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In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac was associated with higher risk for adverse cardiovascular outcomes. The study findings were published online September 4 in BMJ.

Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE), compared with individuals who did not initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4–1.7).

The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, PhD, of the Department of Clinical Epidemiology at Aarhus University in Denmark, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with that associated with ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1–1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE, compared with initiating naproxen (95% CI, 1.1–1.5).

Novel Methodology

The researchers used the longstanding and comprehensive Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications known to elevate cardiovascular risk.

For each 30-day period, the investigators tracked and compared cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.

The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.

Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had as many as 40 excess cardiovascular events per year—about half of them fatal—that were attributable to starting the medication. Although that group had the highest absolute risk, “the relative risks were highest in those with the lowest baseline risk,” said the investigators.

Secondary outcomes for the study included the association between medication use or non-use and each component of the composite primary outcome. These components included first-time occurrences of the nonfatal end points of atrial fibrillation or flutter, ischemic stroke, heart failure, and myocardial infarction. Cardiac death included death from any cardiac cause.

“Supporting use of a combined end point, event rates consistently increased for all individual outcomes” for diclofenac initiators, compared with those who did not start an NSAID, said Dr. Schmidt and his colleagues.

Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, mean age 48 to 56, had to be at least 18 and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6% to 46.3% of the cohorts.

Dr. Schmidt and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a prothrombotic state that also is associated with blood pressure elevation, atherogenesis, and worsening of heart failure.

Diclofenac and ibuprofen entailed similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, and no medication.

Public Health Implications

“Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making,” said Dr. Schmidt and his coauthors.

“Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” noted the investigators. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”

The study was funded by the Department of Clinical Epidemiology Research Foundation, University of Aarhus, and by the Program for Clinical Research Infrastructure, funded by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Research Council. The authors reported that they had no relevant conflicts of interest.

—Kari Oakes

Suggested Reading

Schmidt M, Sørensen HT, Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ. 2018;362:k3426.

For expert commentary on this article, please visit our Migraine Resource Center online at https://www.mdedge.com/neurologyreviews/migraineresourcecenter/article/177937/headache-migraine/physician-commentary

In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac was associated with higher risk for adverse cardiovascular outcomes. The study findings were published online September 4 in BMJ.

Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE), compared with individuals who did not initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4–1.7).

The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, PhD, of the Department of Clinical Epidemiology at Aarhus University in Denmark, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with that associated with ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1–1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE, compared with initiating naproxen (95% CI, 1.1–1.5).

Novel Methodology

The researchers used the longstanding and comprehensive Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications known to elevate cardiovascular risk.

For each 30-day period, the investigators tracked and compared cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.

The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.

Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had as many as 40 excess cardiovascular events per year—about half of them fatal—that were attributable to starting the medication. Although that group had the highest absolute risk, “the relative risks were highest in those with the lowest baseline risk,” said the investigators.

Secondary outcomes for the study included the association between medication use or non-use and each component of the composite primary outcome. These components included first-time occurrences of the nonfatal end points of atrial fibrillation or flutter, ischemic stroke, heart failure, and myocardial infarction. Cardiac death included death from any cardiac cause.

“Supporting use of a combined end point, event rates consistently increased for all individual outcomes” for diclofenac initiators, compared with those who did not start an NSAID, said Dr. Schmidt and his colleagues.

Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, mean age 48 to 56, had to be at least 18 and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6% to 46.3% of the cohorts.

Dr. Schmidt and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a prothrombotic state that also is associated with blood pressure elevation, atherogenesis, and worsening of heart failure.

Diclofenac and ibuprofen entailed similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, and no medication.

Public Health Implications

“Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making,” said Dr. Schmidt and his coauthors.

“Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” noted the investigators. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”

The study was funded by the Department of Clinical Epidemiology Research Foundation, University of Aarhus, and by the Program for Clinical Research Infrastructure, funded by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Research Council. The authors reported that they had no relevant conflicts of interest.

—Kari Oakes

Suggested Reading

Schmidt M, Sørensen HT, Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ. 2018;362:k3426.

For expert commentary on this article, please visit our Migraine Resource Center online at https://www.mdedge.com/neurologyreviews/migraineresourcecenter/article/177937/headache-migraine/physician-commentary

In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac was associated with higher risk for adverse cardiovascular outcomes. The study findings were published online September 4 in BMJ.

Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE), compared with individuals who did not initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4–1.7).

The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, PhD, of the Department of Clinical Epidemiology at Aarhus University in Denmark, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with that associated with ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1–1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE, compared with initiating naproxen (95% CI, 1.1–1.5).

Novel Methodology

The researchers used the longstanding and comprehensive Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications known to elevate cardiovascular risk.

For each 30-day period, the investigators tracked and compared cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.

The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.

Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had as many as 40 excess cardiovascular events per year—about half of them fatal—that were attributable to starting the medication. Although that group had the highest absolute risk, “the relative risks were highest in those with the lowest baseline risk,” said the investigators.

Secondary outcomes for the study included the association between medication use or non-use and each component of the composite primary outcome. These components included first-time occurrences of the nonfatal end points of atrial fibrillation or flutter, ischemic stroke, heart failure, and myocardial infarction. Cardiac death included death from any cardiac cause.

“Supporting use of a combined end point, event rates consistently increased for all individual outcomes” for diclofenac initiators, compared with those who did not start an NSAID, said Dr. Schmidt and his colleagues.

Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, mean age 48 to 56, had to be at least 18 and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6% to 46.3% of the cohorts.

Dr. Schmidt and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a prothrombotic state that also is associated with blood pressure elevation, atherogenesis, and worsening of heart failure.

Diclofenac and ibuprofen entailed similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, and no medication.

Public Health Implications

“Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making,” said Dr. Schmidt and his coauthors.

“Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” noted the investigators. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”

The study was funded by the Department of Clinical Epidemiology Research Foundation, University of Aarhus, and by the Program for Clinical Research Infrastructure, funded by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Research Council. The authors reported that they had no relevant conflicts of interest.

—Kari Oakes

Suggested Reading

Schmidt M, Sørensen HT, Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ. 2018;362:k3426.

