Federal Practitioner

A breakthrough neuromodulation system rapidly restores motor function in patients with a severe spinal cord injury (SCI), new research shows.

The study demonstrated that an epidural electrical stimulation (EES) system developed specifically for spinal cord injuries enabled three men with complete paralysis to stand, walk, cycle, swim, and move their torso within 1 day.

“Thanks to this technology, we have been able to target individuals with the most serious spinal cord injury, meaning those with clinically complete spinal cord injury, with no sensation and no movement in the legs,” Grégoire Courtine, PhD, professor of neuroscience and neurotechnology at the Swiss Federal Institute of Technology, University Hospital Lausanne (Switzerland), and the University of Lausanne, told reporters attending a press briefing.

The study was published online Feb. 7, 2022, in Nature Medicine.
 

More rapid, precise, effective

SCIs involve severed connections between the brain and extremities. To compensate for these lost connections, researchers have investigated stem cell therapy, brain-machine interfaces, and powered exoskeletons.

However, these approaches aren’t yet ready for prime time.

In the meantime, researchers discovered even patients with a “complete” injury may have low-functioning connections and started investigating epidural stimulators designed to treat chronic pain. Recent studies – including three published in 2018 – showed promise for these pain-related stimulators in patients with incomplete SCI.

But using such “repurposed” technology meant the electrode array was relatively narrow and short, “so we could not target all the regions of the spinal cord involving control of leg and trunk movements,” said Dr. Courtine. With the newer technology “we are much more precise, effective, and more rapid in delivering therapy.”

To develop this new approach, the researchers designed a paddle lead with an arrangement of electrodes that targets sacral, lumbar, and low-thoracic dorsal roots involved in leg and trunk movements. They also established a personalized computational framework that allows for optimal surgical placement of this paddle lead.

In addition, they developed software that renders the configuration of individualized activity–dependent stimulation programs rapid, simple, and predictable.

They tested these neurotechnologies in three men with complete sensorimotor paralysis as part of an ongoing clinical trial. The participants, aged 29, 32, and 41 years, suffered an SCI from a motor bike accident 3, 9, and 1 year before enrollment.

All three patients exhibited complete sensorimotor paralysis. They were unable to take any step, and muscles remained quiescent during these attempts.

A neurosurgeon implanted electrodes along the spinal cord of study subjects. Wires from these electrodes were connected to a neurostimulator implanted under the skin in the abdomen.

The men can select different activity-based programs from a tablet that sends signals to the implanted device.
 

Personalized approach

Within a single day of the surgery, the participants were able to stand, walk, cycle, swim, and control trunk movements.

“It was not perfect at the very beginning, but they could train very early on to have a more fluid gait,” said study investigator neurosurgeon Joceylyne Bloch, MD, associate professor, University of Lausanne and University Hospital Lausanne.

At this stage, not all paralyzed patients are eligible for the procedure. Dr. Bloch explained that at least 6 cm of healthy spinal cord under the lesion is needed to implant the electrodes.

“There’s a huge variability of spinal cord anatomy between individuals. That’s why it’s important to study each person individually and to have individual models in order to be precise.”

Researchers envision having “a library of electrode arrays,” added Dr. Courtine. With preoperative imaging of the individual’s spinal cord, “the neurosurgeon can select the more appropriate electrode array for that specific patient.”

Dr. Courtine noted recovery of sensation with the system differs from one individual to another. One study participant, Michel Roccati, now 30, told the briefing he feels a contraction in his muscle during the stimulation.

Currently, only individuals whose injury is more than a year old are included in the study to ensure patients have “a stable lesion” and reached “a plateau of recovery,” said Dr. Bloch. However, animal models show intervening earlier might boost the benefits.

A patient’s age can influence the outcome, as younger patients are likely in better condition and more motivated than older patients, said Dr. Bloch. However, she noted patients closing in on 50 years have responded well to the therapy.

Such stimulation systems may prove useful in treating conditions typically associated with SCI, such as hypertension and bladder control, and perhaps also in patients with Parkinson’s disease, said Dr. Courtine.

The researchers plan to conduct another study that will include a next-generation pulse generator with features that make the stimulation even more effective and user friendly. A voice recognition system could eventually be connected to the system.

“The next step is a minicomputer that you implant in the body that communicates in real time with an external iPhone,” said Dr. Courtine.

ONWARD Medical, which developed the technology, has received a breakthrough device designation from the Food and Drug Administration. The company is in discussions with the FDA to carry out a clinical trial of the device in the United States.
 

A ‘huge step forward’

Peter J. Grahn, PhD, assistant professor, department of physical medicine and rehabilitation and department of neurologic surgery, Mayo Clinic, Rochester, Minn., an author of one of the 2018 studies, said this technology “is a huge step forward” and “really pushes the field.”

Compared with the device used in his study that’s designed to treat neuropathic pain, this new system “is much more capable of dynamic stimulation,” said Dr. Grahn. “You can tailor the stimulation based on which area of the spinal cord you want to target during a specific function.”

There has been “a lot of hope and hype” recently around stem cells and biological molecules that were supposed to be “magic pills” to cure spinal cord dysfunction, said Dr. Grahn. “I don’t think this is one of those.”

However, he questioned the researchers’ use of the word “walking.”

“They say independent stepping or walking is restored on day 1, but the graphs show day 1 function is having over 60% of their body weight supported when they’re taking these steps,” he said.

In addition, the “big question” is how this technology can “be distilled down” into an approach “applicable across rehabilitation centers,” said Dr. Grahn.

The study was supported by numerous organizations, including ONWARD Medical. Dr. Courtine and Dr. Bloch hold various patents in relation with the present work. Dr. Courtine is a consultant with ONWARD Medical, and he and Dr. Bloch are shareholders of ONWARD Medical, a company with direct relationships with the presented work. Dr. Grahn reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A breakthrough neuromodulation system rapidly restores motor function in patients with a severe spinal cord injury (SCI), new research shows.

The study demonstrated that an epidural electrical stimulation (EES) system developed specifically for spinal cord injuries enabled three men with complete paralysis to stand, walk, cycle, swim, and move their torso within 1 day.

“Thanks to this technology, we have been able to target individuals with the most serious spinal cord injury, meaning those with clinically complete spinal cord injury, with no sensation and no movement in the legs,” Grégoire Courtine, PhD, professor of neuroscience and neurotechnology at the Swiss Federal Institute of Technology, University Hospital Lausanne (Switzerland), and the University of Lausanne, told reporters attending a press briefing.

The study was published online Feb. 7, 2022, in Nature Medicine.
 

More rapid, precise, effective

SCIs involve severed connections between the brain and extremities. To compensate for these lost connections, researchers have investigated stem cell therapy, brain-machine interfaces, and powered exoskeletons.

However, these approaches aren’t yet ready for prime time.

In the meantime, researchers discovered even patients with a “complete” injury may have low-functioning connections and started investigating epidural stimulators designed to treat chronic pain. Recent studies – including three published in 2018 – showed promise for these pain-related stimulators in patients with incomplete SCI.

But using such “repurposed” technology meant the electrode array was relatively narrow and short, “so we could not target all the regions of the spinal cord involving control of leg and trunk movements,” said Dr. Courtine. With the newer technology “we are much more precise, effective, and more rapid in delivering therapy.”

To develop this new approach, the researchers designed a paddle lead with an arrangement of electrodes that targets sacral, lumbar, and low-thoracic dorsal roots involved in leg and trunk movements. They also established a personalized computational framework that allows for optimal surgical placement of this paddle lead.

In addition, they developed software that renders the configuration of individualized activity–dependent stimulation programs rapid, simple, and predictable.

They tested these neurotechnologies in three men with complete sensorimotor paralysis as part of an ongoing clinical trial. The participants, aged 29, 32, and 41 years, suffered an SCI from a motor bike accident 3, 9, and 1 year before enrollment.

All three patients exhibited complete sensorimotor paralysis. They were unable to take any step, and muscles remained quiescent during these attempts.

A neurosurgeon implanted electrodes along the spinal cord of study subjects. Wires from these electrodes were connected to a neurostimulator implanted under the skin in the abdomen.

The men can select different activity-based programs from a tablet that sends signals to the implanted device.
 

Personalized approach

Within a single day of the surgery, the participants were able to stand, walk, cycle, swim, and control trunk movements.

“It was not perfect at the very beginning, but they could train very early on to have a more fluid gait,” said study investigator neurosurgeon Joceylyne Bloch, MD, associate professor, University of Lausanne and University Hospital Lausanne.

At this stage, not all paralyzed patients are eligible for the procedure. Dr. Bloch explained that at least 6 cm of healthy spinal cord under the lesion is needed to implant the electrodes.

“There’s a huge variability of spinal cord anatomy between individuals. That’s why it’s important to study each person individually and to have individual models in order to be precise.”

