Mitchel L. Zoler, PhD

WASHINGTON – Finding a drug therapy for patients with Alzheimer’s disease that not only improves symptoms but also slows or stops the underlying disease process and results in disease modification will be a major challenge.

Disease modification “indicates the drug is attacking the underlying biology of the disease. The medications we have now affect only symptoms and are palliative,” Dr. David S. Knopman said in an interview during the Alzheimer’s Association International Conference 2015.

Designing trials capable of identifying disease-modifying drugs “turns out to be very challenging. In principle, a drug with disease-modifying effects would have bigger and more enduring effects, could be started earlier in the disease, and would ultimately be of greater benefit to patients and to society,” said Dr. Knopman, a professor of neurology at the Mayo Clinic in Rochester, Minn. He participated in a session at the meeting focused on the potential design of trials that could test a drug’s disease-modifying effect.

The most likely design that researchers seem ready to use is a “delayed-start” trial, in which placebo-treated patients who serve as controls in the initial, blinded, and randomized phase of an efficacy trial then cross over to open-label treatment once the first segment primary-endpoint stage is finished. In most trials “the open-label, long-term extension will occur anyway,” so adding a delayed-start element following the end of an efficacy trial “does not add a lot of complication to the design,” he said.

Two factors make a delayed-start analysis challenging. First, the drug needs to show efficacy during the initial, double-blinded phase. “Only if you see both a cognitive and some sort of functional-outcome benefit can you engage in the delayed-start analysis, to see if the effect is enduring,” Dr. Knopman said. The second limitation is patient drop out. “An open-label, long-term extension over another 1, 2, 3 years will invariably lead to subjects dropping out because of health issues or social matters and that makes the statistical analysis more complicated.” During one trial that was discussed in depth at the session, about 40% of patients who entered the delayed-start phase had left the study by the time this stage finished 2 years later.

Despite these issues, adding a delayed-start phase to drug trials likely will become increasingly common, Dr. Knopman predicted. Drug developers “will probably include this as a secondary analysis because it doesn’t add much expense or added burden on participants, so it seems like a win-win.” Plus, representatives from the Food and Drug Administration who participated in the session seemed to endorse the general concept, he noted. But the most important caveat remains, he stressed: “You have to first show primary-outcome results. Only then you can talk about disease modification.”

The delayed-start trial design was developed by Eli Lilly. Dr. Knopman received an honorarium from Lilly for chairing the data and safety-monitoring committee for two of their trials through 2012, but since then he has not had a financial relationship with the company. He currently is an investigator in a trial sponsored by Lilly. He said he has no other disclosures.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

WASHINGTON – Finding a drug therapy for patients with Alzheimer’s disease that not only improves symptoms but also slows or stops the underlying disease process and results in disease modification will be a major challenge.

Disease modification “indicates the drug is attacking the underlying biology of the disease. The medications we have now affect only symptoms and are palliative,” Dr. David S. Knopman said in an interview during the Alzheimer’s Association International Conference 2015.

Designing trials capable of identifying disease-modifying drugs “turns out to be very challenging. In principle, a drug with disease-modifying effects would have bigger and more enduring effects, could be started earlier in the disease, and would ultimately be of greater benefit to patients and to society,” said Dr. Knopman, a professor of neurology at the Mayo Clinic in Rochester, Minn. He participated in a session at the meeting focused on the potential design of trials that could test a drug’s disease-modifying effect.

The most likely design that researchers seem ready to use is a “delayed-start” trial, in which placebo-treated patients who serve as controls in the initial, blinded, and randomized phase of an efficacy trial then cross over to open-label treatment once the first segment primary-endpoint stage is finished. In most trials “the open-label, long-term extension will occur anyway,” so adding a delayed-start element following the end of an efficacy trial “does not add a lot of complication to the design,” he said.

Two factors make a delayed-start analysis challenging. First, the drug needs to show efficacy during the initial, double-blinded phase. “Only if you see both a cognitive and some sort of functional-outcome benefit can you engage in the delayed-start analysis, to see if the effect is enduring,” Dr. Knopman said. The second limitation is patient drop out. “An open-label, long-term extension over another 1, 2, 3 years will invariably lead to subjects dropping out because of health issues or social matters and that makes the statistical analysis more complicated.” During one trial that was discussed in depth at the session, about 40% of patients who entered the delayed-start phase had left the study by the time this stage finished 2 years later.

Despite these issues, adding a delayed-start phase to drug trials likely will become increasingly common, Dr. Knopman predicted. Drug developers “will probably include this as a secondary analysis because it doesn’t add much expense or added burden on participants, so it seems like a win-win.” Plus, representatives from the Food and Drug Administration who participated in the session seemed to endorse the general concept, he noted. But the most important caveat remains, he stressed: “You have to first show primary-outcome results. Only then you can talk about disease modification.”

The delayed-start trial design was developed by Eli Lilly. Dr. Knopman received an honorarium from Lilly for chairing the data and safety-monitoring committee for two of their trials through 2012, but since then he has not had a financial relationship with the company. He currently is an investigator in a trial sponsored by Lilly. He said he has no other disclosures.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

WASHINGTON – Finding a drug therapy for patients with Alzheimer’s disease that not only improves symptoms but also slows or stops the underlying disease process and results in disease modification will be a major challenge.

Disease modification “indicates the drug is attacking the underlying biology of the disease. The medications we have now affect only symptoms and are palliative,” Dr. David S. Knopman said in an interview during the Alzheimer’s Association International Conference 2015.

Designing trials capable of identifying disease-modifying drugs “turns out to be very challenging. In principle, a drug with disease-modifying effects would have bigger and more enduring effects, could be started earlier in the disease, and would ultimately be of greater benefit to patients and to society,” said Dr. Knopman, a professor of neurology at the Mayo Clinic in Rochester, Minn. He participated in a session at the meeting focused on the potential design of trials that could test a drug’s disease-modifying effect.

The most likely design that researchers seem ready to use is a “delayed-start” trial, in which placebo-treated patients who serve as controls in the initial, blinded, and randomized phase of an efficacy trial then cross over to open-label treatment once the first segment primary-endpoint stage is finished. In most trials “the open-label, long-term extension will occur anyway,” so adding a delayed-start element following the end of an efficacy trial “does not add a lot of complication to the design,” he said.

Two factors make a delayed-start analysis challenging. First, the drug needs to show efficacy during the initial, double-blinded phase. “Only if you see both a cognitive and some sort of functional-outcome benefit can you engage in the delayed-start analysis, to see if the effect is enduring,” Dr. Knopman said. The second limitation is patient drop out. “An open-label, long-term extension over another 1, 2, 3 years will invariably lead to subjects dropping out because of health issues or social matters and that makes the statistical analysis more complicated.” During one trial that was discussed in depth at the session, about 40% of patients who entered the delayed-start phase had left the study by the time this stage finished 2 years later.

Despite these issues, adding a delayed-start phase to drug trials likely will become increasingly common, Dr. Knopman predicted. Drug developers “will probably include this as a secondary analysis because it doesn’t add much expense or added burden on participants, so it seems like a win-win.” Plus, representatives from the Food and Drug Administration who participated in the session seemed to endorse the general concept, he noted. But the most important caveat remains, he stressed: “You have to first show primary-outcome results. Only then you can talk about disease modification.”

The delayed-start trial design was developed by Eli Lilly. Dr. Knopman received an honorarium from Lilly for chairing the data and safety-monitoring committee for two of their trials through 2012, but since then he has not had a financial relationship with the company. He currently is an investigator in a trial sponsored by Lilly. He said he has no other disclosures.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

WASHINGTON – Postoperative cognitive decline, which occurs in roughly 20% of elderly patients who undergo major surgery, strikes older women with greater severity than it does similarly aged men, according to a retrospective analysis of data collected from 527 older Americans.

“We looked at the sex difference in postoperative cognitive decline and Alzheimer’s disease because of the sex difference in Alzheimer’s disease, where about two-thirds of patients are women,” Dr. Katie J. Schenning said in an interview during the Alzheimer’s Association International Conference 2015. “We know that a lot of the pathologic changes that happen to the brain after anesthesia and surgery are similar to the changes that happen in Alzheimer’s disease patients. But at this point that is all we can say about a link between the two. It is currently unknown whether there is a clear relationship between postoperative cognitive decline and Alzheimer’s disease,” said Dr. Schenning, an anesthesiologist at Oregon Health & Science University in Portland.