For expert commentary on this article, please visit our Migraine Resource Center online at https://www.mdedge.com/neurologyreviews/migraineresourcecenter/article/177937/headache-migraine/physician-commentary

Physicians continue to support advanced alternative payment models despite the fact that operational issues have not improved over the last 4 years and new ones have cropped up, according to a follow-up survey conducted by the RAND Corporation for the American Medical Association.

“All the things we heard in 2014 were still present in 2018. Both the challenges that practices had experienced back in 2014 having to do with data timeliness, data completeness and accuracy, payment model execution, all those challenges persisted,” Mark W. Friedberg, MD, senior physician policy researcher at RAND, said in an interview.

RAND surveyed 31 practices of varying practice size and specialty across six geographic regions, some of which participated in the 2014 survey. Supplemental information was provided by interviews with 32 market observers, 8 health plan leaders, 10 hospital and hospital system leaders, 10 state and local medical society leaders, and 4 chapter leaders with MGMA (formerly the Medical Group Management Association).

“We had thought we would hear that the problem had gotten a little bit better since there has been some investment in trying to tamp down the wide range of measures that are involved in these alternative payment models,” Dr. Friedberg said. “We did not see any evidence of that having any effect on the practices that participated in this study this time around.”

Indeed, concerns reported in 2014 were again reported in 2018, along with a new set of concerns, including the perceived pace of change in alternative payment models (APMs), the complexity of APMs, and physician concerns over two-sided risk models.

“Practices, especially those that participated both times, said in 2014 we had these challenges [of rapid changes in APM models] and since then, things have just gotten a lot faster,” he said, noting that doctors are complaining of models that are going through changes, sometimes without much warning. “They are changing quite rapidly from year to year. If you look at the MACRA QPP [Quality Payment Program] for example, that model changes every year to some extent and those things are hard for them to keep up with.”

Running hand in hand with the change is the complexity of the changes, a result of expanding performance measures and uncertainty with thresholds for penalties and rewards and in some ways has had little impact on improving care.

Dr. Friedberg noted that some practices are hiring people to examine APMs to devise strategic ways to choose and report data for maximum return.

“In a practice, for example, if their quality of care was already very good, what these folks ended up doing was help them choose measures and work the attribution algorithms in a strategic way to either guarantee a bonus or minimize the risk of incurring a penalty,” he said.

He also noted that practices appear to becoming more risk averse.

“We heard a lot more of the following thing, which is that if [practices] were in a two-sided risk model, several of them reported trying and succeeding in some cases offloading the downside risk to partners,” Dr. Friedberg reported. “And what this resulted in was that the practice, even though from the payer’s perspective they are in a two-sided model, the practice was actually in a one-sided model with a partner who is taking all of the downside risk and a portion of the upside risk, leaving a small upside risk proposition that remained for the practice.”

He said the range of partners that were absorbing the downside risk included hospitals, device manufacturers, consulting companies, or private equity firms.

Despite the concerns surrounding APMs, Dr. Friedberg said that “we did not hear practices broadly saying that they just weren’t interested in alternative payment models. In general, practices still remained pretty enthusiastic about these alternative payment models in theory. If they could be made simpler, if the pace of change weren’t quite so fast, that they would have a chance to really do some important care improvements in alternative payment models.”

He noted some of the surveyed practices were able to make investments in care as a direct result of participating in APMs, such as in behavioral health capabilities in primary care, for example, leading to quality of care improvements.

However, these issues could reveal a future unwillingness to participate in APMs, especially two-sided risk models, something at least the Centers for Medicare & Medicaid Services are pushing for as a stated goal of the QPP is to get practices to participate in APMs and take on more risk.

The growing aversion to taking on downside risk could lead practices to simply stay in fee for service and simply take the payment penalty because it is a fixed amount that can be planned for, as opposed to the fluctuations of bonuses and penalties that comes with a rapidly changing APM environment, Dr. Friedberg said.

Going forward, the report makes a number of recommendations to help create an environment that would potentially make APMs more successful, including simplifying the models; creating stable, predictable, and moderately paced pathways to APM participation; making data available in a more timely fashion; minimizing downside risk or helping practices better manage it; and designing APMs that will encourage clinical changes to help improve the effectiveness of care delivered.

[email protected]

Physicians continue to support advanced alternative payment models despite the fact that operational issues have not improved over the last 4 years and new ones have cropped up, according to a follow-up survey conducted by the RAND Corporation for the American Medical Association.

“All the things we heard in 2014 were still present in 2018. Both the challenges that practices had experienced back in 2014 having to do with data timeliness, data completeness and accuracy, payment model execution, all those challenges persisted,” Mark W. Friedberg, MD, senior physician policy researcher at RAND, said in an interview.

RAND surveyed 31 practices of varying practice size and specialty across six geographic regions, some of which participated in the 2014 survey. Supplemental information was provided by interviews with 32 market observers, 8 health plan leaders, 10 hospital and hospital system leaders, 10 state and local medical society leaders, and 4 chapter leaders with MGMA (formerly the Medical Group Management Association).

“We had thought we would hear that the problem had gotten a little bit better since there has been some investment in trying to tamp down the wide range of measures that are involved in these alternative payment models,” Dr. Friedberg said. “We did not see any evidence of that having any effect on the practices that participated in this study this time around.”

Indeed, concerns reported in 2014 were again reported in 2018, along with a new set of concerns, including the perceived pace of change in alternative payment models (APMs), the complexity of APMs, and physician concerns over two-sided risk models.

“Practices, especially those that participated both times, said in 2014 we had these challenges [of rapid changes in APM models] and since then, things have just gotten a lot faster,” he said, noting that doctors are complaining of models that are going through changes, sometimes without much warning. “They are changing quite rapidly from year to year. If you look at the MACRA QPP [Quality Payment Program] for example, that model changes every year to some extent and those things are hard for them to keep up with.”

Running hand in hand with the change is the complexity of the changes, a result of expanding performance measures and uncertainty with thresholds for penalties and rewards and in some ways has had little impact on improving care.