Researchers envision having “a library of electrode arrays,” added Dr. Courtine. With preoperative imaging of the individual’s spinal cord, “the neurosurgeon can select the more appropriate electrode array for that specific patient.”

Dr. Courtine noted recovery of sensation with the system differs from one individual to another. One study participant, Michel Roccati, now 30, told the briefing he feels a contraction in his muscle during the stimulation.

Currently, only individuals whose injury is more than a year old are included in the study to ensure patients have “a stable lesion” and reached “a plateau of recovery,” said Dr. Bloch. However, animal models show intervening earlier might boost the benefits.

A patient’s age can influence the outcome, as younger patients are likely in better condition and more motivated than older patients, said Dr. Bloch. However, she noted patients closing in on 50 years have responded well to the therapy.

Such stimulation systems may prove useful in treating conditions typically associated with SCI, such as hypertension and bladder control, and perhaps also in patients with Parkinson’s disease, said Dr. Courtine.

The researchers plan to conduct another study that will include a next-generation pulse generator with features that make the stimulation even more effective and user friendly. A voice recognition system could eventually be connected to the system.

“The next step is a minicomputer that you implant in the body that communicates in real time with an external iPhone,” said Dr. Courtine.

ONWARD Medical, which developed the technology, has received a breakthrough device designation from the Food and Drug Administration. The company is in discussions with the FDA to carry out a clinical trial of the device in the United States.
 

A ‘huge step forward’

Peter J. Grahn, PhD, assistant professor, department of physical medicine and rehabilitation and department of neurologic surgery, Mayo Clinic, Rochester, Minn., an author of one of the 2018 studies, said this technology “is a huge step forward” and “really pushes the field.”

Compared with the device used in his study that’s designed to treat neuropathic pain, this new system “is much more capable of dynamic stimulation,” said Dr. Grahn. “You can tailor the stimulation based on which area of the spinal cord you want to target during a specific function.”

There has been “a lot of hope and hype” recently around stem cells and biological molecules that were supposed to be “magic pills” to cure spinal cord dysfunction, said Dr. Grahn. “I don’t think this is one of those.”

However, he questioned the researchers’ use of the word “walking.”

“They say independent stepping or walking is restored on day 1, but the graphs show day 1 function is having over 60% of their body weight supported when they’re taking these steps,” he said.

In addition, the “big question” is how this technology can “be distilled down” into an approach “applicable across rehabilitation centers,” said Dr. Grahn.

The study was supported by numerous organizations, including ONWARD Medical. Dr. Courtine and Dr. Bloch hold various patents in relation with the present work. Dr. Courtine is a consultant with ONWARD Medical, and he and Dr. Bloch are shareholders of ONWARD Medical, a company with direct relationships with the presented work. Dr. Grahn reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A breakthrough neuromodulation system rapidly restores motor function in patients with a severe spinal cord injury (SCI), new research shows.

The study demonstrated that an epidural electrical stimulation (EES) system developed specifically for spinal cord injuries enabled three men with complete paralysis to stand, walk, cycle, swim, and move their torso within 1 day.

“Thanks to this technology, we have been able to target individuals with the most serious spinal cord injury, meaning those with clinically complete spinal cord injury, with no sensation and no movement in the legs,” Grégoire Courtine, PhD, professor of neuroscience and neurotechnology at the Swiss Federal Institute of Technology, University Hospital Lausanne (Switzerland), and the University of Lausanne, told reporters attending a press briefing.

The study was published online Feb. 7, 2022, in Nature Medicine.
 

More rapid, precise, effective

SCIs involve severed connections between the brain and extremities. To compensate for these lost connections, researchers have investigated stem cell therapy, brain-machine interfaces, and powered exoskeletons.

However, these approaches aren’t yet ready for prime time.

In the meantime, researchers discovered even patients with a “complete” injury may have low-functioning connections and started investigating epidural stimulators designed to treat chronic pain. Recent studies – including three published in 2018 – showed promise for these pain-related stimulators in patients with incomplete SCI.

But using such “repurposed” technology meant the electrode array was relatively narrow and short, “so we could not target all the regions of the spinal cord involving control of leg and trunk movements,” said Dr. Courtine. With the newer technology “we are much more precise, effective, and more rapid in delivering therapy.”

To develop this new approach, the researchers designed a paddle lead with an arrangement of electrodes that targets sacral, lumbar, and low-thoracic dorsal roots involved in leg and trunk movements. They also established a personalized computational framework that allows for optimal surgical placement of this paddle lead.

In addition, they developed software that renders the configuration of individualized activity–dependent stimulation programs rapid, simple, and predictable.

They tested these neurotechnologies in three men with complete sensorimotor paralysis as part of an ongoing clinical trial. The participants, aged 29, 32, and 41 years, suffered an SCI from a motor bike accident 3, 9, and 1 year before enrollment.

All three patients exhibited complete sensorimotor paralysis. They were unable to take any step, and muscles remained quiescent during these attempts.

A neurosurgeon implanted electrodes along the spinal cord of study subjects. Wires from these electrodes were connected to a neurostimulator implanted under the skin in the abdomen.

The men can select different activity-based programs from a tablet that sends signals to the implanted device.
 

Personalized approach

Within a single day of the surgery, the participants were able to stand, walk, cycle, swim, and control trunk movements.

“It was not perfect at the very beginning, but they could train very early on to have a more fluid gait,” said study investigator neurosurgeon Joceylyne Bloch, MD, associate professor, University of Lausanne and University Hospital Lausanne.

At this stage, not all paralyzed patients are eligible for the procedure. Dr. Bloch explained that at least 6 cm of healthy spinal cord under the lesion is needed to implant the electrodes.

“There’s a huge variability of spinal cord anatomy between individuals. That’s why it’s important to study each person individually and to have individual models in order to be precise.”

Researchers envision having “a library of electrode arrays,” added Dr. Courtine. With preoperative imaging of the individual’s spinal cord, “the neurosurgeon can select the more appropriate electrode array for that specific patient.”

Dr. Courtine noted recovery of sensation with the system differs from one individual to another. One study participant, Michel Roccati, now 30, told the briefing he feels a contraction in his muscle during the stimulation.

Currently, only individuals whose injury is more than a year old are included in the study to ensure patients have “a stable lesion” and reached “a plateau of recovery,” said Dr. Bloch. However, animal models show intervening earlier might boost the benefits.

A patient’s age can influence the outcome, as younger patients are likely in better condition and more motivated than older patients, said Dr. Bloch. However, she noted patients closing in on 50 years have responded well to the therapy.

Such stimulation systems may prove useful in treating conditions typically associated with SCI, such as hypertension and bladder control, and perhaps also in patients with Parkinson’s disease, said Dr. Courtine.

The researchers plan to conduct another study that will include a next-generation pulse generator with features that make the stimulation even more effective and user friendly. A voice recognition system could eventually be connected to the system.

“The next step is a minicomputer that you implant in the body that communicates in real time with an external iPhone,” said Dr. Courtine.

ONWARD Medical, which developed the technology, has received a breakthrough device designation from the Food and Drug Administration. The company is in discussions with the FDA to carry out a clinical trial of the device in the United States.
 

A ‘huge step forward’

Peter J. Grahn, PhD, assistant professor, department of physical medicine and rehabilitation and department of neurologic surgery, Mayo Clinic, Rochester, Minn., an author of one of the 2018 studies, said this technology “is a huge step forward” and “really pushes the field.”

Compared with the device used in his study that’s designed to treat neuropathic pain, this new system “is much more capable of dynamic stimulation,” said Dr. Grahn. “You can tailor the stimulation based on which area of the spinal cord you want to target during a specific function.”

There has been “a lot of hope and hype” recently around stem cells and biological molecules that were supposed to be “magic pills” to cure spinal cord dysfunction, said Dr. Grahn. “I don’t think this is one of those.”

However, he questioned the researchers’ use of the word “walking.”

“They say independent stepping or walking is restored on day 1, but the graphs show day 1 function is having over 60% of their body weight supported when they’re taking these steps,” he said.

In addition, the “big question” is how this technology can “be distilled down” into an approach “applicable across rehabilitation centers,” said Dr. Grahn.

The study was supported by numerous organizations, including ONWARD Medical. Dr. Courtine and Dr. Bloch hold various patents in relation with the present work. Dr. Courtine is a consultant with ONWARD Medical, and he and Dr. Bloch are shareholders of ONWARD Medical, a company with direct relationships with the presented work. Dr. Grahn reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The introduction of hemoglobin A1c as an option for diagnosing type 2 diabetes over a decade ago may have resulted in underdiagnosis, new research indicates.