She and her associates studied data collected longitudinally from two cohorts, the Oregon Brain Aging Study and the Intelligent Systems for Assessment of Aging Changes. At baseline, the average age of the enrollees in the combined group was 83 years, and just under two-thirds were women. During follow-up, 182 of the participants underwent a total of 331 major surgeries, with some undergoing more than one surgery. The most common form of surgery was orthopedic, done in one-third of the patients, followed by general surgery, in a quarter.

The researchers running both studies collected data annually from participants using a battery of neuropsychological evaluations, brain MRIs, and information on their general health. Retrospective analysis of the data showed that following surgery, people showed evidence of statistically significant and clinically meaningful declines in several measures, compared with those who did not undergo surgery, including deficits measured by the Mini-Mental State Examination, instrumental activities of daily living, and logical memory delayed recall. The trajectory of these declines was significantly steeper in women following surgery, compared with men following surgery, Dr. Schenning reported in a poster at the meeting. In addition, the MRI scans showed ventricular enlargement in the postsurgical women but not in men, a change that is characteristic of neuropathology.

“Women who underwent surgery had a more rapid rate of decline in measures of cognition and function than women who did not have surgery, and it affected women in more categories than in men,” Dr. Schenning said.

The risk for postoperative cognitive decline “is one of the things that patients should take into consideration before undergoing elective surgery, especially if they are older or have pre-existing cognitive impairment,” Dr. Schenning suggested. The enhanced risk for postsurgical cognitive decline faced by older women and even the somewhat lesser risk that exists for older men “is certainly something that patients should discuss with their surgeon, anesthesiologist, and family members,” she said.

Dr. Schenning had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Postoperative cognitive decline, which occurs in roughly 20% of elderly patients who undergo major surgery, strikes older women with greater severity than it does similarly aged men, according to a retrospective analysis of data collected from 527 older Americans.

“We looked at the sex difference in postoperative cognitive decline and Alzheimer’s disease because of the sex difference in Alzheimer’s disease, where about two-thirds of patients are women,” Dr. Katie J. Schenning said in an interview during the Alzheimer’s Association International Conference 2015. “We know that a lot of the pathologic changes that happen to the brain after anesthesia and surgery are similar to the changes that happen in Alzheimer’s disease patients. But at this point that is all we can say about a link between the two. It is currently unknown whether there is a clear relationship between postoperative cognitive decline and Alzheimer’s disease,” said Dr. Schenning, an anesthesiologist at Oregon Health & Science University in Portland.

She and her associates studied data collected longitudinally from two cohorts, the Oregon Brain Aging Study and the Intelligent Systems for Assessment of Aging Changes. At baseline, the average age of the enrollees in the combined group was 83 years, and just under two-thirds were women. During follow-up, 182 of the participants underwent a total of 331 major surgeries, with some undergoing more than one surgery. The most common form of surgery was orthopedic, done in one-third of the patients, followed by general surgery, in a quarter.

The researchers running both studies collected data annually from participants using a battery of neuropsychological evaluations, brain MRIs, and information on their general health. Retrospective analysis of the data showed that following surgery, people showed evidence of statistically significant and clinically meaningful declines in several measures, compared with those who did not undergo surgery, including deficits measured by the Mini-Mental State Examination, instrumental activities of daily living, and logical memory delayed recall. The trajectory of these declines was significantly steeper in women following surgery, compared with men following surgery, Dr. Schenning reported in a poster at the meeting. In addition, the MRI scans showed ventricular enlargement in the postsurgical women but not in men, a change that is characteristic of neuropathology.

“Women who underwent surgery had a more rapid rate of decline in measures of cognition and function than women who did not have surgery, and it affected women in more categories than in men,” Dr. Schenning said.

The risk for postoperative cognitive decline “is one of the things that patients should take into consideration before undergoing elective surgery, especially if they are older or have pre-existing cognitive impairment,” Dr. Schenning suggested. The enhanced risk for postsurgical cognitive decline faced by older women and even the somewhat lesser risk that exists for older men “is certainly something that patients should discuss with their surgeon, anesthesiologist, and family members,” she said.

Dr. Schenning had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Postoperative cognitive decline, which occurs in roughly 20% of elderly patients who undergo major surgery, strikes older women with greater severity than it does similarly aged men, according to a retrospective analysis of data collected from 527 older Americans.

“We looked at the sex difference in postoperative cognitive decline and Alzheimer’s disease because of the sex difference in Alzheimer’s disease, where about two-thirds of patients are women,” Dr. Katie J. Schenning said in an interview during the Alzheimer’s Association International Conference 2015. “We know that a lot of the pathologic changes that happen to the brain after anesthesia and surgery are similar to the changes that happen in Alzheimer’s disease patients. But at this point that is all we can say about a link between the two. It is currently unknown whether there is a clear relationship between postoperative cognitive decline and Alzheimer’s disease,” said Dr. Schenning, an anesthesiologist at Oregon Health & Science University in Portland.

She and her associates studied data collected longitudinally from two cohorts, the Oregon Brain Aging Study and the Intelligent Systems for Assessment of Aging Changes. At baseline, the average age of the enrollees in the combined group was 83 years, and just under two-thirds were women. During follow-up, 182 of the participants underwent a total of 331 major surgeries, with some undergoing more than one surgery. The most common form of surgery was orthopedic, done in one-third of the patients, followed by general surgery, in a quarter.

The researchers running both studies collected data annually from participants using a battery of neuropsychological evaluations, brain MRIs, and information on their general health. Retrospective analysis of the data showed that following surgery, people showed evidence of statistically significant and clinically meaningful declines in several measures, compared with those who did not undergo surgery, including deficits measured by the Mini-Mental State Examination, instrumental activities of daily living, and logical memory delayed recall. The trajectory of these declines was significantly steeper in women following surgery, compared with men following surgery, Dr. Schenning reported in a poster at the meeting. In addition, the MRI scans showed ventricular enlargement in the postsurgical women but not in men, a change that is characteristic of neuropathology.

“Women who underwent surgery had a more rapid rate of decline in measures of cognition and function than women who did not have surgery, and it affected women in more categories than in men,” Dr. Schenning said.

The risk for postoperative cognitive decline “is one of the things that patients should take into consideration before undergoing elective surgery, especially if they are older or have pre-existing cognitive impairment,” Dr. Schenning suggested. The enhanced risk for postsurgical cognitive decline faced by older women and even the somewhat lesser risk that exists for older men “is certainly something that patients should discuss with their surgeon, anesthesiologist, and family members,” she said.

Dr. Schenning had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Improved management of patients with type 1 diabetes and the resulting increased longevity it has fostered has produced a new medical concern that few patients faced in the past: their risk for developing dementia as they age into their 60s, 70s, and beyond.

That risk, which turns out to be nearly double that of people without diabetes, closely matches the higher risk faced by patients with type 2 diabetes, based on analysis of data collected during 2002-2014 from more than 490,000 people aged 60 years or older enrolled in the Kaiser Permanente Medical Care Program of Northern California, Rachel Whitmer, Ph.D. reported at the Alzheimer’s Association International Conference 2015.

Her study tracked the dementia incidence in 334 of these Kaiser Permanente enrollees with type 1 diabetes and no dementia at baseline and found the rate ran 73% higher when compared with controls without any type of diabetes in the cohort after adjustment for sex, race, and vascular complications such as hypertension, stroke, and peripheral vascular disease. The patients with type 1 diabetes averaged 71 years old at baseline and their follow-up averaged 7 years. This is the first study to look at the incidence of dementia in elderly patients with type 1 diabetes, Dr. Whitmer said in an interview during the meeting.

Physicians who care for patients with type 1 diabetes should be aware of this increased risk, be on the lookout for signs of developing dementia in these patients, and use the increased risk to help motivate type 1 diabetes patients to be vigilant in controlling their disease to help avoid the microvascular complications that likely contribute to their dementia risk. Patients with type 1 diabetes are especially vulnerable to the consequences of cognitive impairment as they must maintain complex self-management routines of blood glucose monitoring, insulin administration, and keeping close tabs on their diet and exercise, Dr. Whitmer noted.

In 2013, she and her associates published a simple and easy-to-use tool for clinicians to assess the dementia risk in individual patients with type 2 diabetes (Lancet Diabetes Endocrinol. 2013;3:183-90). Further study of the risk factors that contribute to dementia onset in patients with type 1 diabetes will hopefully lead to creation of a similar risk-assessment tool for use in type 1 patients, said Dr. Whitmer, an epidemiologist at the Kaiser Permanente Northern California Division of Research in Oakland.

Dr. Whitmer had no disclosures.