Dr. Friedberg noted that some practices are hiring people to examine APMs to devise strategic ways to choose and report data for maximum return.

“In a practice, for example, if their quality of care was already very good, what these folks ended up doing was help them choose measures and work the attribution algorithms in a strategic way to either guarantee a bonus or minimize the risk of incurring a penalty,” he said.

He also noted that practices appear to becoming more risk averse.

“We heard a lot more of the following thing, which is that if [practices] were in a two-sided risk model, several of them reported trying and succeeding in some cases offloading the downside risk to partners,” Dr. Friedberg reported. “And what this resulted in was that the practice, even though from the payer’s perspective they are in a two-sided model, the practice was actually in a one-sided model with a partner who is taking all of the downside risk and a portion of the upside risk, leaving a small upside risk proposition that remained for the practice.”

He said the range of partners that were absorbing the downside risk included hospitals, device manufacturers, consulting companies, or private equity firms.

Despite the concerns surrounding APMs, Dr. Friedberg said that “we did not hear practices broadly saying that they just weren’t interested in alternative payment models. In general, practices still remained pretty enthusiastic about these alternative payment models in theory. If they could be made simpler, if the pace of change weren’t quite so fast, that they would have a chance to really do some important care improvements in alternative payment models.”

He noted some of the surveyed practices were able to make investments in care as a direct result of participating in APMs, such as in behavioral health capabilities in primary care, for example, leading to quality of care improvements.

However, these issues could reveal a future unwillingness to participate in APMs, especially two-sided risk models, something at least the Centers for Medicare & Medicaid Services are pushing for as a stated goal of the QPP is to get practices to participate in APMs and take on more risk.

The growing aversion to taking on downside risk could lead practices to simply stay in fee for service and simply take the payment penalty because it is a fixed amount that can be planned for, as opposed to the fluctuations of bonuses and penalties that comes with a rapidly changing APM environment, Dr. Friedberg said.

Going forward, the report makes a number of recommendations to help create an environment that would potentially make APMs more successful, including simplifying the models; creating stable, predictable, and moderately paced pathways to APM participation; making data available in a more timely fashion; minimizing downside risk or helping practices better manage it; and designing APMs that will encourage clinical changes to help improve the effectiveness of care delivered.

[email protected]

Physicians continue to support advanced alternative payment models despite the fact that operational issues have not improved over the last 4 years and new ones have cropped up, according to a follow-up survey conducted by the RAND Corporation for the American Medical Association.

“All the things we heard in 2014 were still present in 2018. Both the challenges that practices had experienced back in 2014 having to do with data timeliness, data completeness and accuracy, payment model execution, all those challenges persisted,” Mark W. Friedberg, MD, senior physician policy researcher at RAND, said in an interview.

RAND surveyed 31 practices of varying practice size and specialty across six geographic regions, some of which participated in the 2014 survey. Supplemental information was provided by interviews with 32 market observers, 8 health plan leaders, 10 hospital and hospital system leaders, 10 state and local medical society leaders, and 4 chapter leaders with MGMA (formerly the Medical Group Management Association).

“We had thought we would hear that the problem had gotten a little bit better since there has been some investment in trying to tamp down the wide range of measures that are involved in these alternative payment models,” Dr. Friedberg said. “We did not see any evidence of that having any effect on the practices that participated in this study this time around.”

Indeed, concerns reported in 2014 were again reported in 2018, along with a new set of concerns, including the perceived pace of change in alternative payment models (APMs), the complexity of APMs, and physician concerns over two-sided risk models.

“Practices, especially those that participated both times, said in 2014 we had these challenges [of rapid changes in APM models] and since then, things have just gotten a lot faster,” he said, noting that doctors are complaining of models that are going through changes, sometimes without much warning. “They are changing quite rapidly from year to year. If you look at the MACRA QPP [Quality Payment Program] for example, that model changes every year to some extent and those things are hard for them to keep up with.”

Running hand in hand with the change is the complexity of the changes, a result of expanding performance measures and uncertainty with thresholds for penalties and rewards and in some ways has had little impact on improving care.

Dr. Friedberg noted that some practices are hiring people to examine APMs to devise strategic ways to choose and report data for maximum return.

“In a practice, for example, if their quality of care was already very good, what these folks ended up doing was help them choose measures and work the attribution algorithms in a strategic way to either guarantee a bonus or minimize the risk of incurring a penalty,” he said.

He also noted that practices appear to becoming more risk averse.

“We heard a lot more of the following thing, which is that if [practices] were in a two-sided risk model, several of them reported trying and succeeding in some cases offloading the downside risk to partners,” Dr. Friedberg reported. “And what this resulted in was that the practice, even though from the payer’s perspective they are in a two-sided model, the practice was actually in a one-sided model with a partner who is taking all of the downside risk and a portion of the upside risk, leaving a small upside risk proposition that remained for the practice.”

He said the range of partners that were absorbing the downside risk included hospitals, device manufacturers, consulting companies, or private equity firms.

Despite the concerns surrounding APMs, Dr. Friedberg said that “we did not hear practices broadly saying that they just weren’t interested in alternative payment models. In general, practices still remained pretty enthusiastic about these alternative payment models in theory. If they could be made simpler, if the pace of change weren’t quite so fast, that they would have a chance to really do some important care improvements in alternative payment models.”

He noted some of the surveyed practices were able to make investments in care as a direct result of participating in APMs, such as in behavioral health capabilities in primary care, for example, leading to quality of care improvements.

However, these issues could reveal a future unwillingness to participate in APMs, especially two-sided risk models, something at least the Centers for Medicare & Medicaid Services are pushing for as a stated goal of the QPP is to get practices to participate in APMs and take on more risk.

The growing aversion to taking on downside risk could lead practices to simply stay in fee for service and simply take the payment penalty because it is a fixed amount that can be planned for, as opposed to the fluctuations of bonuses and penalties that comes with a rapidly changing APM environment, Dr. Friedberg said.

