suggested that telling patients they have a twofold increased risk of AML after RAI therapy is misleading. It was emphasized that a twofold increase of a very small number is still a very small number, but Dr. Molenaar suggested that this misses the point.

“I don’t think this is something that you need to discuss with patients, because you should not be giving RAI therapy to thyroid cancer patients with low- or intermediate-risk disease,” he said. Any AML case caused “by a therapy with no proven benefit is one too many,” especially since unnecessary RAI adds inconvenience and cost to treatment.

[email protected]

MADRID – Radioactive iodine treatment is associated with nearly twice the risk of developing acute myeloid leukemia (AML) in patients with well-differentiated thyroid cancer, based on data from the Surveillance Epidemiology and End Results (SEER) registry.

Up to 40% of patients in Europe and North America with well-differentiated thyroid cancer still receive radioactive iodine treatment “even though RAI has no proven benefit in this population,” Remco Molenaar, MD, PhD, of the University of Amsterdam reported at the European Society of Medical Oncology Congress.

Of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014, 55% had surgery only and 45% received surgery plus radioactive iodine treatment. After a median 4.3 years of follow-up, 44 patients developed AML. When cases in those exposed to RAI were cross-referenced to those who were not, the relative risk was increased more than fivefold. When the analysis controlled for an extensive list of potentially confounding variables, the hazard ratio of 1.79 remained statistically significant (P = .03).

“There is a nearly twofold increased risk even though radioactive iodine treatment is not indicated in this population,” Dr. Molenaar said. Moreover, AML following treatment for well-differentiated thyroid cancer was associated with a substantial reduction in expected overall survival, falling from a median 24.4 years to 7.5 years.

Compared with other AML patients, “those who develop AML after RAI also have a worse prognosis,” added Dr. Molenaar, noting the difference in overall survival is highly statistically significant (1.2 vs. 3.5 years; P = .004).

The ESMO-invited discussant, Tim Somervaille, MD, senior group leader of the Leukemia Biology Laboratory at the Cancer Research UK Manchester Institute, called this analysis “a more thorough and detailed study” than previous retrospective analyses, but he added a note of caution: Despite the almost twofold increase in risk, AML remains a rare iatrogenic event in thyroid cancer patients even if it is avoidable by withholding RAI therapy.

“These data do suggest that the risk is measurable and will further provide some downward pressure on the numbers of patients having unnecessary RAI therapy for well-differentiated thyroid cancer,” he said.

In the discussion that followed the presentation, one audience member suggested that telling patients they have a twofold increased risk of AML after RAI therapy is misleading. It was emphasized that a twofold increase of a very small number is still a very small number, but Dr. Molenaar suggested that this misses the point.

“I don’t think this is something that you need to discuss with patients, because you should not be giving RAI therapy to thyroid cancer patients with low- or intermediate-risk disease,” he said. Any AML case caused “by a therapy with no proven benefit is one too many,” especially since unnecessary RAI adds inconvenience and cost to treatment.

[email protected]

SAN FRANCISCO – Dermatologists are often on the frontline when it comes to diagnosing polycystic ovary syndrome (PCOS), which is one reason they should be up to date and aware of the changing diagnostic criteria for the condition, according to Kanade Shinkai, MD.

About one-quarter of patients who are diagnosed with PCOS are seen first by a dermatologist. That’s because skin conditions may be more concerning than reproductive issues in young women.

“Sometimes, people don’t see [irregular menstruation] as a problem,” explained Dr. Shinkai of the department of dermatology at the University of California, San Francisco. “Maybe they’re young, or they’re not trying to get pregnant. But if their hair is falling out, they see that as a problem, or if they have bad acne, or they’re becoming hirsute, they see that as a problem. So, they present to a dermatologist.”

Early recognition of PCOS is important, because many women with the condition go on to develop diabetes, impaired glucose intolerance, hyperlipidemia, hypertension, fertility problems, and obesity.

SAN FRANCISCO – Dermatologists are often on the frontline when it comes to diagnosing polycystic ovary syndrome (PCOS), which is one reason they should be up to date and aware of the changing diagnostic criteria for the condition, according to Kanade Shinkai, MD.

About one-quarter of patients who are diagnosed with PCOS are seen first by a dermatologist. That’s because skin conditions may be more concerning than reproductive issues in young women.

“Sometimes, people don’t see [irregular menstruation] as a problem,” explained Dr. Shinkai of the department of dermatology at the University of California, San Francisco. “Maybe they’re young, or they’re not trying to get pregnant. But if their hair is falling out, they see that as a problem, or if they have bad acne, or they’re becoming hirsute, they see that as a problem. So, they present to a dermatologist.”

Early recognition of PCOS is important, because many women with the condition go on to develop diabetes, impaired glucose intolerance, hyperlipidemia, hypertension, fertility problems, and obesity.

SAN FRANCISCO – Dermatologists are often on the frontline when it comes to diagnosing polycystic ovary syndrome (PCOS), which is one reason they should be up to date and aware of the changing diagnostic criteria for the condition, according to Kanade Shinkai, MD.