WASHINGTON – Improved management of patients with type 1 diabetes and the resulting increased longevity it has fostered has produced a new medical concern that few patients faced in the past: their risk for developing dementia as they age into their 60s, 70s, and beyond.

That risk, which turns out to be nearly double that of people without diabetes, closely matches the higher risk faced by patients with type 2 diabetes, based on analysis of data collected during 2002-2014 from more than 490,000 people aged 60 years or older enrolled in the Kaiser Permanente Medical Care Program of Northern California, Rachel Whitmer, Ph.D. reported at the Alzheimer’s Association International Conference 2015.

Her study tracked the dementia incidence in 334 of these Kaiser Permanente enrollees with type 1 diabetes and no dementia at baseline and found the rate ran 73% higher when compared with controls without any type of diabetes in the cohort after adjustment for sex, race, and vascular complications such as hypertension, stroke, and peripheral vascular disease. The patients with type 1 diabetes averaged 71 years old at baseline and their follow-up averaged 7 years. This is the first study to look at the incidence of dementia in elderly patients with type 1 diabetes, Dr. Whitmer said in an interview during the meeting.

Physicians who care for patients with type 1 diabetes should be aware of this increased risk, be on the lookout for signs of developing dementia in these patients, and use the increased risk to help motivate type 1 diabetes patients to be vigilant in controlling their disease to help avoid the microvascular complications that likely contribute to their dementia risk. Patients with type 1 diabetes are especially vulnerable to the consequences of cognitive impairment as they must maintain complex self-management routines of blood glucose monitoring, insulin administration, and keeping close tabs on their diet and exercise, Dr. Whitmer noted.

In 2013, she and her associates published a simple and easy-to-use tool for clinicians to assess the dementia risk in individual patients with type 2 diabetes (Lancet Diabetes Endocrinol. 2013;3:183-90). Further study of the risk factors that contribute to dementia onset in patients with type 1 diabetes will hopefully lead to creation of a similar risk-assessment tool for use in type 1 patients, said Dr. Whitmer, an epidemiologist at the Kaiser Permanente Northern California Division of Research in Oakland.

Dr. Whitmer had no disclosures.

WASHINGTON – Improved management of patients with type 1 diabetes and the resulting increased longevity it has fostered has produced a new medical concern that few patients faced in the past: their risk for developing dementia as they age into their 60s, 70s, and beyond.

That risk, which turns out to be nearly double that of people without diabetes, closely matches the higher risk faced by patients with type 2 diabetes, based on analysis of data collected during 2002-2014 from more than 490,000 people aged 60 years or older enrolled in the Kaiser Permanente Medical Care Program of Northern California, Rachel Whitmer, Ph.D. reported at the Alzheimer’s Association International Conference 2015.

Her study tracked the dementia incidence in 334 of these Kaiser Permanente enrollees with type 1 diabetes and no dementia at baseline and found the rate ran 73% higher when compared with controls without any type of diabetes in the cohort after adjustment for sex, race, and vascular complications such as hypertension, stroke, and peripheral vascular disease. The patients with type 1 diabetes averaged 71 years old at baseline and their follow-up averaged 7 years. This is the first study to look at the incidence of dementia in elderly patients with type 1 diabetes, Dr. Whitmer said in an interview during the meeting.

Physicians who care for patients with type 1 diabetes should be aware of this increased risk, be on the lookout for signs of developing dementia in these patients, and use the increased risk to help motivate type 1 diabetes patients to be vigilant in controlling their disease to help avoid the microvascular complications that likely contribute to their dementia risk. Patients with type 1 diabetes are especially vulnerable to the consequences of cognitive impairment as they must maintain complex self-management routines of blood glucose monitoring, insulin administration, and keeping close tabs on their diet and exercise, Dr. Whitmer noted.

In 2013, she and her associates published a simple and easy-to-use tool for clinicians to assess the dementia risk in individual patients with type 2 diabetes (Lancet Diabetes Endocrinol. 2013;3:183-90). Further study of the risk factors that contribute to dementia onset in patients with type 1 diabetes will hopefully lead to creation of a similar risk-assessment tool for use in type 1 patients, said Dr. Whitmer, an epidemiologist at the Kaiser Permanente Northern California Division of Research in Oakland.

Dr. Whitmer had no disclosures.

WASHINGTON – Improved management of patients with type 1 diabetes and the resulting increased longevity it has fostered has produced a new medical concern that few patients faced in the past: their risk for developing dementia as they age into their 60s, 70s, and beyond.

That risk, which turns out to be nearly double that of people without diabetes, closely matches the higher risk faced by patients with type 2 diabetes, based on analysis of data collected during 2002-2014 from more than 490,000 people aged 60 years or older enrolled in the Kaiser Permanente Medical Care Program of Northern California, Rachel Whitmer, Ph.D. reported at the Alzheimer’s Association International Conference 2015.

Her study tracked the dementia incidence in 334 of these Kaiser Permanente enrollees with type 1 diabetes and no dementia at baseline and found the rate ran 73% higher when compared with controls without any type of diabetes in the cohort after adjustment for sex, race, and vascular complications such as hypertension, stroke, and peripheral vascular disease. The patients with type 1 diabetes averaged 71 years old at baseline and their follow-up averaged 7 years. This is the first study to look at the incidence of dementia in elderly patients with type 1 diabetes, Dr. Whitmer said in an interview during the meeting.

Physicians who care for patients with type 1 diabetes should be aware of this increased risk, be on the lookout for signs of developing dementia in these patients, and use the increased risk to help motivate type 1 diabetes patients to be vigilant in controlling their disease to help avoid the microvascular complications that likely contribute to their dementia risk. Patients with type 1 diabetes are especially vulnerable to the consequences of cognitive impairment as they must maintain complex self-management routines of blood glucose monitoring, insulin administration, and keeping close tabs on their diet and exercise, Dr. Whitmer noted.

In 2013, she and her associates published a simple and easy-to-use tool for clinicians to assess the dementia risk in individual patients with type 2 diabetes (Lancet Diabetes Endocrinol. 2013;3:183-90). Further study of the risk factors that contribute to dementia onset in patients with type 1 diabetes will hopefully lead to creation of a similar risk-assessment tool for use in type 1 patients, said Dr. Whitmer, an epidemiologist at the Kaiser Permanente Northern California Division of Research in Oakland.

Dr. Whitmer had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Improved management of patients with type 1 diabetes and the resulting increased longevity it has fostered has produced a new medical concern that few patients faced in the past: their risk for developing dementia as they age into their 60s, 70s, and beyond.

That risk, which turns out to be nearly double that of people without diabetes, closely matches the higher risk faced by patients with type 2 diabetes, based on analysis of data collected during 2002-2014 from more than 490,000 people aged 60 years or older enrolled in the Kaiser Permanente Medical Care Program of Northern California, Rachel Whitmer, Ph.D. reported at the Alzheimer’s Association International Conference 2015.

Her study tracked the dementia incidence in 334 of these Kaiser Permanente enrollees with type 1 diabetes and no dementia at baseline and found the rate ran 73% higher when compared with controls without any type of diabetes in the cohort after adjustment for sex, race, and vascular complications such as hypertension, stroke, and peripheral vascular disease. The patients with type 1 diabetes averaged 71 years old at baseline and their follow-up averaged 7 years. This is the first study to look at the incidence of dementia in elderly patients with type 1 diabetes, Dr. Whitmer said in an interview during the meeting.

Physicians who care for patients with type 1 diabetes should be aware of this increased risk, be on the lookout for signs of developing dementia in these patients, and use the increased risk to help motivate type 1 diabetes patients to be vigilant in controlling their disease to help avoid the microvascular complications that likely contribute to their dementia risk. Patients with type 1 diabetes are especially vulnerable to the consequences of cognitive impairment as they must maintain complex self-management routines of blood glucose monitoring, insulin administration, and keeping close tabs on their diet and exercise, Dr. Whitmer noted.

In 2013, she and her associates published a simple and easy-to-use tool for clinicians to assess the dementia risk in individual patients with type 2 diabetes (Lancet Diabetes Endocrinol. 2013;3:183-90). Further study of the risk factors that contribute to dementia onset in patients with type 1 diabetes will hopefully lead to creation of a similar risk-assessment tool for use in type 1 patients, said Dr. Whitmer, an epidemiologist at the Kaiser Permanente Northern California Division of Research in Oakland.

Dr. Whitmer had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Improved management of patients with type 1 diabetes and the resulting increased longevity it has fostered has produced a new medical concern that few patients faced in the past: their risk for developing dementia as they age into their 60s, 70s, and beyond.