In 2011, the World Health Organization advised that A1c measurement, with a cutoff value of 6.5%, could be used to diagnose diabetes. The American Diabetes Association had issued similar guidance in 2010.

Prior to that time, the less-convenient 2-hour oral glucose tolerance test (OGTT) and fasting blood glucose (FBG) were the only recommended tests. While WHO made no recommendations for interpreting values below 6.5%, the ADA designated 5.7%-6.4% as prediabetes.

The new study, published online in The Lancet Regional Health–Europe, showed that the incidence of type 2 diabetes in Denmark had been increasing prior to the 2012 adoption of A1c as a diagnostic option but declined thereafter. And all-cause mortality among people with type 2 diabetes, which had been dropping, began to increase after that time.  

“Our findings suggest that fewer patients have been diagnosed with [type 2 diabetes] since A1c testing was introduced as a convenient diagnostic option. We may thus be missing a group with borderline increased A1c values that is still at high metabolic and cardiovascular risk,” Jakob S. Knudsen, MD, of the department of clinical epidemiology, Aarhus (Denmark) University Hospital, and colleagues wrote.

Therefore, Dr. Knudsen said in an interview, clinicians should “consider testing with FBG or OGTT when presented with borderline A1c values.”

The reason for the increase in mortality after incident type 2 diabetes diagnosis, he said, “is that the patients who would have reduced the average mortality are no longer diagnosed...This does not reflect that we are treating already diagnosed patients any worse, rather some patients are not diagnosed.”

But M. Sue Kirkman, MD, emeritus professor of medicine at the University of North Carolina at Chapel Hill, who was part of the writing group for the 2010 ADA guidelines, isn’t convinced.

“This is an interesting paper, but it is a bit hard to believe that a change in WHO recommendations would have such a large and almost immediate impact on incidence and mortality. It seems likely that ... factors [other] than just the changes in recommendations for the diagnostic test account for these findings,” she said.

Dr. Kirkman pointed to new data just out from the Centers for Disease Control and Prevention on Jan. 26 that don›t show evidence of a higher proportion of people in the United States who have undiagnosed diabetes, “which would be expected if more cases were being ‘missed’ by A1c.”

She added that the CDC incidence data “show a continuing steady rate of decline in incidence that began in 2008, before any organizations recommended using A1c to screen for or diagnose diabetes.” Moreover, “there is evidence that type 2 diabetes incidence has fallen or plateaued in many countries since 2006, well before the WHO recommendation, with most of the studies from developed countries.”

But Dr. Knudsen also cited other data, including a study that showed a drop or stabilization in diagnosed diabetes incidence in high-income countries since 2010.

“That study concluded that the reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources, which was a main objective of our study,” wrote Dr. Knudsen and coauthors.

Dr. Knudsen said in an interview: “We are not the first to make the point that this sudden change is related to A1c introduction...but we are the first to have the data to clearly show that is the case.”

Diabetes incidence dropped but mortality rose after 2010

The population-based longitudinal study used four Danish medical databases and included 415,553 patients treated for type 2 diabetes for the first time from 1995-2018 and 2,060,279 matched comparators not treated for diabetes.

From 1995 until the 2012 introduction of A1c as a diagnostic option, the annual standardized incidence rates of type 2 diabetes more than doubled, from 193 per 100,000 population to 396 per 100,000 population, at a rate of 4.1% per year.

But from 2011 to 2018, the annual standardized incidence rate declined by 36%, to 253 per 100,000 population, a 5.7% annualized decrease.

The increase prior to 2011 occurred in both men and women and in all age groups, while the subsequent decline was seen primarily in the older age groups. The all-cause mortality risk within the first year after diabetes diagnosis was higher than subsequent 1-year mortality risks and not different between men and women.

From the periods 1995-1997 to 2010-2012, the adjusted mortality rate among those with type 2 diabetes decreased by 44%, from 72 deaths per 1000 person-years to 40 deaths per 1000 person-years (adjusted mortality rate ratio, 0.55). After that low level in 2010-2012, mortality increased by 27% to 48 per 1000 person-years (adjusted mortality rate ratio 0.69, compared with 1995-1997).  

The reversed mortality trend after 2010-2012 was caused almost entirely by the increase in the first year after diabetes diagnosis, Dr. Knudsen and colleagues noted.

According to Dr. Kirkman, “A1c is strongly predictive of complications and mortality. That plus its ease of use and the fact that more people may be screened mean it’s still a good option. But for any of these tests, people who are slightly below the cut-point should not be considered normal or low risk.”

Indeed, Dr. Knudsen and colleagues said, “these findings may have implications for clinical practice and suggest that a more multifactorial view of metabolic risk is needed.”

Dr. Knudsen and Dr. Kirkman have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The introduction of hemoglobin A1c as an option for diagnosing type 2 diabetes over a decade ago may have resulted in underdiagnosis, new research indicates.

In 2011, the World Health Organization advised that A1c measurement, with a cutoff value of 6.5%, could be used to diagnose diabetes. The American Diabetes Association had issued similar guidance in 2010.

Prior to that time, the less-convenient 2-hour oral glucose tolerance test (OGTT) and fasting blood glucose (FBG) were the only recommended tests. While WHO made no recommendations for interpreting values below 6.5%, the ADA designated 5.7%-6.4% as prediabetes.

The new study, published online in The Lancet Regional Health–Europe, showed that the incidence of type 2 diabetes in Denmark had been increasing prior to the 2012 adoption of A1c as a diagnostic option but declined thereafter. And all-cause mortality among people with type 2 diabetes, which had been dropping, began to increase after that time.  

“Our findings suggest that fewer patients have been diagnosed with [type 2 diabetes] since A1c testing was introduced as a convenient diagnostic option. We may thus be missing a group with borderline increased A1c values that is still at high metabolic and cardiovascular risk,” Jakob S. Knudsen, MD, of the department of clinical epidemiology, Aarhus (Denmark) University Hospital, and colleagues wrote.

Therefore, Dr. Knudsen said in an interview, clinicians should “consider testing with FBG or OGTT when presented with borderline A1c values.”

The reason for the increase in mortality after incident type 2 diabetes diagnosis, he said, “is that the patients who would have reduced the average mortality are no longer diagnosed...This does not reflect that we are treating already diagnosed patients any worse, rather some patients are not diagnosed.”

But M. Sue Kirkman, MD, emeritus professor of medicine at the University of North Carolina at Chapel Hill, who was part of the writing group for the 2010 ADA guidelines, isn’t convinced.

“This is an interesting paper, but it is a bit hard to believe that a change in WHO recommendations would have such a large and almost immediate impact on incidence and mortality. It seems likely that ... factors [other] than just the changes in recommendations for the diagnostic test account for these findings,” she said.

Dr. Kirkman pointed to new data just out from the Centers for Disease Control and Prevention on Jan. 26 that don›t show evidence of a higher proportion of people in the United States who have undiagnosed diabetes, “which would be expected if more cases were being ‘missed’ by A1c.”

She added that the CDC incidence data “show a continuing steady rate of decline in incidence that began in 2008, before any organizations recommended using A1c to screen for or diagnose diabetes.” Moreover, “there is evidence that type 2 diabetes incidence has fallen or plateaued in many countries since 2006, well before the WHO recommendation, with most of the studies from developed countries.”

But Dr. Knudsen also cited other data, including a study that showed a drop or stabilization in diagnosed diabetes incidence in high-income countries since 2010.

“That study concluded that the reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources, which was a main objective of our study,” wrote Dr. Knudsen and coauthors.

Dr. Knudsen said in an interview: “We are not the first to make the point that this sudden change is related to A1c introduction...but we are the first to have the data to clearly show that is the case.”

Diabetes incidence dropped but mortality rose after 2010

The population-based longitudinal study used four Danish medical databases and included 415,553 patients treated for type 2 diabetes for the first time from 1995-2018 and 2,060,279 matched comparators not treated for diabetes.

From 1995 until the 2012 introduction of A1c as a diagnostic option, the annual standardized incidence rates of type 2 diabetes more than doubled, from 193 per 100,000 population to 396 per 100,000 population, at a rate of 4.1% per year.

But from 2011 to 2018, the annual standardized incidence rate declined by 36%, to 253 per 100,000 population, a 5.7% annualized decrease.

The increase prior to 2011 occurred in both men and women and in all age groups, while the subsequent decline was seen primarily in the older age groups. The all-cause mortality risk within the first year after diabetes diagnosis was higher than subsequent 1-year mortality risks and not different between men and women.

From the periods 1995-1997 to 2010-2012, the adjusted mortality rate among those with type 2 diabetes decreased by 44%, from 72 deaths per 1000 person-years to 40 deaths per 1000 person-years (adjusted mortality rate ratio, 0.55). After that low level in 2010-2012, mortality increased by 27% to 48 per 1000 person-years (adjusted mortality rate ratio 0.69, compared with 1995-1997).  