Going forward, the report makes a number of recommendations to help create an environment that would potentially make APMs more successful, including simplifying the models; creating stable, predictable, and moderately paced pathways to APM participation; making data available in a more timely fashion; minimizing downside risk or helping practices better manage it; and designing APMs that will encourage clinical changes to help improve the effectiveness of care delivered.

[email protected]

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.

Michele G. Sullivan/MDedge News

These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.

The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).

A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.

In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.

“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”

The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.


OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).

At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.

“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.

The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”

The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.

[email protected]

SOURCE: Oertel FC et al. ECTRIMS 2018, Abstract 212.

BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.

Michele G. Sullivan/MDedge News

These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.

The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).

A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.

In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.

“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”

The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.


OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).

At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.

“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.

The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”

The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.

[email protected]

SOURCE: Oertel FC et al. ECTRIMS 2018, Abstract 212.

BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.

Michele G. Sullivan/MDedge News

These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.

The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).

A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.

In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.

“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”

The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.


OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).

At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.

“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.

The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”

The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.

[email protected]

SOURCE: Oertel FC et al. ECTRIMS 2018, Abstract 212.

Measuring left ventricular ejection fraction (LVEF) before administering doxorubicin-based chemotherapy doesn’t appear to add clinically meaningful information, according to an analysis of diffuse large B-cell lymphoma (DLBCL) patients.

Current guidelines recommend prescreening with either echocardiography or multiple-gated acquisition (MUGA) scan to identify asymptomatic left ventricular dysfunction before administering doxorubicin-containing chemotherapy, since doxorubicin is known for its cardiotoxicity.

But other studies have challenged the usefulness of routine LVEF screening in DLBCL patients.

In the current study, Deborah L. Enns, PhD, and her colleagues at Virginia Mason Medical Center in Seattle reviewed the medical records of 291 patients diagnosed with DLBCL between 2001 and 2013.

In total, 206 patients with normal LVEF and 8 patients with low LVEF received doxorubicin (P = .006). But while that association appears to support routine prescreening to inform clinical decision making, the link disappeared when the researchers factored out previous cardiac disease (P = .51).

“It is possible that previous [heart failure] may have played a larger role in shaping treatment decisions than did LVEF test results alone,” the researchers wrote. The report is in Mayo Clinic Proceedings: Innovations, Quality & Outcomes.

In addition, for patients who had their LVEF measured, the researchers found no difference in posttreatment incidence of heart failure based on whether patients received doxorubicin (7.0%) or did not (6.8%). The same was true for patients with LVEF values of less than 50% before treatment (13% vs. 14%).

The researchers noted that there are several reasons why LVEF prescreening may not be needed before treatment in DLBCL. For instance, DLBCL patients typically receive low cumulative doses of doxorubicin. Also, doxorubicin’s high efficacy in DLBCL should be balanced with the relatively low risk of death from heart failure due to doxorubicin treatment, at around 4% after 5 years for patients without preexisting cardiac conditions.

“We recommend that the policy of routinely performing prescreening LVEF measurements in all patients with DLBCL before administering anthracycline-based chemotherapy treatments be reevaluated,” the researchers wrote.

They reported having no competing interests.

[email protected]

SOURCE: Enns DL et al. Mayo Clin Proc Innov Qual Outcomes. 2018 Aug 3;2(3):277-85.

Measuring left ventricular ejection fraction (LVEF) before administering doxorubicin-based chemotherapy doesn’t appear to add clinically meaningful information, according to an analysis of diffuse large B-cell lymphoma (DLBCL) patients.

Current guidelines recommend prescreening with either echocardiography or multiple-gated acquisition (MUGA) scan to identify asymptomatic left ventricular dysfunction before administering doxorubicin-containing chemotherapy, since doxorubicin is known for its cardiotoxicity.

But other studies have challenged the usefulness of routine LVEF screening in DLBCL patients.

In the current study, Deborah L. Enns, PhD, and her colleagues at Virginia Mason Medical Center in Seattle reviewed the medical records of 291 patients diagnosed with DLBCL between 2001 and 2013.

In total, 206 patients with normal LVEF and 8 patients with low LVEF received doxorubicin (P = .006). But while that association appears to support routine prescreening to inform clinical decision making, the link disappeared when the researchers factored out previous cardiac disease (P = .51).

“It is possible that previous [heart failure] may have played a larger role in shaping treatment decisions than did LVEF test results alone,” the researchers wrote. The report is in Mayo Clinic Proceedings: Innovations, Quality & Outcomes.

In addition, for patients who had their LVEF measured, the researchers found no difference in posttreatment incidence of heart failure based on whether patients received doxorubicin (7.0%) or did not (6.8%). The same was true for patients with LVEF values of less than 50% before treatment (13% vs. 14%).

The researchers noted that there are several reasons why LVEF prescreening may not be needed before treatment in DLBCL. For instance, DLBCL patients typically receive low cumulative doses of doxorubicin. Also, doxorubicin’s high efficacy in DLBCL should be balanced with the relatively low risk of death from heart failure due to doxorubicin treatment, at around 4% after 5 years for patients without preexisting cardiac conditions.

“We recommend that the policy of routinely performing prescreening LVEF measurements in all patients with DLBCL before administering anthracycline-based chemotherapy treatments be reevaluated,” the researchers wrote.

They reported having no competing interests.

[email protected]

SOURCE: Enns DL et al. Mayo Clin Proc Innov Qual Outcomes. 2018 Aug 3;2(3):277-85.

Measuring left ventricular ejection fraction (LVEF) before administering doxorubicin-based chemotherapy doesn’t appear to add clinically meaningful information, according to an analysis of diffuse large B-cell lymphoma (DLBCL) patients.

Current guidelines recommend prescreening with either echocardiography or multiple-gated acquisition (MUGA) scan to identify asymptomatic left ventricular dysfunction before administering doxorubicin-containing chemotherapy, since doxorubicin is known for its cardiotoxicity.

But other studies have challenged the usefulness of routine LVEF screening in DLBCL patients.