That risk, which turns out to be nearly double that of people without diabetes, closely matches the higher risk faced by patients with type 2 diabetes, based on analysis of data collected during 2002-2014 from more than 490,000 people aged 60 years or older enrolled in the Kaiser Permanente Medical Care Program of Northern California, Rachel Whitmer, Ph.D. reported at the Alzheimer’s Association International Conference 2015.

Her study tracked the dementia incidence in 334 of these Kaiser Permanente enrollees with type 1 diabetes and no dementia at baseline and found the rate ran 73% higher when compared with controls without any type of diabetes in the cohort after adjustment for sex, race, and vascular complications such as hypertension, stroke, and peripheral vascular disease. The patients with type 1 diabetes averaged 71 years old at baseline and their follow-up averaged 7 years. This is the first study to look at the incidence of dementia in elderly patients with type 1 diabetes, Dr. Whitmer said in an interview during the meeting.

Physicians who care for patients with type 1 diabetes should be aware of this increased risk, be on the lookout for signs of developing dementia in these patients, and use the increased risk to help motivate type 1 diabetes patients to be vigilant in controlling their disease to help avoid the microvascular complications that likely contribute to their dementia risk. Patients with type 1 diabetes are especially vulnerable to the consequences of cognitive impairment as they must maintain complex self-management routines of blood glucose monitoring, insulin administration, and keeping close tabs on their diet and exercise, Dr. Whitmer noted.

In 2013, she and her associates published a simple and easy-to-use tool for clinicians to assess the dementia risk in individual patients with type 2 diabetes (Lancet Diabetes Endocrinol. 2013;3:183-90). Further study of the risk factors that contribute to dementia onset in patients with type 1 diabetes will hopefully lead to creation of a similar risk-assessment tool for use in type 1 patients, said Dr. Whitmer, an epidemiologist at the Kaiser Permanente Northern California Division of Research in Oakland.

Dr. Whitmer had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

ROME – Baricitinib, a novel biologic drug that selectively inhibits certain janus kinases, showed safety and efficacy for treatment of rheumatoid arthritis in a two separate, multicenter, phase III trials that together involved more than 1,200 adult patients.

One study showed baricitinib’s efficacy for rheumatoid arthritis (RA), compared with placebo, in patients previously treated unsuccessfully with at least one tumor necrosis factor (TNF) inhibitor, while the second trial showed similar outcomes in RA patients never before treated with a TNF inhibitor or with any other biologic drug.

Mitchel L. Zoler/Frontline Medical News

“The safety looks acceptable, and the ACR [American College of Rheumatology] 20, 50, and 70 responses look like it will be effective. It looks like a very promising drug that will be another addition to our armamentarium,” Dr. João Fonseca, professor of rheumatology at the University of Lisbon, said at the European Congress of Rheumatology.

But the data so far did not seem to distinguish baricitinib from a similar Janus kinase inhibitor already on the market in Europe and the United States, tofacitinib (Xeljanz), said Dr. Roy Fleischmann, a Dallas-based rheumatologist. “I’m not sure baricitinib is different from tofacitinib in terms of its clinical effect,” he said in an interview, though he hedged that so far results have been reported from just two of the four phase III trials run to date using baricitinib.

Results in patients with prior TNF inhibitor experience

One of the trials, RA-BEACON, enrolled 527 patients with moderate or severe RA at 103 sites in 21 countries including the United States. Patients had to have been treated with at least one TNF inhibitor and could also have been previously treated with other biologic disease-modifying antirheumatic drugs (DMARDs) with either an inadequate response or intolerance to the treatment. More than half the patients had received treatment with at least two biologic DMARDS, and about a quarter had previously been on at least three. Average age of the enrolled patients was 56 years, about 80% were women, and the average duration of RA was 14 years.

The researchers randomized a third of enrolled patients to receive 2 mg of oral baricitinib once daily, a third received 4 mg baricitinib once daily, and a third received placebo. The study’s primary end point was the percentage of patients who achieved an ACR20 response after 12 weeks of treatment, but patients remained on treatment for 24 weeks.

Mitchel L. Zoler/Frontline Medical News

The primary endpoint occurred in 27% of patients on placebo, 49% of those on the 2-mg dose, and 55% of those on the 4-mg dose, statistically significant differences between placebo and each of the active-treatment arms, said Dr. Mark C. Genovese, professor of immunology and rheumatology at Stanford (Calif.) University. Increased ACR20 responses associated with baricitinib treatment first became discernible, compared with placebo, after 1 week on treatment, and after 4 weeks of treatment the impact of baricitinib treatment began to plateau, Dr. Genovese reported.

A notable secondary endpoint was the incidence of remission as measured by the percentage of patients achieving a disease activity score in 28 joints (DAS28) of less than 2.6. When calculated via C-reactive protein levels, remission occurred in 22% of patients after 24 weeks on the 4-mg daily dosage, compared with 6% of placebo patients. DAS28 calculations that used erythrocyte sedimentation rate showed that the rate of remission after 24 weeks among patients on the higher baricitinib dosage reached 9%, compared with a 3% rate among placebo patients.

The safety and tolerability of baricitinib appeared “satisfactory,” Dr. Genovese said. After 24 weeks, patients on the higher dosage had a 10% rate of serious adverse events, compared with a 7% rate in the placebo patients. The overall rate of serious infections was identical in the 4-mg/day group and the placebo patients; herpes zoster occurred in 4% of patients on the higher dosage after 24 weeks, compared with a 1% rate in the placebo group. The rate of grades 1 and 2 neutropenia were also somewhat elevated in patients on the higher dosage after 24 weeks, with a 7% rate of grade 1 neutropenia and a 4% rate of grade 2.

Results in patients without biologic DMARD experience

The RA-BUILD trial had a design very similar to that of RA-BEACON except it exclusively enrolled patients with no prior treatment with any biologic DMARD. The study enrolled 684 patients at 147 centers in 22 countries including the United States. The primary endpoint of the study, the rate of ACR20 responders after 12 weeks on treatment, occurred in 66% of patients randomized to receive 2 mg oral baricitinib daily, 62% of patients receiving 4 mg daily, and 40% of patients on placebo, reported Dr. Maxime Dougados, professor and chief of rheumatology at Cochin Hospital in Paris. The differences between each of the active-treatment groups and the control group were statistically significant.

Mitchel L. Zoler/Frontline Medical News

The rate of patients achieving remission, measured by a clinical disease activity index of 2.8 or less, occurred in 15% of patients who received 2 mg baricitinib daily after 24 weeks as well as in 15% of patients who received the 4-mg dosage after 24 weeks, compared with a 4% rate among the placebo patients, and the comparisons between each of the active-treatment arms and the control group revealed statistically significant differences.

Dr. Dougados also reported data on rates of radiographic progression after 24 weeks, as measured by the van der Heijde modified Sharp score, which showed that treatment with the 4-mg/day dosage of baricitinib resulted in significant reductions in both erosions and joint space narrowing, compared with placebo patients.

Baricitinib treatment in the RA-BUILD study produced a safety profile similar to that seen in the RA-BEACON trial. Dr. Dougados called the safety and tolerability profiles seen in this study “satisfactory.”

RA-BEACON and RA-BUILD were sponsored by Eli Lilly, the company developing baricitinib. Dr. Genovese disclosed ties with Eli Lilly, AbbVie, Astellas, Galapagos, Pfizer, and Vertex. Dr. Dougados has ties with Eli Lilly, AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fonseca disclosed ties with 12 drug companies. Dr. Fleischmann has ties with many drug companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

ROME – Baricitinib, a novel biologic drug that selectively inhibits certain janus kinases, showed safety and efficacy for treatment of rheumatoid arthritis in a two separate, multicenter, phase III trials that together involved more than 1,200 adult patients.

One study showed baricitinib’s efficacy for rheumatoid arthritis (RA), compared with placebo, in patients previously treated unsuccessfully with at least one tumor necrosis factor (TNF) inhibitor, while the second trial showed similar outcomes in RA patients never before treated with a TNF inhibitor or with any other biologic drug.

Mitchel L. Zoler/Frontline Medical News

“The safety looks acceptable, and the ACR [American College of Rheumatology] 20, 50, and 70 responses look like it will be effective. It looks like a very promising drug that will be another addition to our armamentarium,” Dr. João Fonseca, professor of rheumatology at the University of Lisbon, said at the European Congress of Rheumatology.