The reversed mortality trend after 2010-2012 was caused almost entirely by the increase in the first year after diabetes diagnosis, Dr. Knudsen and colleagues noted.

According to Dr. Kirkman, “A1c is strongly predictive of complications and mortality. That plus its ease of use and the fact that more people may be screened mean it’s still a good option. But for any of these tests, people who are slightly below the cut-point should not be considered normal or low risk.”

Indeed, Dr. Knudsen and colleagues said, “these findings may have implications for clinical practice and suggest that a more multifactorial view of metabolic risk is needed.”

Dr. Knudsen and Dr. Kirkman have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The introduction of hemoglobin A1c as an option for diagnosing type 2 diabetes over a decade ago may have resulted in underdiagnosis, new research indicates.

In 2011, the World Health Organization advised that A1c measurement, with a cutoff value of 6.5%, could be used to diagnose diabetes. The American Diabetes Association had issued similar guidance in 2010.

Prior to that time, the less-convenient 2-hour oral glucose tolerance test (OGTT) and fasting blood glucose (FBG) were the only recommended tests. While WHO made no recommendations for interpreting values below 6.5%, the ADA designated 5.7%-6.4% as prediabetes.

The new study, published online in The Lancet Regional Health–Europe, showed that the incidence of type 2 diabetes in Denmark had been increasing prior to the 2012 adoption of A1c as a diagnostic option but declined thereafter. And all-cause mortality among people with type 2 diabetes, which had been dropping, began to increase after that time.  

“Our findings suggest that fewer patients have been diagnosed with [type 2 diabetes] since A1c testing was introduced as a convenient diagnostic option. We may thus be missing a group with borderline increased A1c values that is still at high metabolic and cardiovascular risk,” Jakob S. Knudsen, MD, of the department of clinical epidemiology, Aarhus (Denmark) University Hospital, and colleagues wrote.

Therefore, Dr. Knudsen said in an interview, clinicians should “consider testing with FBG or OGTT when presented with borderline A1c values.”

The reason for the increase in mortality after incident type 2 diabetes diagnosis, he said, “is that the patients who would have reduced the average mortality are no longer diagnosed...This does not reflect that we are treating already diagnosed patients any worse, rather some patients are not diagnosed.”

But M. Sue Kirkman, MD, emeritus professor of medicine at the University of North Carolina at Chapel Hill, who was part of the writing group for the 2010 ADA guidelines, isn’t convinced.

“This is an interesting paper, but it is a bit hard to believe that a change in WHO recommendations would have such a large and almost immediate impact on incidence and mortality. It seems likely that ... factors [other] than just the changes in recommendations for the diagnostic test account for these findings,” she said.

Dr. Kirkman pointed to new data just out from the Centers for Disease Control and Prevention on Jan. 26 that don›t show evidence of a higher proportion of people in the United States who have undiagnosed diabetes, “which would be expected if more cases were being ‘missed’ by A1c.”

She added that the CDC incidence data “show a continuing steady rate of decline in incidence that began in 2008, before any organizations recommended using A1c to screen for or diagnose diabetes.” Moreover, “there is evidence that type 2 diabetes incidence has fallen or plateaued in many countries since 2006, well before the WHO recommendation, with most of the studies from developed countries.”

But Dr. Knudsen also cited other data, including a study that showed a drop or stabilization in diagnosed diabetes incidence in high-income countries since 2010.

“That study concluded that the reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources, which was a main objective of our study,” wrote Dr. Knudsen and coauthors.

Dr. Knudsen said in an interview: “We are not the first to make the point that this sudden change is related to A1c introduction...but we are the first to have the data to clearly show that is the case.”

Diabetes incidence dropped but mortality rose after 2010

The population-based longitudinal study used four Danish medical databases and included 415,553 patients treated for type 2 diabetes for the first time from 1995-2018 and 2,060,279 matched comparators not treated for diabetes.

From 1995 until the 2012 introduction of A1c as a diagnostic option, the annual standardized incidence rates of type 2 diabetes more than doubled, from 193 per 100,000 population to 396 per 100,000 population, at a rate of 4.1% per year.

But from 2011 to 2018, the annual standardized incidence rate declined by 36%, to 253 per 100,000 population, a 5.7% annualized decrease.

The increase prior to 2011 occurred in both men and women and in all age groups, while the subsequent decline was seen primarily in the older age groups. The all-cause mortality risk within the first year after diabetes diagnosis was higher than subsequent 1-year mortality risks and not different between men and women.

From the periods 1995-1997 to 2010-2012, the adjusted mortality rate among those with type 2 diabetes decreased by 44%, from 72 deaths per 1000 person-years to 40 deaths per 1000 person-years (adjusted mortality rate ratio, 0.55). After that low level in 2010-2012, mortality increased by 27% to 48 per 1000 person-years (adjusted mortality rate ratio 0.69, compared with 1995-1997).  

The reversed mortality trend after 2010-2012 was caused almost entirely by the increase in the first year after diabetes diagnosis, Dr. Knudsen and colleagues noted.

According to Dr. Kirkman, “A1c is strongly predictive of complications and mortality. That plus its ease of use and the fact that more people may be screened mean it’s still a good option. But for any of these tests, people who are slightly below the cut-point should not be considered normal or low risk.”

Indeed, Dr. Knudsen and colleagues said, “these findings may have implications for clinical practice and suggest that a more multifactorial view of metabolic risk is needed.”

Dr. Knudsen and Dr. Kirkman have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

A version of this article first appeared on Medscape.com.

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

A version of this article first appeared on Medscape.com.

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

A version of this article first appeared on Medscape.com.

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

A version of this article first appeared on Medscape.com.

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

A version of this article first appeared on Medscape.com.

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

A version of this article first appeared on Medscape.com.

In 2014, amidst stories of delays at Veterans Health Administration facilities, Congress established the Veterans Choice Program, which expanded access to private sector health care practitioners. When the program expired in 2018, lawmakers replaced it with the Veterans Community Care Program (VCCP) as part of the US Department of Veterans Affairs (VA) Maintaining Internal Systems and Strengthening Integrated Outside Networks Act (38 USC § 1703 MISSION Act). Since then, the VCCP has grown exponentially; 34% of current veteran health care visits are with private clinicians.

Along with broader private sector access, the MISSION Act also mandated the creation of quality-of-care standards for both VA and VCCP, and stipulated that data be compiled and made available to “provide covered veterans relevant comparative information to make informed decisions regarding their health care.” Two-and-a-half years later, data about the quality of VCCP care remains largely unknown.

Access to Care Website  

In the lead up to the MISSION Act, the VA launched its Access to Care website, an online tool that publishes institutional performance data on key metrics so that veterans can make “more informed choices about where, when, and how they receive their health care.” Following the bill’s passage, the VA added a MISSION Act Quality Standards section, which includes results of 27 conventional quality measures for every VA facility. These scores are posted alongside data of regional facilities.

This trailblazing tool is exceedingly comprehensive. Yet, multiple website gaps compromise its utility for veterans deliberating whether to obtain VCCP care, including:

1. Data isn’t about VCCP care. The hospitals are selected because they are local, not whether they participate in VCCP.  Further, it appears that aggregate scores include non-VCCP facilities.
2. Missing conditions/treatments. While the website contains quality scores for an ample range of procedures, it lacks information for many conditions that disproportionately affect veterans. A veteran with posttraumatic stress disorder (PTSD) or traumatic brain injury (TBI), for example, has no data to check.
3. Skewed comparison population. Private sector practitioners primarily treat nonveteran patients, a population that is, on average, healthier and of higher socioeconomic status when compared with VA patients. Outcomes differ, for example, when patients have coexisting mental illness or homelessness. For VCCP scores to be beneficial for comparisons, they should derive from treated veterans or be accurately risk-adjusted.
4. Tangential measures. The Institute of Medicine defined health care quality as “improvement of outcomes.” Patients considering health care options benefit from information about treatment effectiveness and symptom reduction. But because obtaining that quality data is labor intensive, proxy measures are substituted. For example, the measure advising smokers to quit is the closest the website comes to reporting on the quality of mental health care.

High-Performers

The VA initiated a second means to inform veterans about the quality of furnished care. Specifically, they guided third-party administrators (TPAs)—TriWest Healthcare Alliance and Optum—in creating algorithms designating that VCCP individual clinicians, practice groups, and hospitals can be deemed high performing providers (HPPs). The algorithms are calculated using a mix of Healthcare Effectiveness Data and Information Set (HEDIS), Physician Quality Reporting System (PQRS), and Blue Health Intelligence (BHI) primary and specialty care measures. The designations are intended to be accessible to local VA community care schedulers to connect veterans with HPPs.