In the current study, Deborah L. Enns, PhD, and her colleagues at Virginia Mason Medical Center in Seattle reviewed the medical records of 291 patients diagnosed with DLBCL between 2001 and 2013.

In total, 206 patients with normal LVEF and 8 patients with low LVEF received doxorubicin (P = .006). But while that association appears to support routine prescreening to inform clinical decision making, the link disappeared when the researchers factored out previous cardiac disease (P = .51).

“It is possible that previous [heart failure] may have played a larger role in shaping treatment decisions than did LVEF test results alone,” the researchers wrote. The report is in Mayo Clinic Proceedings: Innovations, Quality & Outcomes.

In addition, for patients who had their LVEF measured, the researchers found no difference in posttreatment incidence of heart failure based on whether patients received doxorubicin (7.0%) or did not (6.8%). The same was true for patients with LVEF values of less than 50% before treatment (13% vs. 14%).

The researchers noted that there are several reasons why LVEF prescreening may not be needed before treatment in DLBCL. For instance, DLBCL patients typically receive low cumulative doses of doxorubicin. Also, doxorubicin’s high efficacy in DLBCL should be balanced with the relatively low risk of death from heart failure due to doxorubicin treatment, at around 4% after 5 years for patients without preexisting cardiac conditions.

“We recommend that the policy of routinely performing prescreening LVEF measurements in all patients with DLBCL before administering anthracycline-based chemotherapy treatments be reevaluated,” the researchers wrote.

They reported having no competing interests.

[email protected]

SOURCE: Enns DL et al. Mayo Clin Proc Innov Qual Outcomes. 2018 Aug 3;2(3):277-85.

Discontinuing ibrutinib therapy because of disease progression was associated with worse survival, according to a real-world study of ibrutinib dosing in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma patients.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

Researchers at the University of Rochester Wilmot Cancer Institute in New York, who performed the single-center study, also found that optimal dosing early on in treatment has a significant impact on disease progression.

“Treating physicians need to be aware of these outcomes when initiating therapy on patients with high-risk CLL or lymphoma, as well as those with significant comorbidities or immune deficiencies,” AnnaLynn M. Williams. MS, and her colleagues reported in Clinical Lymphoma, Myeloma and Leukemia.

The researchers examined the impact of ibrutinib discontinuation and dose adherence on overall and progression-free survival in 170 patients with non-Hodgkin lymphoma and CLL treated with the drug at the Wilmot Cancer Institute between Jan. 1, 2014, and Dec. 1, 2016.

The study comprised 115 patients with CLL, 23 patients with Waldenstrom macroglobulinemia, 21 patients with mantle cell lymphoma, and 11 patients with other non-Hodgkin lymphomas. The median age of patients who started ibrutinib was 68 years, and the median treatment duration was 14.3 months. About a third of patients were taking ibrutinib as a first-line treatment.

Overall, 51 patients (30%) permanently discontinued ibrutinib during the study period, with more than half of the discontinuations stemming from adverse events or comorbidities. About 35% of the discontinuations were due to disease progression.

Median overall survival after discontinuation due to disease progression was 1.7 months. When patients discontinued for other reasons, median overall survival was not reached, compared with stopping for disease progression (P = .0008).

The researchers reported that among patients who discontinued for nonprogression reasons, 67% were alive after 1 year. Among CLL patients, 80% were alive after 1 year.

Among 20 patients who had a dose adherence of less than 80% in the first 8 weeks, the researchers found worse progression-free survival (P = .002) and overall survival (P = .021). Among CLL patients only, progression-free survival was significantly worse (P = .043) but overall survival was not (P = .816).

The study also included five patients who reduced their ibrutinib dose in the first 8 weeks – down to 280 mg in two patients, 140 mg in two patients, and 420 mg in one patient. Again, the researchers observed worse progression-free survival (P = .004) and overall survival (P = .014), compared with patients who maintained their dosing level.

Interrupting ibrutinib dosing had an impact on survival but not as much as discontinuation. Among 10 patients who interrupted therapy for more than a week and then restarted, progression-free survival was worse, compared with those who stayed on treatment continuously (P = .047), but overall survival was not significantly worse (P = .577).

“This would suggest that the ideal treatment strategy would be to recommend initiation of therapy at standard dosing and interruption as needed as directed in the [Food and Drug Administration] label,” the researchers wrote.

The study was funded by the National Cancer Institute and the Cadregari Endowment Fund. The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Williams AM et al. Clin Lymphoma Myeloma Leuk. 2018 Oct 12. doi: 10.1016/j.clml.2018.10.005.

Discontinuing ibrutinib therapy because of disease progression was associated with worse survival, according to a real-world study of ibrutinib dosing in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma patients.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

Researchers at the University of Rochester Wilmot Cancer Institute in New York, who performed the single-center study, also found that optimal dosing early on in treatment has a significant impact on disease progression.

“Treating physicians need to be aware of these outcomes when initiating therapy on patients with high-risk CLL or lymphoma, as well as those with significant comorbidities or immune deficiencies,” AnnaLynn M. Williams. MS, and her colleagues reported in Clinical Lymphoma, Myeloma and Leukemia.

The researchers examined the impact of ibrutinib discontinuation and dose adherence on overall and progression-free survival in 170 patients with non-Hodgkin lymphoma and CLL treated with the drug at the Wilmot Cancer Institute between Jan. 1, 2014, and Dec. 1, 2016.

The study comprised 115 patients with CLL, 23 patients with Waldenstrom macroglobulinemia, 21 patients with mantle cell lymphoma, and 11 patients with other non-Hodgkin lymphomas. The median age of patients who started ibrutinib was 68 years, and the median treatment duration was 14.3 months. About a third of patients were taking ibrutinib as a first-line treatment.

Overall, 51 patients (30%) permanently discontinued ibrutinib during the study period, with more than half of the discontinuations stemming from adverse events or comorbidities. About 35% of the discontinuations were due to disease progression.

Median overall survival after discontinuation due to disease progression was 1.7 months. When patients discontinued for other reasons, median overall survival was not reached, compared with stopping for disease progression (P = .0008).