But the data so far did not seem to distinguish baricitinib from a similar Janus kinase inhibitor already on the market in Europe and the United States, tofacitinib (Xeljanz), said Dr. Roy Fleischmann, a Dallas-based rheumatologist. “I’m not sure baricitinib is different from tofacitinib in terms of its clinical effect,” he said in an interview, though he hedged that so far results have been reported from just two of the four phase III trials run to date using baricitinib.

Results in patients with prior TNF inhibitor experience

One of the trials, RA-BEACON, enrolled 527 patients with moderate or severe RA at 103 sites in 21 countries including the United States. Patients had to have been treated with at least one TNF inhibitor and could also have been previously treated with other biologic disease-modifying antirheumatic drugs (DMARDs) with either an inadequate response or intolerance to the treatment. More than half the patients had received treatment with at least two biologic DMARDS, and about a quarter had previously been on at least three. Average age of the enrolled patients was 56 years, about 80% were women, and the average duration of RA was 14 years.

The researchers randomized a third of enrolled patients to receive 2 mg of oral baricitinib once daily, a third received 4 mg baricitinib once daily, and a third received placebo. The study’s primary end point was the percentage of patients who achieved an ACR20 response after 12 weeks of treatment, but patients remained on treatment for 24 weeks.

Mitchel L. Zoler/Frontline Medical News

The primary endpoint occurred in 27% of patients on placebo, 49% of those on the 2-mg dose, and 55% of those on the 4-mg dose, statistically significant differences between placebo and each of the active-treatment arms, said Dr. Mark C. Genovese, professor of immunology and rheumatology at Stanford (Calif.) University. Increased ACR20 responses associated with baricitinib treatment first became discernible, compared with placebo, after 1 week on treatment, and after 4 weeks of treatment the impact of baricitinib treatment began to plateau, Dr. Genovese reported.

A notable secondary endpoint was the incidence of remission as measured by the percentage of patients achieving a disease activity score in 28 joints (DAS28) of less than 2.6. When calculated via C-reactive protein levels, remission occurred in 22% of patients after 24 weeks on the 4-mg daily dosage, compared with 6% of placebo patients. DAS28 calculations that used erythrocyte sedimentation rate showed that the rate of remission after 24 weeks among patients on the higher baricitinib dosage reached 9%, compared with a 3% rate among placebo patients.

The safety and tolerability of baricitinib appeared “satisfactory,” Dr. Genovese said. After 24 weeks, patients on the higher dosage had a 10% rate of serious adverse events, compared with a 7% rate in the placebo patients. The overall rate of serious infections was identical in the 4-mg/day group and the placebo patients; herpes zoster occurred in 4% of patients on the higher dosage after 24 weeks, compared with a 1% rate in the placebo group. The rate of grades 1 and 2 neutropenia were also somewhat elevated in patients on the higher dosage after 24 weeks, with a 7% rate of grade 1 neutropenia and a 4% rate of grade 2.

Results in patients without biologic DMARD experience

The RA-BUILD trial had a design very similar to that of RA-BEACON except it exclusively enrolled patients with no prior treatment with any biologic DMARD. The study enrolled 684 patients at 147 centers in 22 countries including the United States. The primary endpoint of the study, the rate of ACR20 responders after 12 weeks on treatment, occurred in 66% of patients randomized to receive 2 mg oral baricitinib daily, 62% of patients receiving 4 mg daily, and 40% of patients on placebo, reported Dr. Maxime Dougados, professor and chief of rheumatology at Cochin Hospital in Paris. The differences between each of the active-treatment groups and the control group were statistically significant.

Mitchel L. Zoler/Frontline Medical News

The rate of patients achieving remission, measured by a clinical disease activity index of 2.8 or less, occurred in 15% of patients who received 2 mg baricitinib daily after 24 weeks as well as in 15% of patients who received the 4-mg dosage after 24 weeks, compared with a 4% rate among the placebo patients, and the comparisons between each of the active-treatment arms and the control group revealed statistically significant differences.

Dr. Dougados also reported data on rates of radiographic progression after 24 weeks, as measured by the van der Heijde modified Sharp score, which showed that treatment with the 4-mg/day dosage of baricitinib resulted in significant reductions in both erosions and joint space narrowing, compared with placebo patients.

Baricitinib treatment in the RA-BUILD study produced a safety profile similar to that seen in the RA-BEACON trial. Dr. Dougados called the safety and tolerability profiles seen in this study “satisfactory.”

RA-BEACON and RA-BUILD were sponsored by Eli Lilly, the company developing baricitinib. Dr. Genovese disclosed ties with Eli Lilly, AbbVie, Astellas, Galapagos, Pfizer, and Vertex. Dr. Dougados has ties with Eli Lilly, AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fonseca disclosed ties with 12 drug companies. Dr. Fleischmann has ties with many drug companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

ROME – Baricitinib, a novel biologic drug that selectively inhibits certain janus kinases, showed safety and efficacy for treatment of rheumatoid arthritis in a two separate, multicenter, phase III trials that together involved more than 1,200 adult patients.

One study showed baricitinib’s efficacy for rheumatoid arthritis (RA), compared with placebo, in patients previously treated unsuccessfully with at least one tumor necrosis factor (TNF) inhibitor, while the second trial showed similar outcomes in RA patients never before treated with a TNF inhibitor or with any other biologic drug.

Mitchel L. Zoler/Frontline Medical News

“The safety looks acceptable, and the ACR [American College of Rheumatology] 20, 50, and 70 responses look like it will be effective. It looks like a very promising drug that will be another addition to our armamentarium,” Dr. João Fonseca, professor of rheumatology at the University of Lisbon, said at the European Congress of Rheumatology.

But the data so far did not seem to distinguish baricitinib from a similar Janus kinase inhibitor already on the market in Europe and the United States, tofacitinib (Xeljanz), said Dr. Roy Fleischmann, a Dallas-based rheumatologist. “I’m not sure baricitinib is different from tofacitinib in terms of its clinical effect,” he said in an interview, though he hedged that so far results have been reported from just two of the four phase III trials run to date using baricitinib.

Results in patients with prior TNF inhibitor experience

One of the trials, RA-BEACON, enrolled 527 patients with moderate or severe RA at 103 sites in 21 countries including the United States. Patients had to have been treated with at least one TNF inhibitor and could also have been previously treated with other biologic disease-modifying antirheumatic drugs (DMARDs) with either an inadequate response or intolerance to the treatment. More than half the patients had received treatment with at least two biologic DMARDS, and about a quarter had previously been on at least three. Average age of the enrolled patients was 56 years, about 80% were women, and the average duration of RA was 14 years.

The researchers randomized a third of enrolled patients to receive 2 mg of oral baricitinib once daily, a third received 4 mg baricitinib once daily, and a third received placebo. The study’s primary end point was the percentage of patients who achieved an ACR20 response after 12 weeks of treatment, but patients remained on treatment for 24 weeks.

Mitchel L. Zoler/Frontline Medical News

The primary endpoint occurred in 27% of patients on placebo, 49% of those on the 2-mg dose, and 55% of those on the 4-mg dose, statistically significant differences between placebo and each of the active-treatment arms, said Dr. Mark C. Genovese, professor of immunology and rheumatology at Stanford (Calif.) University. Increased ACR20 responses associated with baricitinib treatment first became discernible, compared with placebo, after 1 week on treatment, and after 4 weeks of treatment the impact of baricitinib treatment began to plateau, Dr. Genovese reported.

A notable secondary endpoint was the incidence of remission as measured by the percentage of patients achieving a disease activity score in 28 joints (DAS28) of less than 2.6. When calculated via C-reactive protein levels, remission occurred in 22% of patients after 24 weeks on the 4-mg daily dosage, compared with 6% of placebo patients. DAS28 calculations that used erythrocyte sedimentation rate showed that the rate of remission after 24 weeks among patients on the higher baricitinib dosage reached 9%, compared with a 3% rate among placebo patients.

The safety and tolerability of baricitinib appeared “satisfactory,” Dr. Genovese said. After 24 weeks, patients on the higher dosage had a 10% rate of serious adverse events, compared with a 7% rate in the placebo patients. The overall rate of serious infections was identical in the 4-mg/day group and the placebo patients; herpes zoster occurred in 4% of patients on the higher dosage after 24 weeks, compared with a 1% rate in the placebo group. The rate of grades 1 and 2 neutropenia were also somewhat elevated in patients on the higher dosage after 24 weeks, with a 7% rate of grade 1 neutropenia and a 4% rate of grade 2.