Many aspects of the HPP system are not yet public, including the measures that comprise the algorithms and when the designations will become operational. From what is publicly discoverable about HPP designations, there are crucial gaps like those on the Access to Care website. Behavioral and mental health conditions, for instance, are intentionally excluded in HPP monitoring. HPP algorithms draw from care provided to the general population; an HPP’s patient panel may contain no veterans (with their common comorbidities) at all. Most limiting, there’s no expectation that VCCP clinicians be high performing. Of the 1.2 million program clinicians treating veterans as of November 2020, only a nominal 13.4% were HPP.

After studying the HPP system, VA Partnered Evidence-based Policy Resource Center acknowledged that “it remains unclear whether the quality metrics and referral system result in higher quality of care for VA patients or whether the program improves veteran health.”

Quality of VCCP Mental Health Treatment

The MISSION Act mandated the VA to “establish standards and requirements for the provision of care by non-VA health care practitioners in clinical areas for which the Department of Veterans Affairs has special expertise, including PTSD, military sexual trauma-related conditions (MST), and TBI.” This requirement arose from a recognition that mental health care provided in the private sector pales in comparison to the VA’s rigorous evidence-based training, consultation, case review and care delivery. For example, over 8500 VA clinicians have received training in evidence-based cognitive processing therapy and/or prolonged exposure therapy for PTSD.

The MISSION Act also mandated that VCCP providers must “fulfill training requirements established by the Secretary on how to deliver evidence-based treatments in the clinical areas for which the Department of Veterans Affairs has special expertise” before furnishing care pursuant to a contract with the VA. However, the VA elected to disregard the directive, and left it up to VCCP clinician’s discretion whether to obtain training or proficiency.

Two bills introduced in Congress in 2021 aim to uphold these vital mandates for the VCCP program. The Veterans’ Culturally Competent Care Act requires VCCP mental health practitioners to take courses on the evaluation and management of suicide, PTSD, TBI, and MST. The Lethal Means Safety Training Act aligns VCCP clinicians suicide prevention training with existing VA standards.

Recommendations to Assure the Quality of VCCP Care

With review and revision of VCCP quality standards now underway, the following remedial actions are recommended:

1. VCCP metrics must be compiled using data on veterans’ care, not the general population, and be published on the Access to Care website. This indispensable information is published on the website for VA care but not for VCCP. Unless VCCP is required to track their veterans, apples-to-apples comparisons of quality of care will remain difficult to attain. Supplemental research that directly contrasts quality of VA to VCCP care should be posted. For example, a 2021 study of enrolled veterans brought by ambulance to VA or community emergency rooms found that all 170 VA medical centers had lower comparative death rates.
2. VCCP providers should be held to the same quality standards as those applied to VA clinicians. In a 2020 critical issue update on implementation of the MISSION Act, major veterans service organizations (VSOs) recommended that competency, training, and quality standards for non-VA community clinicians must be equivalent to benchmarks expected of VA clinicians. That includes credentials, initial and follow-up training, diagnostic screening, care-delivery, and documentation standards. Enacting the Veterans’ Culturally Competent Care Act and the Lethal Means Safety Training Act would begin to meet the MISSION Act’s clear statutory language.
3. The VA and VCCP should add quality information about major diagnostic categories. This will allow veterans to make informed decisions about their personal condition. For most health diagnoses, there is no searchable listing by disorder. 
4. Quality assessments should be realigned to focus on outcome measures. For prospective patients, outcome results provide the most meaningful basis for comparing and selecting clinicians. Proxy measures may have little bearing on whether veterans receive effective care. (As Albert Einstein’s famously observed, “Not everything that can be counted counts.”). Also, the specific measures used for a clinician’s HPP designation should be delineated.
5. The VA must enforce the MISSION Act’s instruction to renew or cancel contracts based on demonstrated quality of care. As VSOs emphasized, “if the private sector is unwilling or unable to match the VA’s access and quality standards, the VA must consider whether it needs to find new community partners.”  

Seventeen billion dollars is spent yearly on purchased health care whose quality remains indeterminate. Ironclad commitments are needed from Congress and the VA to ensure that the effectiveness of, and standards for, veterans care options in the private sector match that in the VA.

In 2014, amidst stories of delays at Veterans Health Administration facilities, Congress established the Veterans Choice Program, which expanded access to private sector health care practitioners. When the program expired in 2018, lawmakers replaced it with the Veterans Community Care Program (VCCP) as part of the US Department of Veterans Affairs (VA) Maintaining Internal Systems and Strengthening Integrated Outside Networks Act (38 USC § 1703 MISSION Act). Since then, the VCCP has grown exponentially; 34% of current veteran health care visits are with private clinicians.

Along with broader private sector access, the MISSION Act also mandated the creation of quality-of-care standards for both VA and VCCP, and stipulated that data be compiled and made available to “provide covered veterans relevant comparative information to make informed decisions regarding their health care.” Two-and-a-half years later, data about the quality of VCCP care remains largely unknown.

Access to Care Website  

In the lead up to the MISSION Act, the VA launched its Access to Care website, an online tool that publishes institutional performance data on key metrics so that veterans can make “more informed choices about where, when, and how they receive their health care.” Following the bill’s passage, the VA added a MISSION Act Quality Standards section, which includes results of 27 conventional quality measures for every VA facility. These scores are posted alongside data of regional facilities.

This trailblazing tool is exceedingly comprehensive. Yet, multiple website gaps compromise its utility for veterans deliberating whether to obtain VCCP care, including:

1. Data isn’t about VCCP care. The hospitals are selected because they are local, not whether they participate in VCCP.  Further, it appears that aggregate scores include non-VCCP facilities.
2. Missing conditions/treatments. While the website contains quality scores for an ample range of procedures, it lacks information for many conditions that disproportionately affect veterans. A veteran with posttraumatic stress disorder (PTSD) or traumatic brain injury (TBI), for example, has no data to check.
3. Skewed comparison population. Private sector practitioners primarily treat nonveteran patients, a population that is, on average, healthier and of higher socioeconomic status when compared with VA patients. Outcomes differ, for example, when patients have coexisting mental illness or homelessness. For VCCP scores to be beneficial for comparisons, they should derive from treated veterans or be accurately risk-adjusted.
4. Tangential measures. The Institute of Medicine defined health care quality as “improvement of outcomes.” Patients considering health care options benefit from information about treatment effectiveness and symptom reduction. But because obtaining that quality data is labor intensive, proxy measures are substituted. For example, the measure advising smokers to quit is the closest the website comes to reporting on the quality of mental health care.

High-Performers

The VA initiated a second means to inform veterans about the quality of furnished care. Specifically, they guided third-party administrators (TPAs)—TriWest Healthcare Alliance and Optum—in creating algorithms designating that VCCP individual clinicians, practice groups, and hospitals can be deemed high performing providers (HPPs). The algorithms are calculated using a mix of Healthcare Effectiveness Data and Information Set (HEDIS), Physician Quality Reporting System (PQRS), and Blue Health Intelligence (BHI) primary and specialty care measures. The designations are intended to be accessible to local VA community care schedulers to connect veterans with HPPs.

Many aspects of the HPP system are not yet public, including the measures that comprise the algorithms and when the designations will become operational. From what is publicly discoverable about HPP designations, there are crucial gaps like those on the Access to Care website. Behavioral and mental health conditions, for instance, are intentionally excluded in HPP monitoring. HPP algorithms draw from care provided to the general population; an HPP’s patient panel may contain no veterans (with their common comorbidities) at all. Most limiting, there’s no expectation that VCCP clinicians be high performing. Of the 1.2 million program clinicians treating veterans as of November 2020, only a nominal 13.4% were HPP.

After studying the HPP system, VA Partnered Evidence-based Policy Resource Center acknowledged that “it remains unclear whether the quality metrics and referral system result in higher quality of care for VA patients or whether the program improves veteran health.”

Quality of VCCP Mental Health Treatment

The MISSION Act mandated the VA to “establish standards and requirements for the provision of care by non-VA health care practitioners in clinical areas for which the Department of Veterans Affairs has special expertise, including PTSD, military sexual trauma-related conditions (MST), and TBI.” This requirement arose from a recognition that mental health care provided in the private sector pales in comparison to the VA’s rigorous evidence-based training, consultation, case review and care delivery. For example, over 8500 VA clinicians have received training in evidence-based cognitive processing therapy and/or prolonged exposure therapy for PTSD.

The MISSION Act also mandated that VCCP providers must “fulfill training requirements established by the Secretary on how to deliver evidence-based treatments in the clinical areas for which the Department of Veterans Affairs has special expertise” before furnishing care pursuant to a contract with the VA. However, the VA elected to disregard the directive, and left it up to VCCP clinician’s discretion whether to obtain training or proficiency.