The researchers reported that among patients who discontinued for nonprogression reasons, 67% were alive after 1 year. Among CLL patients, 80% were alive after 1 year.

Among 20 patients who had a dose adherence of less than 80% in the first 8 weeks, the researchers found worse progression-free survival (P = .002) and overall survival (P = .021). Among CLL patients only, progression-free survival was significantly worse (P = .043) but overall survival was not (P = .816).

The study also included five patients who reduced their ibrutinib dose in the first 8 weeks – down to 280 mg in two patients, 140 mg in two patients, and 420 mg in one patient. Again, the researchers observed worse progression-free survival (P = .004) and overall survival (P = .014), compared with patients who maintained their dosing level.

Interrupting ibrutinib dosing had an impact on survival but not as much as discontinuation. Among 10 patients who interrupted therapy for more than a week and then restarted, progression-free survival was worse, compared with those who stayed on treatment continuously (P = .047), but overall survival was not significantly worse (P = .577).

“This would suggest that the ideal treatment strategy would be to recommend initiation of therapy at standard dosing and interruption as needed as directed in the [Food and Drug Administration] label,” the researchers wrote.

The study was funded by the National Cancer Institute and the Cadregari Endowment Fund. The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Williams AM et al. Clin Lymphoma Myeloma Leuk. 2018 Oct 12. doi: 10.1016/j.clml.2018.10.005.

Discontinuing ibrutinib therapy because of disease progression was associated with worse survival, according to a real-world study of ibrutinib dosing in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma patients.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

Researchers at the University of Rochester Wilmot Cancer Institute in New York, who performed the single-center study, also found that optimal dosing early on in treatment has a significant impact on disease progression.

“Treating physicians need to be aware of these outcomes when initiating therapy on patients with high-risk CLL or lymphoma, as well as those with significant comorbidities or immune deficiencies,” AnnaLynn M. Williams. MS, and her colleagues reported in Clinical Lymphoma, Myeloma and Leukemia.

The researchers examined the impact of ibrutinib discontinuation and dose adherence on overall and progression-free survival in 170 patients with non-Hodgkin lymphoma and CLL treated with the drug at the Wilmot Cancer Institute between Jan. 1, 2014, and Dec. 1, 2016.

The study comprised 115 patients with CLL, 23 patients with Waldenstrom macroglobulinemia, 21 patients with mantle cell lymphoma, and 11 patients with other non-Hodgkin lymphomas. The median age of patients who started ibrutinib was 68 years, and the median treatment duration was 14.3 months. About a third of patients were taking ibrutinib as a first-line treatment.

Overall, 51 patients (30%) permanently discontinued ibrutinib during the study period, with more than half of the discontinuations stemming from adverse events or comorbidities. About 35% of the discontinuations were due to disease progression.

Median overall survival after discontinuation due to disease progression was 1.7 months. When patients discontinued for other reasons, median overall survival was not reached, compared with stopping for disease progression (P = .0008).

The researchers reported that among patients who discontinued for nonprogression reasons, 67% were alive after 1 year. Among CLL patients, 80% were alive after 1 year.

Among 20 patients who had a dose adherence of less than 80% in the first 8 weeks, the researchers found worse progression-free survival (P = .002) and overall survival (P = .021). Among CLL patients only, progression-free survival was significantly worse (P = .043) but overall survival was not (P = .816).

The study also included five patients who reduced their ibrutinib dose in the first 8 weeks – down to 280 mg in two patients, 140 mg in two patients, and 420 mg in one patient. Again, the researchers observed worse progression-free survival (P = .004) and overall survival (P = .014), compared with patients who maintained their dosing level.

Interrupting ibrutinib dosing had an impact on survival but not as much as discontinuation. Among 10 patients who interrupted therapy for more than a week and then restarted, progression-free survival was worse, compared with those who stayed on treatment continuously (P = .047), but overall survival was not significantly worse (P = .577).

“This would suggest that the ideal treatment strategy would be to recommend initiation of therapy at standard dosing and interruption as needed as directed in the [Food and Drug Administration] label,” the researchers wrote.

The study was funded by the National Cancer Institute and the Cadregari Endowment Fund. The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Williams AM et al. Clin Lymphoma Myeloma Leuk. 2018 Oct 12. doi: 10.1016/j.clml.2018.10.005.

The Food and Drug Administration has granted priority review to an anti-CD20, chemotherapy-free combination – ibrutinib plus obinutuzumab – for the frontline treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The agency will review the combination in previously untreated adults.

Ibrutinib (Imbruvica) is already approved as a single agent for adults with CLL/SLL for all lines of therapy and in combination with bendamustine and rituximab. Obinutuzumab (Gazyva) has been approved for patients with previously untreated CLL, in combination with chlorambucil.

The current application, which is sponsored by Janssen and Pharmacyclics, is based on results from the phase 3 iLLUMINATE trial. Preliminary results announced by Janssen and Pharmacyclics showed that ibrutinib plus obinutuzumab had statistically significant better progression-free survival, compared with chlorambucil plus obinutuzumab, as assessed by an independent review committee.

Complete results from the trial will be presented at an upcoming medical meeting, according to the sponsors.

[email protected]

The Food and Drug Administration has granted priority review to an anti-CD20, chemotherapy-free combination – ibrutinib plus obinutuzumab – for the frontline treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The agency will review the combination in previously untreated adults.

Ibrutinib (Imbruvica) is already approved as a single agent for adults with CLL/SLL for all lines of therapy and in combination with bendamustine and rituximab. Obinutuzumab (Gazyva) has been approved for patients with previously untreated CLL, in combination with chlorambucil.

The current application, which is sponsored by Janssen and Pharmacyclics, is based on results from the phase 3 iLLUMINATE trial. Preliminary results announced by Janssen and Pharmacyclics showed that ibrutinib plus obinutuzumab had statistically significant better progression-free survival, compared with chlorambucil plus obinutuzumab, as assessed by an independent review committee.

Complete results from the trial will be presented at an upcoming medical meeting, according to the sponsors.