Results in patients without biologic DMARD experience

The RA-BUILD trial had a design very similar to that of RA-BEACON except it exclusively enrolled patients with no prior treatment with any biologic DMARD. The study enrolled 684 patients at 147 centers in 22 countries including the United States. The primary endpoint of the study, the rate of ACR20 responders after 12 weeks on treatment, occurred in 66% of patients randomized to receive 2 mg oral baricitinib daily, 62% of patients receiving 4 mg daily, and 40% of patients on placebo, reported Dr. Maxime Dougados, professor and chief of rheumatology at Cochin Hospital in Paris. The differences between each of the active-treatment groups and the control group were statistically significant.

Mitchel L. Zoler/Frontline Medical News

The rate of patients achieving remission, measured by a clinical disease activity index of 2.8 or less, occurred in 15% of patients who received 2 mg baricitinib daily after 24 weeks as well as in 15% of patients who received the 4-mg dosage after 24 weeks, compared with a 4% rate among the placebo patients, and the comparisons between each of the active-treatment arms and the control group revealed statistically significant differences.

Dr. Dougados also reported data on rates of radiographic progression after 24 weeks, as measured by the van der Heijde modified Sharp score, which showed that treatment with the 4-mg/day dosage of baricitinib resulted in significant reductions in both erosions and joint space narrowing, compared with placebo patients.

Baricitinib treatment in the RA-BUILD study produced a safety profile similar to that seen in the RA-BEACON trial. Dr. Dougados called the safety and tolerability profiles seen in this study “satisfactory.”

RA-BEACON and RA-BUILD were sponsored by Eli Lilly, the company developing baricitinib. Dr. Genovese disclosed ties with Eli Lilly, AbbVie, Astellas, Galapagos, Pfizer, and Vertex. Dr. Dougados has ties with Eli Lilly, AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fonseca disclosed ties with 12 drug companies. Dr. Fleischmann has ties with many drug companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The past decade has seen several new classes of biologic drugs approved by the Food and Drug Administration for treating rheumatoid arthritis, but despite this cornucopia the field is in something of a holding pattern. None of the biologic options really stand out from the competition, said Dr. Roy Fleischmann, a Dallas-based rheumatologist with an active practice who has participated in countless new-drug trials over the years.

The best to be said for the wide variety of biologic treatment options available today is that they allow switching from one class to another to find what works best for each individual rheumatoid arthritis patient, Dr. Fleischmann told me when I spoke with him in June at the European Congress of Rheumatology.

“In my practice, I constantly change drugs,” and by doing so and finding what works he gets about half his patients into sustained remission, he said.

But when he looks at the range of biologics available today “it’s pretty clear that it makes no difference what you use. I could use a tumor necrosis factor [TNF] inhibitor, I could use abatacept [Orencia]. I could use tocilizumab [Actemra], Rituxan [rituximab], tofacitinib [Xeljanz]. I can use any of them. I can use them first-line or second-line, and I’ll probably see the same results.”

Rheumatologists in U.S. practice today generally turn to a TNF inhibitor first, but that’s “because of habit,” Dr. Fleischmann said. “They often say they have more experience with the TNF inhibitor,” but the safety of all the biologics approved for rheumatoid arthritis seems generally the same, he said. “The truth is you can use any of them.”

He also discounted the prospect that, someday, biosimilar TNF inhibitors may be on the U.S. market and edge the competition on price, saying that he remains skeptical and cautious about using a biosimilar infliximab or another biosimilar TNF inhibitor. Plus, as of now, no biosimilar suitable for treating rheumatoid arthritis has received U.S. approval.

Among the bio-originals with U.S. approval for rheumatoid arthritis, clinicians could start patients on whichever they want. “I don’t think it makes a difference which bio-original you use,” Dr. Fleischmann said.

Dr. Fleischmann said that he’s consulted for and has received research support from most of the companies that have developed and market biological drugs for rheumatoid arthritis.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The past decade has seen several new classes of biologic drugs approved by the Food and Drug Administration for treating rheumatoid arthritis, but despite this cornucopia the field is in something of a holding pattern. None of the biologic options really stand out from the competition, said Dr. Roy Fleischmann, a Dallas-based rheumatologist with an active practice who has participated in countless new-drug trials over the years.

The best to be said for the wide variety of biologic treatment options available today is that they allow switching from one class to another to find what works best for each individual rheumatoid arthritis patient, Dr. Fleischmann told me when I spoke with him in June at the European Congress of Rheumatology.

“In my practice, I constantly change drugs,” and by doing so and finding what works he gets about half his patients into sustained remission, he said.

But when he looks at the range of biologics available today “it’s pretty clear that it makes no difference what you use. I could use a tumor necrosis factor [TNF] inhibitor, I could use abatacept [Orencia]. I could use tocilizumab [Actemra], Rituxan [rituximab], tofacitinib [Xeljanz]. I can use any of them. I can use them first-line or second-line, and I’ll probably see the same results.”

Rheumatologists in U.S. practice today generally turn to a TNF inhibitor first, but that’s “because of habit,” Dr. Fleischmann said. “They often say they have more experience with the TNF inhibitor,” but the safety of all the biologics approved for rheumatoid arthritis seems generally the same, he said. “The truth is you can use any of them.”

He also discounted the prospect that, someday, biosimilar TNF inhibitors may be on the U.S. market and edge the competition on price, saying that he remains skeptical and cautious about using a biosimilar infliximab or another biosimilar TNF inhibitor. Plus, as of now, no biosimilar suitable for treating rheumatoid arthritis has received U.S. approval.

Among the bio-originals with U.S. approval for rheumatoid arthritis, clinicians could start patients on whichever they want. “I don’t think it makes a difference which bio-original you use,” Dr. Fleischmann said.

Dr. Fleischmann said that he’s consulted for and has received research support from most of the companies that have developed and market biological drugs for rheumatoid arthritis.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The past decade has seen several new classes of biologic drugs approved by the Food and Drug Administration for treating rheumatoid arthritis, but despite this cornucopia the field is in something of a holding pattern. None of the biologic options really stand out from the competition, said Dr. Roy Fleischmann, a Dallas-based rheumatologist with an active practice who has participated in countless new-drug trials over the years.

The best to be said for the wide variety of biologic treatment options available today is that they allow switching from one class to another to find what works best for each individual rheumatoid arthritis patient, Dr. Fleischmann told me when I spoke with him in June at the European Congress of Rheumatology.

“In my practice, I constantly change drugs,” and by doing so and finding what works he gets about half his patients into sustained remission, he said.

But when he looks at the range of biologics available today “it’s pretty clear that it makes no difference what you use. I could use a tumor necrosis factor [TNF] inhibitor, I could use abatacept [Orencia]. I could use tocilizumab [Actemra], Rituxan [rituximab], tofacitinib [Xeljanz]. I can use any of them. I can use them first-line or second-line, and I’ll probably see the same results.”

Rheumatologists in U.S. practice today generally turn to a TNF inhibitor first, but that’s “because of habit,” Dr. Fleischmann said. “They often say they have more experience with the TNF inhibitor,” but the safety of all the biologics approved for rheumatoid arthritis seems generally the same, he said. “The truth is you can use any of them.”

He also discounted the prospect that, someday, biosimilar TNF inhibitors may be on the U.S. market and edge the competition on price, saying that he remains skeptical and cautious about using a biosimilar infliximab or another biosimilar TNF inhibitor. Plus, as of now, no biosimilar suitable for treating rheumatoid arthritis has received U.S. approval.

Among the bio-originals with U.S. approval for rheumatoid arthritis, clinicians could start patients on whichever they want. “I don’t think it makes a difference which bio-original you use,” Dr. Fleischmann said.

Dr. Fleischmann said that he’s consulted for and has received research support from most of the companies that have developed and market biological drugs for rheumatoid arthritis.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

ROME – Tumor necrosis factor inhibitors remain the mainstay of treatment for patients with psoriatic arthritis who don’t fully respond to treatment with a nonsteroidal anti-inflammatory drug and at least one conventional synthetic disease-modifying antirheumatic drug in newly updated treatment recommendations written by a task force of the European League Against Rheumatism.