Two bills introduced in Congress in 2021 aim to uphold these vital mandates for the VCCP program. The Veterans’ Culturally Competent Care Act requires VCCP mental health practitioners to take courses on the evaluation and management of suicide, PTSD, TBI, and MST. The Lethal Means Safety Training Act aligns VCCP clinicians suicide prevention training with existing VA standards.

Recommendations to Assure the Quality of VCCP Care

With review and revision of VCCP quality standards now underway, the following remedial actions are recommended:

1. VCCP metrics must be compiled using data on veterans’ care, not the general population, and be published on the Access to Care website. This indispensable information is published on the website for VA care but not for VCCP. Unless VCCP is required to track their veterans, apples-to-apples comparisons of quality of care will remain difficult to attain. Supplemental research that directly contrasts quality of VA to VCCP care should be posted. For example, a 2021 study of enrolled veterans brought by ambulance to VA or community emergency rooms found that all 170 VA medical centers had lower comparative death rates.
2. VCCP providers should be held to the same quality standards as those applied to VA clinicians. In a 2020 critical issue update on implementation of the MISSION Act, major veterans service organizations (VSOs) recommended that competency, training, and quality standards for non-VA community clinicians must be equivalent to benchmarks expected of VA clinicians. That includes credentials, initial and follow-up training, diagnostic screening, care-delivery, and documentation standards. Enacting the Veterans’ Culturally Competent Care Act and the Lethal Means Safety Training Act would begin to meet the MISSION Act’s clear statutory language.
3. The VA and VCCP should add quality information about major diagnostic categories. This will allow veterans to make informed decisions about their personal condition. For most health diagnoses, there is no searchable listing by disorder. 
4. Quality assessments should be realigned to focus on outcome measures. For prospective patients, outcome results provide the most meaningful basis for comparing and selecting clinicians. Proxy measures may have little bearing on whether veterans receive effective care. (As Albert Einstein’s famously observed, “Not everything that can be counted counts.”). Also, the specific measures used for a clinician’s HPP designation should be delineated.
5. The VA must enforce the MISSION Act’s instruction to renew or cancel contracts based on demonstrated quality of care. As VSOs emphasized, “if the private sector is unwilling or unable to match the VA’s access and quality standards, the VA must consider whether it needs to find new community partners.”  

Seventeen billion dollars is spent yearly on purchased health care whose quality remains indeterminate. Ironclad commitments are needed from Congress and the VA to ensure that the effectiveness of, and standards for, veterans care options in the private sector match that in the VA.

In 2014, amidst stories of delays at Veterans Health Administration facilities, Congress established the Veterans Choice Program, which expanded access to private sector health care practitioners. When the program expired in 2018, lawmakers replaced it with the Veterans Community Care Program (VCCP) as part of the US Department of Veterans Affairs (VA) Maintaining Internal Systems and Strengthening Integrated Outside Networks Act (38 USC § 1703 MISSION Act). Since then, the VCCP has grown exponentially; 34% of current veteran health care visits are with private clinicians.

Along with broader private sector access, the MISSION Act also mandated the creation of quality-of-care standards for both VA and VCCP, and stipulated that data be compiled and made available to “provide covered veterans relevant comparative information to make informed decisions regarding their health care.” Two-and-a-half years later, data about the quality of VCCP care remains largely unknown.

Access to Care Website  

In the lead up to the MISSION Act, the VA launched its Access to Care website, an online tool that publishes institutional performance data on key metrics so that veterans can make “more informed choices about where, when, and how they receive their health care.” Following the bill’s passage, the VA added a MISSION Act Quality Standards section, which includes results of 27 conventional quality measures for every VA facility. These scores are posted alongside data of regional facilities.

This trailblazing tool is exceedingly comprehensive. Yet, multiple website gaps compromise its utility for veterans deliberating whether to obtain VCCP care, including:

1. Data isn’t about VCCP care. The hospitals are selected because they are local, not whether they participate in VCCP.  Further, it appears that aggregate scores include non-VCCP facilities.
2. Missing conditions/treatments. While the website contains quality scores for an ample range of procedures, it lacks information for many conditions that disproportionately affect veterans. A veteran with posttraumatic stress disorder (PTSD) or traumatic brain injury (TBI), for example, has no data to check.
3. Skewed comparison population. Private sector practitioners primarily treat nonveteran patients, a population that is, on average, healthier and of higher socioeconomic status when compared with VA patients. Outcomes differ, for example, when patients have coexisting mental illness or homelessness. For VCCP scores to be beneficial for comparisons, they should derive from treated veterans or be accurately risk-adjusted.
4. Tangential measures. The Institute of Medicine defined health care quality as “improvement of outcomes.” Patients considering health care options benefit from information about treatment effectiveness and symptom reduction. But because obtaining that quality data is labor intensive, proxy measures are substituted. For example, the measure advising smokers to quit is the closest the website comes to reporting on the quality of mental health care.

High-Performers

The VA initiated a second means to inform veterans about the quality of furnished care. Specifically, they guided third-party administrators (TPAs)—TriWest Healthcare Alliance and Optum—in creating algorithms designating that VCCP individual clinicians, practice groups, and hospitals can be deemed high performing providers (HPPs). The algorithms are calculated using a mix of Healthcare Effectiveness Data and Information Set (HEDIS), Physician Quality Reporting System (PQRS), and Blue Health Intelligence (BHI) primary and specialty care measures. The designations are intended to be accessible to local VA community care schedulers to connect veterans with HPPs.

Many aspects of the HPP system are not yet public, including the measures that comprise the algorithms and when the designations will become operational. From what is publicly discoverable about HPP designations, there are crucial gaps like those on the Access to Care website. Behavioral and mental health conditions, for instance, are intentionally excluded in HPP monitoring. HPP algorithms draw from care provided to the general population; an HPP’s patient panel may contain no veterans (with their common comorbidities) at all. Most limiting, there’s no expectation that VCCP clinicians be high performing. Of the 1.2 million program clinicians treating veterans as of November 2020, only a nominal 13.4% were HPP.

After studying the HPP system, VA Partnered Evidence-based Policy Resource Center acknowledged that “it remains unclear whether the quality metrics and referral system result in higher quality of care for VA patients or whether the program improves veteran health.”

Quality of VCCP Mental Health Treatment

The MISSION Act mandated the VA to “establish standards and requirements for the provision of care by non-VA health care practitioners in clinical areas for which the Department of Veterans Affairs has special expertise, including PTSD, military sexual trauma-related conditions (MST), and TBI.” This requirement arose from a recognition that mental health care provided in the private sector pales in comparison to the VA’s rigorous evidence-based training, consultation, case review and care delivery. For example, over 8500 VA clinicians have received training in evidence-based cognitive processing therapy and/or prolonged exposure therapy for PTSD.

The MISSION Act also mandated that VCCP providers must “fulfill training requirements established by the Secretary on how to deliver evidence-based treatments in the clinical areas for which the Department of Veterans Affairs has special expertise” before furnishing care pursuant to a contract with the VA. However, the VA elected to disregard the directive, and left it up to VCCP clinician’s discretion whether to obtain training or proficiency.

Two bills introduced in Congress in 2021 aim to uphold these vital mandates for the VCCP program. The Veterans’ Culturally Competent Care Act requires VCCP mental health practitioners to take courses on the evaluation and management of suicide, PTSD, TBI, and MST. The Lethal Means Safety Training Act aligns VCCP clinicians suicide prevention training with existing VA standards.

Recommendations to Assure the Quality of VCCP Care

With review and revision of VCCP quality standards now underway, the following remedial actions are recommended:

1. VCCP metrics must be compiled using data on veterans’ care, not the general population, and be published on the Access to Care website. This indispensable information is published on the website for VA care but not for VCCP. Unless VCCP is required to track their veterans, apples-to-apples comparisons of quality of care will remain difficult to attain. Supplemental research that directly contrasts quality of VA to VCCP care should be posted. For example, a 2021 study of enrolled veterans brought by ambulance to VA or community emergency rooms found that all 170 VA medical centers had lower comparative death rates.
2. VCCP providers should be held to the same quality standards as those applied to VA clinicians. In a 2020 critical issue update on implementation of the MISSION Act, major veterans service organizations (VSOs) recommended that competency, training, and quality standards for non-VA community clinicians must be equivalent to benchmarks expected of VA clinicians. That includes credentials, initial and follow-up training, diagnostic screening, care-delivery, and documentation standards. Enacting the Veterans’ Culturally Competent Care Act and the Lethal Means Safety Training Act would begin to meet the MISSION Act’s clear statutory language.
3. The VA and VCCP should add quality information about major diagnostic categories. This will allow veterans to make informed decisions about their personal condition. For most health diagnoses, there is no searchable listing by disorder. 
4. Quality assessments should be realigned to focus on outcome measures. For prospective patients, outcome results provide the most meaningful basis for comparing and selecting clinicians. Proxy measures may have little bearing on whether veterans receive effective care. (As Albert Einstein’s famously observed, “Not everything that can be counted counts.”). Also, the specific measures used for a clinician’s HPP designation should be delineated.
5. The VA must enforce the MISSION Act’s instruction to renew or cancel contracts based on demonstrated quality of care. As VSOs emphasized, “if the private sector is unwilling or unable to match the VA’s access and quality standards, the VA must consider whether it needs to find new community partners.”  