[email protected]

The Food and Drug Administration has granted priority review to an anti-CD20, chemotherapy-free combination – ibrutinib plus obinutuzumab – for the frontline treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The agency will review the combination in previously untreated adults.

Ibrutinib (Imbruvica) is already approved as a single agent for adults with CLL/SLL for all lines of therapy and in combination with bendamustine and rituximab. Obinutuzumab (Gazyva) has been approved for patients with previously untreated CLL, in combination with chlorambucil.

The current application, which is sponsored by Janssen and Pharmacyclics, is based on results from the phase 3 iLLUMINATE trial. Preliminary results announced by Janssen and Pharmacyclics showed that ibrutinib plus obinutuzumab had statistically significant better progression-free survival, compared with chlorambucil plus obinutuzumab, as assessed by an independent review committee.

Complete results from the trial will be presented at an upcoming medical meeting, according to the sponsors.

[email protected]

In contrast to other recent studies, androgen deprivation therapy (ADT) had no link to dementia in a observational cohort study of more than 45,000 men with prostate cancer who received definitive radiotherapy, investigators have reported.

No significant associations were found between ADT and Alzheimer’s disease or vascular dementia, or between shorter or longer courses of ADT and any dementia studied, according to Rishi Deka, PhD, of Veterans Affairs San Diego Health Care System, La Jolla, Calif., and coinvestigators.

“These results may mitigate concerns regarding the long-term risks of ADT on cognitive health in the treatment of prostate cancer,” Dr. Deka and colleagues wrote in JAMA Oncology.

Two other recent studies showed strong, statistically significant associations between ADT and dementia in prostate cancer. However, those studies combined patients with local and metastatic disease, receiving ADT in the upfront or recurrent settings, while the present study looked specifically at men with nonmetastatic prostate cancer who received radiotherapy.

“Different treatment modalities and disease stages are associated with substantial selection bias that may predispose results to false associations,” noted Dr. Deka and coauthors.

Their observational cohort study comprised 45,218 men diagnosed with nonmetastatic prostate cancer at the U.S. Department of Veterans Affairs who underwent radiotherapy with or without ADT. The investigators excluded men who had a diagnosis of dementia within 1 year of the prostate cancer diagnosis or who had prior diagnoses of dementia, stroke, or cognitive impairment.

A total of 1,497 patients were diagnosed with dementia over a median of 6.8 years of follow-up: 404 with Alzheimer disease, 335 with vascular dementia, and 758 with other types or unclassified dementias.

The investigators found no significant association between use of ADT and development of any dementia, the primary outcome of the analysis (subdistribution hazard ratio [SHR], 1.04; 95% confidence interval, 0.94-1.16; P = .43).

Likewise, there was no association between ADT and vascular dementia, specifically, with an SHR of 1.20 (95% CI, 0.97-1.50; P = .10) or Alzheimer’s disease, with an SHR of 1.11 (95% CI, 0.91-1.36; P = .29).

Duration of ADT longer than 1 year was not significantly associated with dementia, nor was duration shorter than 1 year, with SHRs, of 1.08 and 1.01 respectively, the analysis shows.

The SHRs in these and other analysis reported ranged from 1.00 to 1.21. That is substantially lower than hazard ratios of 1.66 to 2.32 in one previous study linking ADT to dementia, according to the investigators, suggesting that the results of the current analysis were not due to inadequate power to detect differences.

Nevertheless, the findings may not be generalizable to some other populations, they cautioned, since it was focused demographically on veterans, and was limited to radiotherapy-treated patients.

Dr. Deka and coauthors reported no conflict of interest. Their study was funded by grants from the University of California San Diego Center for Precision Radiation Medicine.

SOURCE: Deka R et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4423.

In contrast to other recent studies, androgen deprivation therapy (ADT) had no link to dementia in a observational cohort study of more than 45,000 men with prostate cancer who received definitive radiotherapy, investigators have reported.

No significant associations were found between ADT and Alzheimer’s disease or vascular dementia, or between shorter or longer courses of ADT and any dementia studied, according to Rishi Deka, PhD, of Veterans Affairs San Diego Health Care System, La Jolla, Calif., and coinvestigators.

“These results may mitigate concerns regarding the long-term risks of ADT on cognitive health in the treatment of prostate cancer,” Dr. Deka and colleagues wrote in JAMA Oncology.

Two other recent studies showed strong, statistically significant associations between ADT and dementia in prostate cancer. However, those studies combined patients with local and metastatic disease, receiving ADT in the upfront or recurrent settings, while the present study looked specifically at men with nonmetastatic prostate cancer who received radiotherapy.

“Different treatment modalities and disease stages are associated with substantial selection bias that may predispose results to false associations,” noted Dr. Deka and coauthors.

Their observational cohort study comprised 45,218 men diagnosed with nonmetastatic prostate cancer at the U.S. Department of Veterans Affairs who underwent radiotherapy with or without ADT. The investigators excluded men who had a diagnosis of dementia within 1 year of the prostate cancer diagnosis or who had prior diagnoses of dementia, stroke, or cognitive impairment.

A total of 1,497 patients were diagnosed with dementia over a median of 6.8 years of follow-up: 404 with Alzheimer disease, 335 with vascular dementia, and 758 with other types or unclassified dementias.

The investigators found no significant association between use of ADT and development of any dementia, the primary outcome of the analysis (subdistribution hazard ratio [SHR], 1.04; 95% confidence interval, 0.94-1.16; P = .43).

Likewise, there was no association between ADT and vascular dementia, specifically, with an SHR of 1.20 (95% CI, 0.97-1.50; P = .10) or Alzheimer’s disease, with an SHR of 1.11 (95% CI, 0.91-1.36; P = .29).

Duration of ADT longer than 1 year was not significantly associated with dementia, nor was duration shorter than 1 year, with SHRs, of 1.08 and 1.01 respectively, the analysis shows.

The SHRs in these and other analysis reported ranged from 1.00 to 1.21. That is substantially lower than hazard ratios of 1.66 to 2.32 in one previous study linking ADT to dementia, according to the investigators, suggesting that the results of the current analysis were not due to inadequate power to detect differences.