The revised recommendations for psoriatic arthritis (PsA) replace what EULAR had last released in 2011 and published in 2012 (Ann. Rheum. Dis. 2012;71:4-12) and also add three new drug options not mentioned in the 2011 version that the panel now endorsed as alternatives to a tumor necrosis factor (TNF) inhibitor when a TNF inhibitor is not appropriate. The three additions are ustekinumab (Stelara), which acts by inhibiting interleukin- (IL-)12 and IL-23, secukinumab (Cosentyx), which acts by inhibiting IL-17, and apremilast (Otezla), which inhibits phosphodiesterase-4. Ustekinumab and secukinumab are considered biological disease-modifying antirheumatic drugs (bDMARDs), like the TNF inhibitors, while apremilast occupies a new classification niche as a targeted synthetic DMARD, said Dr. Laure Gossec, convener of the PsA treatment task force, at the European Congress of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

Although ustekinumab, secukinumab, and apremilast all have a role to play in managing selected PsA patients, they all remain second line to TNF inhibitors, stressed Dr. Gossec, professor of rheumatology at Pierre and Marie Curie University in Paris. A TNF inhibitor is the first agent to turn to when treatment with an NSAID and a conventional synthetic DMARD fails to bring about remission or minimal disease activity essentially because of its much longer track record of safety and efficacy, she said. Specifically, TNF inhibitors have been studied long term and have demonstrated their safety in registries, they have not been surpassed for efficacy by any other agent using indirect comparisons, and now that biosimilar TNF inhibitors have entered the market they also could potentially offer a price advantage, compared with newer agents.

But for some patients, TNF inhibitors are not appropriate, such as a patient with certain comorbidities or a history of infections that would make a TNF inhibitor contraindicated, she said. For these patients, one of the other types of biologic DMARDS now available would be the top alternative. In other patients, a comorbidity profile or a history of infections might make any biologic DMARD contraindicated, in which case the targeted synthetic DMARD apremilast is an appropriate alternative, she said.

The revised recommendations contain several other new items:

• For patients with active enthesitis, dactylitis, or both and an insufficient response to an NSAID or local glucocorticoid injections, then a TNF inhibitor or alternatively an IL-12 and IL-23 inhibitor (currently ustekinumab) or an IL-17 inhibitor (currently secukinumab) may be considered. Conventional synthetic DMARDS are ineffective for these patients, while in contrast all of the biologic DMARDs are effective, but the TNF inhibitors have an edge because of greater experience with the class in this setting.

• For patients with predominantly axial disease that is active and insufficiently responsive to NSAID treatment, a biologic DMARD should be considered, specifically a TNF inhibitor. Conventional synthetic DMARDs also have no efficacy for these patients, and few data exist regarding the efficacy of IL-12 and IL-23 inhibitors or IL-17 inhibitors.

• When patients fail to respond adequately to one biologic DMARD, switching to another biologic DMARD should be considered. This could involve switching from one TNF inhibitor to another, as some evidence exists that this could be effective. Alternatively, it could involve switching to a IL-12 and IL-23 inhibitor, an IL-17 inhibitor, or possibly a targeted synthetic DMARD (currently apremilast). The task force did not endorse any particular order of these drugs when switching occurs.

Dr. Gossec has been a consultant to AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Janssen, Novartis, Pfizer, Roche, and UCB.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

ROME – Tumor necrosis factor inhibitors remain the mainstay of treatment for patients with psoriatic arthritis who don’t fully respond to treatment with a nonsteroidal anti-inflammatory drug and at least one conventional synthetic disease-modifying antirheumatic drug in newly updated treatment recommendations written by a task force of the European League Against Rheumatism.

The revised recommendations for psoriatic arthritis (PsA) replace what EULAR had last released in 2011 and published in 2012 (Ann. Rheum. Dis. 2012;71:4-12) and also add three new drug options not mentioned in the 2011 version that the panel now endorsed as alternatives to a tumor necrosis factor (TNF) inhibitor when a TNF inhibitor is not appropriate. The three additions are ustekinumab (Stelara), which acts by inhibiting interleukin- (IL-)12 and IL-23, secukinumab (Cosentyx), which acts by inhibiting IL-17, and apremilast (Otezla), which inhibits phosphodiesterase-4. Ustekinumab and secukinumab are considered biological disease-modifying antirheumatic drugs (bDMARDs), like the TNF inhibitors, while apremilast occupies a new classification niche as a targeted synthetic DMARD, said Dr. Laure Gossec, convener of the PsA treatment task force, at the European Congress of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

Although ustekinumab, secukinumab, and apremilast all have a role to play in managing selected PsA patients, they all remain second line to TNF inhibitors, stressed Dr. Gossec, professor of rheumatology at Pierre and Marie Curie University in Paris. A TNF inhibitor is the first agent to turn to when treatment with an NSAID and a conventional synthetic DMARD fails to bring about remission or minimal disease activity essentially because of its much longer track record of safety and efficacy, she said. Specifically, TNF inhibitors have been studied long term and have demonstrated their safety in registries, they have not been surpassed for efficacy by any other agent using indirect comparisons, and now that biosimilar TNF inhibitors have entered the market they also could potentially offer a price advantage, compared with newer agents.

But for some patients, TNF inhibitors are not appropriate, such as a patient with certain comorbidities or a history of infections that would make a TNF inhibitor contraindicated, she said. For these patients, one of the other types of biologic DMARDS now available would be the top alternative. In other patients, a comorbidity profile or a history of infections might make any biologic DMARD contraindicated, in which case the targeted synthetic DMARD apremilast is an appropriate alternative, she said.

The revised recommendations contain several other new items:

• For patients with active enthesitis, dactylitis, or both and an insufficient response to an NSAID or local glucocorticoid injections, then a TNF inhibitor or alternatively an IL-12 and IL-23 inhibitor (currently ustekinumab) or an IL-17 inhibitor (currently secukinumab) may be considered. Conventional synthetic DMARDS are ineffective for these patients, while in contrast all of the biologic DMARDs are effective, but the TNF inhibitors have an edge because of greater experience with the class in this setting.

• For patients with predominantly axial disease that is active and insufficiently responsive to NSAID treatment, a biologic DMARD should be considered, specifically a TNF inhibitor. Conventional synthetic DMARDs also have no efficacy for these patients, and few data exist regarding the efficacy of IL-12 and IL-23 inhibitors or IL-17 inhibitors.

• When patients fail to respond adequately to one biologic DMARD, switching to another biologic DMARD should be considered. This could involve switching from one TNF inhibitor to another, as some evidence exists that this could be effective. Alternatively, it could involve switching to a IL-12 and IL-23 inhibitor, an IL-17 inhibitor, or possibly a targeted synthetic DMARD (currently apremilast). The task force did not endorse any particular order of these drugs when switching occurs.

Dr. Gossec has been a consultant to AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Janssen, Novartis, Pfizer, Roche, and UCB.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

ROME – Tumor necrosis factor inhibitors remain the mainstay of treatment for patients with psoriatic arthritis who don’t fully respond to treatment with a nonsteroidal anti-inflammatory drug and at least one conventional synthetic disease-modifying antirheumatic drug in newly updated treatment recommendations written by a task force of the European League Against Rheumatism.

The revised recommendations for psoriatic arthritis (PsA) replace what EULAR had last released in 2011 and published in 2012 (Ann. Rheum. Dis. 2012;71:4-12) and also add three new drug options not mentioned in the 2011 version that the panel now endorsed as alternatives to a tumor necrosis factor (TNF) inhibitor when a TNF inhibitor is not appropriate. The three additions are ustekinumab (Stelara), which acts by inhibiting interleukin- (IL-)12 and IL-23, secukinumab (Cosentyx), which acts by inhibiting IL-17, and apremilast (Otezla), which inhibits phosphodiesterase-4. Ustekinumab and secukinumab are considered biological disease-modifying antirheumatic drugs (bDMARDs), like the TNF inhibitors, while apremilast occupies a new classification niche as a targeted synthetic DMARD, said Dr. Laure Gossec, convener of the PsA treatment task force, at the European Congress of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

Although ustekinumab, secukinumab, and apremilast all have a role to play in managing selected PsA patients, they all remain second line to TNF inhibitors, stressed Dr. Gossec, professor of rheumatology at Pierre and Marie Curie University in Paris. A TNF inhibitor is the first agent to turn to when treatment with an NSAID and a conventional synthetic DMARD fails to bring about remission or minimal disease activity essentially because of its much longer track record of safety and efficacy, she said. Specifically, TNF inhibitors have been studied long term and have demonstrated their safety in registries, they have not been surpassed for efficacy by any other agent using indirect comparisons, and now that biosimilar TNF inhibitors have entered the market they also could potentially offer a price advantage, compared with newer agents.

But for some patients, TNF inhibitors are not appropriate, such as a patient with certain comorbidities or a history of infections that would make a TNF inhibitor contraindicated, she said. For these patients, one of the other types of biologic DMARDS now available would be the top alternative. In other patients, a comorbidity profile or a history of infections might make any biologic DMARD contraindicated, in which case the targeted synthetic DMARD apremilast is an appropriate alternative, she said.