Seventeen billion dollars is spent yearly on purchased health care whose quality remains indeterminate. Ironclad commitments are needed from Congress and the VA to ensure that the effectiveness of, and standards for, veterans care options in the private sector match that in the VA.

The U.S. Food and Drug Administration has approved rilpivirine and cabotegravir (Cabenuva) to 2-month dosing for adults living with HIV-1 infection.

Cabenuva was first approved by the FDA in January 2021 to be administered once monthly to treat HIV-1 infection in virologically suppressed adults. The medication was the first injectable complete antiretroviral regimen approved by the FDA.

Cabenuva can replace a current treatment in virologically suppressed adults on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to rilpivirine and cabotegravir, the Janssen Pharmaceutical Companies of Johnson & Johnson said in a press release. Janssen and ViiV Healthcare codeveloped the injectable antiretroviral medication Cabenuva.

The expanded label approval “marks an important step forward in advancing the treatment landscape for people living with HIV,” said Candice Long, the president of infectious diseases and vaccines at Janssen Therapeutics, in a Feb. 1 press release. “With this milestone, adults living with HIV have a treatment option that further reduces the frequency of medication.”

This expanded approval was based on global clinical trial of 1,045 adults with HIV-1, which found Cabenuva administered every 8 weeks (3 mL dose of both cabotegravir and rilpivirine) to be noninferior to the 4-week regimen (2 mL dose of both medicines). At week 48 of the trial, the proportion of participants with viral loads above 50 copies per milliliter was 1.7% in the 2-month arm and 1.0% in the 1-month arm. The study found that rates of virological suppression were similar for both the 1-month and 2-month regimens (93.5% and 94.3%, respectively).

The most common side effects were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Adverse reactions reported in individuals receiving the regimen every 2 months or once monthly were similar. Cabenuva is contraindicated for patients with a hypersensitivity reaction to cabotegravir or rilpivirine or for those receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and more than one dose of systemic dexamethasone.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved rilpivirine and cabotegravir (Cabenuva) to 2-month dosing for adults living with HIV-1 infection.

Cabenuva was first approved by the FDA in January 2021 to be administered once monthly to treat HIV-1 infection in virologically suppressed adults. The medication was the first injectable complete antiretroviral regimen approved by the FDA.

Cabenuva can replace a current treatment in virologically suppressed adults on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to rilpivirine and cabotegravir, the Janssen Pharmaceutical Companies of Johnson & Johnson said in a press release. Janssen and ViiV Healthcare codeveloped the injectable antiretroviral medication Cabenuva.

The expanded label approval “marks an important step forward in advancing the treatment landscape for people living with HIV,” said Candice Long, the president of infectious diseases and vaccines at Janssen Therapeutics, in a Feb. 1 press release. “With this milestone, adults living with HIV have a treatment option that further reduces the frequency of medication.”

This expanded approval was based on global clinical trial of 1,045 adults with HIV-1, which found Cabenuva administered every 8 weeks (3 mL dose of both cabotegravir and rilpivirine) to be noninferior to the 4-week regimen (2 mL dose of both medicines). At week 48 of the trial, the proportion of participants with viral loads above 50 copies per milliliter was 1.7% in the 2-month arm and 1.0% in the 1-month arm. The study found that rates of virological suppression were similar for both the 1-month and 2-month regimens (93.5% and 94.3%, respectively).

The most common side effects were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Adverse reactions reported in individuals receiving the regimen every 2 months or once monthly were similar. Cabenuva is contraindicated for patients with a hypersensitivity reaction to cabotegravir or rilpivirine or for those receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and more than one dose of systemic dexamethasone.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved rilpivirine and cabotegravir (Cabenuva) to 2-month dosing for adults living with HIV-1 infection.

Cabenuva was first approved by the FDA in January 2021 to be administered once monthly to treat HIV-1 infection in virologically suppressed adults. The medication was the first injectable complete antiretroviral regimen approved by the FDA.

Cabenuva can replace a current treatment in virologically suppressed adults on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to rilpivirine and cabotegravir, the Janssen Pharmaceutical Companies of Johnson & Johnson said in a press release. Janssen and ViiV Healthcare codeveloped the injectable antiretroviral medication Cabenuva.

The expanded label approval “marks an important step forward in advancing the treatment landscape for people living with HIV,” said Candice Long, the president of infectious diseases and vaccines at Janssen Therapeutics, in a Feb. 1 press release. “With this milestone, adults living with HIV have a treatment option that further reduces the frequency of medication.”

This expanded approval was based on global clinical trial of 1,045 adults with HIV-1, which found Cabenuva administered every 8 weeks (3 mL dose of both cabotegravir and rilpivirine) to be noninferior to the 4-week regimen (2 mL dose of both medicines). At week 48 of the trial, the proportion of participants with viral loads above 50 copies per milliliter was 1.7% in the 2-month arm and 1.0% in the 1-month arm. The study found that rates of virological suppression were similar for both the 1-month and 2-month regimens (93.5% and 94.3%, respectively).

The most common side effects were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Adverse reactions reported in individuals receiving the regimen every 2 months or once monthly were similar. Cabenuva is contraindicated for patients with a hypersensitivity reaction to cabotegravir or rilpivirine or for those receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and more than one dose of systemic dexamethasone.

A version of this article first appeared on Medscape.com.

Total knee replacement (TKR) is one of the most common surgeries worldwide, with > 1 million performed last year. Many patients have seen tremendous benefit from TKR; however, studies have shown that up to 20% of patients are not satisfied with the results of this procedure.^1,2 This equates to about 200,000 patients worldwide every year who are dissatisfied. This is a huge concern to patients, surgeons, implant manufacturers, hospitals, and health care payers.

Many attempts to improve satisfaction in TKR have been tried, including computer navigation, minimally invasive surgery, rotating platform prostheses, gender-specific implants, different materials, changes in pain management, and revised postoperative rehabilitation.^3-7 However, these efforts show no significant improvement in satisfaction.

The most common method of TKR today involves using a long rod placed through a drill hole in the femur. Standardized cuts on the femur and tibia are made through metal cutting blocks. Only metal mechanical instruments are used to perform the surgery, and all patients are aligned the same. However, anatomic studies have shown that patient anatomy in 3 dimensions (3D) varies widely from patient to patient.⁸ Our current technique seems far removed from modern engineering, where we now see extensive use of artificial intelligence (AI) to improve outcomes.

Machine learning (ML) is considered a subset of AI that involves the use of various computer algorithms. ML allows the computer to learn and continually improve analysis of data. Large sets of inputs and outputs are used to train the machine to make autonomous recommendations or decisions.^9,10

Seven years ago, our team at the Phoenix Veteran Affairs Medical Center in Arizona published a randomized controlled trial evaluating a new, individualized alignment technique for TKR.¹¹ This method used 3D-printed guides made from an MRI of an individual patient’s knee. Instead of aligning all knee replacements the same, each patient was aligned according to their unique anatomy. Compared with the conventional alignment technique, the newer technique showed significant improvement in all outcome scores and range of motion at 2 years postsurgery. There has been a great deal of interest in individualizing TKR, and many articles and techniques have followed.¹²

Our surgical technique has evolved since publishing our trial. Currently, knee X-rays are digitally templated for each patient. Understanding the patient’s preoperative alignment can then assist in planning a TKR in 3D. A plastic 3D-printed guide is manufactured in Belgium, shipped to the US, sterilized, and used in surgery. These guides fit accurately on the patient’s anatomy and allow precise angles and depth of resection for each surgical bone cut. Our research has shown that these guides are accurate to within 0.5° and 0.5 mm for the bone cuts performed in surgery. After surgery, we track patient-reported outcomes (PROs), which can then be used in ML or logistic regression analysis to determine alignment factors that contribute to the best outcome.¹³

Soon, use of a robot will take the place of the templating and preplanning, allowing the 3D plan to be immediately produced in surgery by the software installed in the robot.^14-16 Each patient’s preoperative alignment can then be immediately compared with the postoperative result, and smartphone technology can allow a patient to input their PRO after the surgery is healed.¹⁷

Collecting all this information in a large database can allow ML analyses of the outcomes and individual alignment.^14-17 As the factors contributing to the best clinical results are determined, the computer can be programmed to learn how to make the best recommendations for alignment of each patient, which can be incorporated into the robotic platform for each surgery. Also pre- and postoperative factors can be added to the ML platform so we can identify the best preoperative patient parameters, anticoagulation program postoperative rehabilitation program, etc, to help drive higher PROs and satisfaction.