About one-quarter of patients who are diagnosed with PCOS are seen first by a dermatologist. That’s because skin conditions may be more concerning than reproductive issues in young women.

“Sometimes, people don’t see [irregular menstruation] as a problem,” explained Dr. Shinkai of the department of dermatology at the University of California, San Francisco. “Maybe they’re young, or they’re not trying to get pregnant. But if their hair is falling out, they see that as a problem, or if they have bad acne, or they’re becoming hirsute, they see that as a problem. So, they present to a dermatologist.”

Early recognition of PCOS is important, because many women with the condition go on to develop diabetes, impaired glucose intolerance, hyperlipidemia, hypertension, fertility problems, and obesity.

The fate of the Deferred Action for Childhood Arrivals (DACA) program remains uncertain after an unexpected change of tune by President Donald J. Trump to support of protecting young undocumented immigrants from deportation.

Earlier this month, President Trump announced he would phase out the Obama administration’s DACA program, a policy that protected immigrants who came to the United States as children from deportation and authorized them to work in the United States. In a Sept. 5 statement, President Trump said winding down the DACA program was in the nation’s best interest, and that there can be no principled immigration reform if the executive branch is able to “rewrite or nullify federal laws at will.” The Trump administration allowed Congress 6 months to pass legislation that would replace DACA or preserve some of its provisions before the program terminated in March 2018.

Gage Skidmore/flickr/CC BY-SA 2.0

DACA demise could strand medical students

The DACA program was created by the Obama administration in 2012 as a way of protecting young, undocumented immigrants from deportation after Congress repeatedly blocked legislation that would develop such a safe haven. The policy allowed about 800,000 young adults brought to the United States illegally as children to work legally in the United States and remain in the country without fear of deportation.

If the Trump administration moves forward with termination, the program’s end will affect the growing number of medical students with DACA status and likely jeopardize the funding invested in their training. Sixty-two medical schools accept applications from DACA applicants, according to the Association of American Medical Colleges. For the 2016-2017 school year, 113 students with DACA status applied to U.S. medical schools, and there were 65 medical students enrolled who had DACA status. AAMC does not collect data on medical students with DACA status; the National Resident Matching Program, likewise, does not collect data on residents with DACA status.

Medical groups push for DREAM Act passage

Dozens of physician and medical associations are also pushing Congress to pass the DREAM Act. On Sept. 14, more than 50 medical and health care groups, including the American Medical Association, the American Academy of Family Physicians, the American College of Physicians, the American Academy of Dermatology Association, and the American Academy of Pediatrics sent a letter to congressional leaders urging them to pass the bill.

“On behalf of the undersigned health professions organizations, we urge you to ensure that all members of the health care workforce with Deferred Action for Childhood Arrivals (DACA) status are able to continue their employment, education, training, and research, with passage of a permanent legislative remedy, such as the bipartisan, bicameral Dream Act of 2017,” the letter stated. “By providing a legal pathway to permanent residency for undocumented Americans brought to the U.S. as children, Congress can help our country produce a diverse and culturally responsive health care workforce to meet the needs of underserved populations, improve cultural awareness, and promote health equity.”

The Immigration Reform Law Institute praised President Trump’s Sept. 5 decision to rescind the DACA program, calling the policy an affront to Congress and a violation of the U.S. Constitution.

“Contrary to former President Obama’s claims, not only is DACA not authorized by federal statute, but prior to the unlawful program, deferred action has only ever been applied to small numbers of illegal aliens on a case-by-case basis,” Dale Wilcox, executive director, said in a statement. “Applying it to approximately 15% of the illegal alien population was never a proper exercise of the president’s discretion under the Constitution and is inconsistent with the president’s duty to take care that the laws be faithfully executed. By rescinding DACA, President Trump has put an end to the previous administration’s flagrant violation of our immigration laws and its abuse of hard-working American taxpayers.”

[email protected]

On Twitter @legal_med

The fate of the Deferred Action for Childhood Arrivals (DACA) program remains uncertain after an unexpected change of tune by President Donald J. Trump to support of protecting young undocumented immigrants from deportation.

Earlier this month, President Trump announced he would phase out the Obama administration’s DACA program, a policy that protected immigrants who came to the United States as children from deportation and authorized them to work in the United States. In a Sept. 5 statement, President Trump said winding down the DACA program was in the nation’s best interest, and that there can be no principled immigration reform if the executive branch is able to “rewrite or nullify federal laws at will.” The Trump administration allowed Congress 6 months to pass legislation that would replace DACA or preserve some of its provisions before the program terminated in March 2018.

Gage Skidmore/flickr/CC BY-SA 2.0

DACA demise could strand medical students

The DACA program was created by the Obama administration in 2012 as a way of protecting young, undocumented immigrants from deportation after Congress repeatedly blocked legislation that would develop such a safe haven. The policy allowed about 800,000 young adults brought to the United States illegally as children to work legally in the United States and remain in the country without fear of deportation.

If the Trump administration moves forward with termination, the program’s end will affect the growing number of medical students with DACA status and likely jeopardize the funding invested in their training. Sixty-two medical schools accept applications from DACA applicants, according to the Association of American Medical Colleges. For the 2016-2017 school year, 113 students with DACA status applied to U.S. medical schools, and there were 65 medical students enrolled who had DACA status. AAMC does not collect data on medical students with DACA status; the National Resident Matching Program, likewise, does not collect data on residents with DACA status.