Nevertheless, the findings may not be generalizable to some other populations, they cautioned, since it was focused demographically on veterans, and was limited to radiotherapy-treated patients.

Dr. Deka and coauthors reported no conflict of interest. Their study was funded by grants from the University of California San Diego Center for Precision Radiation Medicine.

SOURCE: Deka R et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4423.

In contrast to other recent studies, androgen deprivation therapy (ADT) had no link to dementia in a observational cohort study of more than 45,000 men with prostate cancer who received definitive radiotherapy, investigators have reported.

No significant associations were found between ADT and Alzheimer’s disease or vascular dementia, or between shorter or longer courses of ADT and any dementia studied, according to Rishi Deka, PhD, of Veterans Affairs San Diego Health Care System, La Jolla, Calif., and coinvestigators.

“These results may mitigate concerns regarding the long-term risks of ADT on cognitive health in the treatment of prostate cancer,” Dr. Deka and colleagues wrote in JAMA Oncology.

Two other recent studies showed strong, statistically significant associations between ADT and dementia in prostate cancer. However, those studies combined patients with local and metastatic disease, receiving ADT in the upfront or recurrent settings, while the present study looked specifically at men with nonmetastatic prostate cancer who received radiotherapy.

“Different treatment modalities and disease stages are associated with substantial selection bias that may predispose results to false associations,” noted Dr. Deka and coauthors.

Their observational cohort study comprised 45,218 men diagnosed with nonmetastatic prostate cancer at the U.S. Department of Veterans Affairs who underwent radiotherapy with or without ADT. The investigators excluded men who had a diagnosis of dementia within 1 year of the prostate cancer diagnosis or who had prior diagnoses of dementia, stroke, or cognitive impairment.

A total of 1,497 patients were diagnosed with dementia over a median of 6.8 years of follow-up: 404 with Alzheimer disease, 335 with vascular dementia, and 758 with other types or unclassified dementias.

The investigators found no significant association between use of ADT and development of any dementia, the primary outcome of the analysis (subdistribution hazard ratio [SHR], 1.04; 95% confidence interval, 0.94-1.16; P = .43).

Likewise, there was no association between ADT and vascular dementia, specifically, with an SHR of 1.20 (95% CI, 0.97-1.50; P = .10) or Alzheimer’s disease, with an SHR of 1.11 (95% CI, 0.91-1.36; P = .29).

Duration of ADT longer than 1 year was not significantly associated with dementia, nor was duration shorter than 1 year, with SHRs, of 1.08 and 1.01 respectively, the analysis shows.

The SHRs in these and other analysis reported ranged from 1.00 to 1.21. That is substantially lower than hazard ratios of 1.66 to 2.32 in one previous study linking ADT to dementia, according to the investigators, suggesting that the results of the current analysis were not due to inadequate power to detect differences.

Nevertheless, the findings may not be generalizable to some other populations, they cautioned, since it was focused demographically on veterans, and was limited to radiotherapy-treated patients.

Dr. Deka and coauthors reported no conflict of interest. Their study was funded by grants from the University of California San Diego Center for Precision Radiation Medicine.

SOURCE: Deka R et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4423.

Checkpoint inhibitors are so new that not enough patients have received them to allow clinicians to predict who will benefit most. But researchers from the National Cancer Institute, Center for Cancer Institute; Harvard University in Cambridge, Massachusetts; University of Pennsylvania in Philadelphia; and University of Maryland in College Park may have found a clue: A gene expression predictor.

They began by looking at neuroblastoma cases where the immune system seemed to mount “an unprompted, successful immune response” to cancer, causing spontaneous tumor regression. The researchers were able to define gene expression features that separated regressing from nonregressing disease.

The researchers then computed Immuno-PREdictive Scores (IMPRES) for each patient sample. The higher the score, the more likely was spontaneous regression. Analyzing 297 samples from several studies, they found the predictor identified nearly all patients who responded to the inhibitors and more than half of those who did not. “Importantly,” the researchers say, their predictor was accurate across many different melanoma patient datasets.

Checkpoint inhibitors are so new that not enough patients have received them to allow clinicians to predict who will benefit most. But researchers from the National Cancer Institute, Center for Cancer Institute; Harvard University in Cambridge, Massachusetts; University of Pennsylvania in Philadelphia; and University of Maryland in College Park may have found a clue: A gene expression predictor.

They began by looking at neuroblastoma cases where the immune system seemed to mount “an unprompted, successful immune response” to cancer, causing spontaneous tumor regression. The researchers were able to define gene expression features that separated regressing from nonregressing disease.

The researchers then computed Immuno-PREdictive Scores (IMPRES) for each patient sample. The higher the score, the more likely was spontaneous regression. Analyzing 297 samples from several studies, they found the predictor identified nearly all patients who responded to the inhibitors and more than half of those who did not. “Importantly,” the researchers say, their predictor was accurate across many different melanoma patient datasets.

Checkpoint inhibitors are so new that not enough patients have received them to allow clinicians to predict who will benefit most. But researchers from the National Cancer Institute, Center for Cancer Institute; Harvard University in Cambridge, Massachusetts; University of Pennsylvania in Philadelphia; and University of Maryland in College Park may have found a clue: A gene expression predictor.

They began by looking at neuroblastoma cases where the immune system seemed to mount “an unprompted, successful immune response” to cancer, causing spontaneous tumor regression. The researchers were able to define gene expression features that separated regressing from nonregressing disease.

The researchers then computed Immuno-PREdictive Scores (IMPRES) for each patient sample. The higher the score, the more likely was spontaneous regression. Analyzing 297 samples from several studies, they found the predictor identified nearly all patients who responded to the inhibitors and more than half of those who did not. “Importantly,” the researchers say, their predictor was accurate across many different melanoma patient datasets.

BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.

Sara Freeman/MDedge News

SOURCE: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.

BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.

Sara Freeman/MDedge News

SOURCE: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.

BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.

Sara Freeman/MDedge News

SOURCE: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.