Multiple surgical robots for TKR are now on the market. Orthopedic literature includes ML algorithms to improve outcomes after total hip arthroplasty.¹⁸ The EHR can be used to develop models to predict poor outcomes after TKR. Integrating these models into clinical decision support could improve patient selection, education, and satisfaction.¹⁹ AI for adult spinal surgery using predictive analytics can help surgeons better inform patients about outcomes after corrective surgery.^20,21

With worldwide TKRs expected to exceed 3 million over the next decade, ML using large databases, robotic surgery, and PROs could be key to improving our TKR outcomes.²² This form of AI may reduce the large number of patients currently not satisfied with their knee replacement.

Total knee replacement (TKR) is one of the most common surgeries worldwide, with > 1 million performed last year. Many patients have seen tremendous benefit from TKR; however, studies have shown that up to 20% of patients are not satisfied with the results of this procedure.^1,2 This equates to about 200,000 patients worldwide every year who are dissatisfied. This is a huge concern to patients, surgeons, implant manufacturers, hospitals, and health care payers.

Many attempts to improve satisfaction in TKR have been tried, including computer navigation, minimally invasive surgery, rotating platform prostheses, gender-specific implants, different materials, changes in pain management, and revised postoperative rehabilitation.^3-7 However, these efforts show no significant improvement in satisfaction.

The most common method of TKR today involves using a long rod placed through a drill hole in the femur. Standardized cuts on the femur and tibia are made through metal cutting blocks. Only metal mechanical instruments are used to perform the surgery, and all patients are aligned the same. However, anatomic studies have shown that patient anatomy in 3 dimensions (3D) varies widely from patient to patient.⁸ Our current technique seems far removed from modern engineering, where we now see extensive use of artificial intelligence (AI) to improve outcomes.

Machine learning (ML) is considered a subset of AI that involves the use of various computer algorithms. ML allows the computer to learn and continually improve analysis of data. Large sets of inputs and outputs are used to train the machine to make autonomous recommendations or decisions.^9,10

Seven years ago, our team at the Phoenix Veteran Affairs Medical Center in Arizona published a randomized controlled trial evaluating a new, individualized alignment technique for TKR.¹¹ This method used 3D-printed guides made from an MRI of an individual patient’s knee. Instead of aligning all knee replacements the same, each patient was aligned according to their unique anatomy. Compared with the conventional alignment technique, the newer technique showed significant improvement in all outcome scores and range of motion at 2 years postsurgery. There has been a great deal of interest in individualizing TKR, and many articles and techniques have followed.¹²

Our surgical technique has evolved since publishing our trial. Currently, knee X-rays are digitally templated for each patient. Understanding the patient’s preoperative alignment can then assist in planning a TKR in 3D. A plastic 3D-printed guide is manufactured in Belgium, shipped to the US, sterilized, and used in surgery. These guides fit accurately on the patient’s anatomy and allow precise angles and depth of resection for each surgical bone cut. Our research has shown that these guides are accurate to within 0.5° and 0.5 mm for the bone cuts performed in surgery. After surgery, we track patient-reported outcomes (PROs), which can then be used in ML or logistic regression analysis to determine alignment factors that contribute to the best outcome.¹³

Soon, use of a robot will take the place of the templating and preplanning, allowing the 3D plan to be immediately produced in surgery by the software installed in the robot.^14-16 Each patient’s preoperative alignment can then be immediately compared with the postoperative result, and smartphone technology can allow a patient to input their PRO after the surgery is healed.¹⁷

Collecting all this information in a large database can allow ML analyses of the outcomes and individual alignment.^14-17 As the factors contributing to the best clinical results are determined, the computer can be programmed to learn how to make the best recommendations for alignment of each patient, which can be incorporated into the robotic platform for each surgery. Also pre- and postoperative factors can be added to the ML platform so we can identify the best preoperative patient parameters, anticoagulation program postoperative rehabilitation program, etc, to help drive higher PROs and satisfaction.

Multiple surgical robots for TKR are now on the market. Orthopedic literature includes ML algorithms to improve outcomes after total hip arthroplasty.¹⁸ The EHR can be used to develop models to predict poor outcomes after TKR. Integrating these models into clinical decision support could improve patient selection, education, and satisfaction.¹⁹ AI for adult spinal surgery using predictive analytics can help surgeons better inform patients about outcomes after corrective surgery.^20,21

With worldwide TKRs expected to exceed 3 million over the next decade, ML using large databases, robotic surgery, and PROs could be key to improving our TKR outcomes.²² This form of AI may reduce the large number of patients currently not satisfied with their knee replacement.

Total knee replacement (TKR) is one of the most common surgeries worldwide, with > 1 million performed last year. Many patients have seen tremendous benefit from TKR; however, studies have shown that up to 20% of patients are not satisfied with the results of this procedure.^1,2 This equates to about 200,000 patients worldwide every year who are dissatisfied. This is a huge concern to patients, surgeons, implant manufacturers, hospitals, and health care payers.

Many attempts to improve satisfaction in TKR have been tried, including computer navigation, minimally invasive surgery, rotating platform prostheses, gender-specific implants, different materials, changes in pain management, and revised postoperative rehabilitation.^3-7 However, these efforts show no significant improvement in satisfaction.

The most common method of TKR today involves using a long rod placed through a drill hole in the femur. Standardized cuts on the femur and tibia are made through metal cutting blocks. Only metal mechanical instruments are used to perform the surgery, and all patients are aligned the same. However, anatomic studies have shown that patient anatomy in 3 dimensions (3D) varies widely from patient to patient.⁸ Our current technique seems far removed from modern engineering, where we now see extensive use of artificial intelligence (AI) to improve outcomes.

Machine learning (ML) is considered a subset of AI that involves the use of various computer algorithms. ML allows the computer to learn and continually improve analysis of data. Large sets of inputs and outputs are used to train the machine to make autonomous recommendations or decisions.^9,10

Seven years ago, our team at the Phoenix Veteran Affairs Medical Center in Arizona published a randomized controlled trial evaluating a new, individualized alignment technique for TKR.¹¹ This method used 3D-printed guides made from an MRI of an individual patient’s knee. Instead of aligning all knee replacements the same, each patient was aligned according to their unique anatomy. Compared with the conventional alignment technique, the newer technique showed significant improvement in all outcome scores and range of motion at 2 years postsurgery. There has been a great deal of interest in individualizing TKR, and many articles and techniques have followed.¹²

Our surgical technique has evolved since publishing our trial. Currently, knee X-rays are digitally templated for each patient. Understanding the patient’s preoperative alignment can then assist in planning a TKR in 3D. A plastic 3D-printed guide is manufactured in Belgium, shipped to the US, sterilized, and used in surgery. These guides fit accurately on the patient’s anatomy and allow precise angles and depth of resection for each surgical bone cut. Our research has shown that these guides are accurate to within 0.5° and 0.5 mm for the bone cuts performed in surgery. After surgery, we track patient-reported outcomes (PROs), which can then be used in ML or logistic regression analysis to determine alignment factors that contribute to the best outcome.¹³

Soon, use of a robot will take the place of the templating and preplanning, allowing the 3D plan to be immediately produced in surgery by the software installed in the robot.^14-16 Each patient’s preoperative alignment can then be immediately compared with the postoperative result, and smartphone technology can allow a patient to input their PRO after the surgery is healed.¹⁷

Collecting all this information in a large database can allow ML analyses of the outcomes and individual alignment.^14-17 As the factors contributing to the best clinical results are determined, the computer can be programmed to learn how to make the best recommendations for alignment of each patient, which can be incorporated into the robotic platform for each surgery. Also pre- and postoperative factors can be added to the ML platform so we can identify the best preoperative patient parameters, anticoagulation program postoperative rehabilitation program, etc, to help drive higher PROs and satisfaction.

Multiple surgical robots for TKR are now on the market. Orthopedic literature includes ML algorithms to improve outcomes after total hip arthroplasty.¹⁸ The EHR can be used to develop models to predict poor outcomes after TKR. Integrating these models into clinical decision support could improve patient selection, education, and satisfaction.¹⁹ AI for adult spinal surgery using predictive analytics can help surgeons better inform patients about outcomes after corrective surgery.^20,21

With worldwide TKRs expected to exceed 3 million over the next decade, ML using large databases, robotic surgery, and PROs could be key to improving our TKR outcomes.²² This form of AI may reduce the large number of patients currently not satisfied with their knee replacement.