Medical groups push for DREAM Act passage

Dozens of physician and medical associations are also pushing Congress to pass the DREAM Act. On Sept. 14, more than 50 medical and health care groups, including the American Medical Association, the American Academy of Family Physicians, the American College of Physicians, the American Academy of Dermatology Association, and the American Academy of Pediatrics sent a letter to congressional leaders urging them to pass the bill.

“On behalf of the undersigned health professions organizations, we urge you to ensure that all members of the health care workforce with Deferred Action for Childhood Arrivals (DACA) status are able to continue their employment, education, training, and research, with passage of a permanent legislative remedy, such as the bipartisan, bicameral Dream Act of 2017,” the letter stated. “By providing a legal pathway to permanent residency for undocumented Americans brought to the U.S. as children, Congress can help our country produce a diverse and culturally responsive health care workforce to meet the needs of underserved populations, improve cultural awareness, and promote health equity.”

The Immigration Reform Law Institute praised President Trump’s Sept. 5 decision to rescind the DACA program, calling the policy an affront to Congress and a violation of the U.S. Constitution.

“Contrary to former President Obama’s claims, not only is DACA not authorized by federal statute, but prior to the unlawful program, deferred action has only ever been applied to small numbers of illegal aliens on a case-by-case basis,” Dale Wilcox, executive director, said in a statement. “Applying it to approximately 15% of the illegal alien population was never a proper exercise of the president’s discretion under the Constitution and is inconsistent with the president’s duty to take care that the laws be faithfully executed. By rescinding DACA, President Trump has put an end to the previous administration’s flagrant violation of our immigration laws and its abuse of hard-working American taxpayers.”

[email protected]

On Twitter @legal_med

The fate of the Deferred Action for Childhood Arrivals (DACA) program remains uncertain after an unexpected change of tune by President Donald J. Trump to support of protecting young undocumented immigrants from deportation.

Earlier this month, President Trump announced he would phase out the Obama administration’s DACA program, a policy that protected immigrants who came to the United States as children from deportation and authorized them to work in the United States. In a Sept. 5 statement, President Trump said winding down the DACA program was in the nation’s best interest, and that there can be no principled immigration reform if the executive branch is able to “rewrite or nullify federal laws at will.” The Trump administration allowed Congress 6 months to pass legislation that would replace DACA or preserve some of its provisions before the program terminated in March 2018.

Gage Skidmore/flickr/CC BY-SA 2.0

DACA demise could strand medical students

The DACA program was created by the Obama administration in 2012 as a way of protecting young, undocumented immigrants from deportation after Congress repeatedly blocked legislation that would develop such a safe haven. The policy allowed about 800,000 young adults brought to the United States illegally as children to work legally in the United States and remain in the country without fear of deportation.

If the Trump administration moves forward with termination, the program’s end will affect the growing number of medical students with DACA status and likely jeopardize the funding invested in their training. Sixty-two medical schools accept applications from DACA applicants, according to the Association of American Medical Colleges. For the 2016-2017 school year, 113 students with DACA status applied to U.S. medical schools, and there were 65 medical students enrolled who had DACA status. AAMC does not collect data on medical students with DACA status; the National Resident Matching Program, likewise, does not collect data on residents with DACA status.

Medical groups push for DREAM Act passage

Dozens of physician and medical associations are also pushing Congress to pass the DREAM Act. On Sept. 14, more than 50 medical and health care groups, including the American Medical Association, the American Academy of Family Physicians, the American College of Physicians, the American Academy of Dermatology Association, and the American Academy of Pediatrics sent a letter to congressional leaders urging them to pass the bill.

“On behalf of the undersigned health professions organizations, we urge you to ensure that all members of the health care workforce with Deferred Action for Childhood Arrivals (DACA) status are able to continue their employment, education, training, and research, with passage of a permanent legislative remedy, such as the bipartisan, bicameral Dream Act of 2017,” the letter stated. “By providing a legal pathway to permanent residency for undocumented Americans brought to the U.S. as children, Congress can help our country produce a diverse and culturally responsive health care workforce to meet the needs of underserved populations, improve cultural awareness, and promote health equity.”

The Immigration Reform Law Institute praised President Trump’s Sept. 5 decision to rescind the DACA program, calling the policy an affront to Congress and a violation of the U.S. Constitution.

“Contrary to former President Obama’s claims, not only is DACA not authorized by federal statute, but prior to the unlawful program, deferred action has only ever been applied to small numbers of illegal aliens on a case-by-case basis,” Dale Wilcox, executive director, said in a statement. “Applying it to approximately 15% of the illegal alien population was never a proper exercise of the president’s discretion under the Constitution and is inconsistent with the president’s duty to take care that the laws be faithfully executed. By rescinding DACA, President Trump has put an end to the previous administration’s flagrant violation of our immigration laws and its abuse of hard-working American taxpayers.”

[email protected]

On Twitter @legal_med