The revised recommendations contain several other new items:

• For patients with active enthesitis, dactylitis, or both and an insufficient response to an NSAID or local glucocorticoid injections, then a TNF inhibitor or alternatively an IL-12 and IL-23 inhibitor (currently ustekinumab) or an IL-17 inhibitor (currently secukinumab) may be considered. Conventional synthetic DMARDS are ineffective for these patients, while in contrast all of the biologic DMARDs are effective, but the TNF inhibitors have an edge because of greater experience with the class in this setting.

• For patients with predominantly axial disease that is active and insufficiently responsive to NSAID treatment, a biologic DMARD should be considered, specifically a TNF inhibitor. Conventional synthetic DMARDs also have no efficacy for these patients, and few data exist regarding the efficacy of IL-12 and IL-23 inhibitors or IL-17 inhibitors.

• When patients fail to respond adequately to one biologic DMARD, switching to another biologic DMARD should be considered. This could involve switching from one TNF inhibitor to another, as some evidence exists that this could be effective. Alternatively, it could involve switching to a IL-12 and IL-23 inhibitor, an IL-17 inhibitor, or possibly a targeted synthetic DMARD (currently apremilast). The task force did not endorse any particular order of these drugs when switching occurs.

Dr. Gossec has been a consultant to AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Janssen, Novartis, Pfizer, Roche, and UCB.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

ROME – Obese people had a 50% increased rate of developing rheumatoid arthritis compared with normal or underweight people, in a case-control study of more than 2,000 Swedish residents for which researchers used prospectively collected data.

The increased rate of developing rheumatoid arthritis (RA) conferred by obesity occurred in both women and in men, it was greatest in the subgroup of people who developed RA symptoms when they were age 50 years or younger, and it was greatest in the subgroup of people seropositive for anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), or both Dr. Lotta Ljung said at the European Congress of Rheumatology.

The findings add to the growing body of evidence documenting obesity as a risk factor for development of RA, said Dr. Ljung, a rheumatologist at Umeå (Sweden) University.

She and her associates used data collected in two Swedish population-based cohorts followed prospectively, the Västerbotten Intervention Programme and the Northern Sweden portion of the MONICA project. The two databases included baseline and long-term follow-up data during 1985-2013 from more than 110,000 Swedish citizens, average age 52 years at baseline, and average body mass index of 26 kg/m². The databases included 557 patients with incident RA, which appeared an average of 6 years following entry into their database, with 83% of the cases showing seropositivity for ACPA, RF, or both. The researchers matched these cases on a 3:1 basis with 1,671 controls without RA by their sex, year of birth, cohort, examination year, and region of residence in Sweden.

Mitchel L. Zoler/Frontline Medical News

In an analysis that controlled for both smoking and education level, people who entered one of the databases with a BMI of 30 kg/m² or higher, defined as obesity, had a statistically significant 50% increased rate of developing RA during follow-up, compared with people who entered with a BMI of less than 25 kg/m², which corresponded to normal- or under-weight. Those with a BMI of 25-29.99 kg/m², the overweight group, had a borderline statistically significant 20% increased rate of developing RA during follow-up, compared with the reference group, Dr. Ljung reported.

An analysis that examined the link between incident RA and baseline BMI as a continuous variable showed a 2% increased rate of incident RA for each 1-unit increase in BMI, but this relationship fell short of statistical significance after adjustment for smoking and education level. A second analysis that looked at waist circumference as a continuous variable showed a statistically significant 2% rise in RA incidence for each 1-cm increase in waist circumference at baseline after adjustment.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

*Correction, 7/7/15: An earlier version of this article misstated information in the Vitals section.

ROME – Obese people had a 50% increased rate of developing rheumatoid arthritis compared with normal or underweight people, in a case-control study of more than 2,000 Swedish residents for which researchers used prospectively collected data.

The increased rate of developing rheumatoid arthritis (RA) conferred by obesity occurred in both women and in men, it was greatest in the subgroup of people who developed RA symptoms when they were age 50 years or younger, and it was greatest in the subgroup of people seropositive for anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), or both Dr. Lotta Ljung said at the European Congress of Rheumatology.

The findings add to the growing body of evidence documenting obesity as a risk factor for development of RA, said Dr. Ljung, a rheumatologist at Umeå (Sweden) University.

She and her associates used data collected in two Swedish population-based cohorts followed prospectively, the Västerbotten Intervention Programme and the Northern Sweden portion of the MONICA project. The two databases included baseline and long-term follow-up data during 1985-2013 from more than 110,000 Swedish citizens, average age 52 years at baseline, and average body mass index of 26 kg/m². The databases included 557 patients with incident RA, which appeared an average of 6 years following entry into their database, with 83% of the cases showing seropositivity for ACPA, RF, or both. The researchers matched these cases on a 3:1 basis with 1,671 controls without RA by their sex, year of birth, cohort, examination year, and region of residence in Sweden.

Mitchel L. Zoler/Frontline Medical News

In an analysis that controlled for both smoking and education level, people who entered one of the databases with a BMI of 30 kg/m² or higher, defined as obesity, had a statistically significant 50% increased rate of developing RA during follow-up, compared with people who entered with a BMI of less than 25 kg/m², which corresponded to normal- or under-weight. Those with a BMI of 25-29.99 kg/m², the overweight group, had a borderline statistically significant 20% increased rate of developing RA during follow-up, compared with the reference group, Dr. Ljung reported.

An analysis that examined the link between incident RA and baseline BMI as a continuous variable showed a 2% increased rate of incident RA for each 1-unit increase in BMI, but this relationship fell short of statistical significance after adjustment for smoking and education level. A second analysis that looked at waist circumference as a continuous variable showed a statistically significant 2% rise in RA incidence for each 1-cm increase in waist circumference at baseline after adjustment.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

*Correction, 7/7/15: An earlier version of this article misstated information in the Vitals section.

ROME – Obese people had a 50% increased rate of developing rheumatoid arthritis compared with normal or underweight people, in a case-control study of more than 2,000 Swedish residents for which researchers used prospectively collected data.

The increased rate of developing rheumatoid arthritis (RA) conferred by obesity occurred in both women and in men, it was greatest in the subgroup of people who developed RA symptoms when they were age 50 years or younger, and it was greatest in the subgroup of people seropositive for anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), or both Dr. Lotta Ljung said at the European Congress of Rheumatology.

The findings add to the growing body of evidence documenting obesity as a risk factor for development of RA, said Dr. Ljung, a rheumatologist at Umeå (Sweden) University.

She and her associates used data collected in two Swedish population-based cohorts followed prospectively, the Västerbotten Intervention Programme and the Northern Sweden portion of the MONICA project. The two databases included baseline and long-term follow-up data during 1985-2013 from more than 110,000 Swedish citizens, average age 52 years at baseline, and average body mass index of 26 kg/m². The databases included 557 patients with incident RA, which appeared an average of 6 years following entry into their database, with 83% of the cases showing seropositivity for ACPA, RF, or both. The researchers matched these cases on a 3:1 basis with 1,671 controls without RA by their sex, year of birth, cohort, examination year, and region of residence in Sweden.

Mitchel L. Zoler/Frontline Medical News

In an analysis that controlled for both smoking and education level, people who entered one of the databases with a BMI of 30 kg/m² or higher, defined as obesity, had a statistically significant 50% increased rate of developing RA during follow-up, compared with people who entered with a BMI of less than 25 kg/m², which corresponded to normal- or under-weight. Those with a BMI of 25-29.99 kg/m², the overweight group, had a borderline statistically significant 20% increased rate of developing RA during follow-up, compared with the reference group, Dr. Ljung reported.

An analysis that examined the link between incident RA and baseline BMI as a continuous variable showed a 2% increased rate of incident RA for each 1-unit increase in BMI, but this relationship fell short of statistical significance after adjustment for smoking and education level. A second analysis that looked at waist circumference as a continuous variable showed a statistically significant 2% rise in RA incidence for each 1-cm increase in waist circumference at baseline after adjustment.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

*Correction, 7/7/15: An earlier version of this article misstated information in the Vitals section.

The nature of U.S. transcatheter aortic valve replacement (TAVR) shifted dramatically in mid-June when the Food and Drug Administration, in two separate actions timed just days apart, approved marketing of next-generation models for the only two transcatheter aortic valve replacement systems on the U.S. market.

For inoperable or high-risk patients in came the Edwards Sapien 3 and the CoreValve Evolut R systems, and out went the Sapien XT and the original CoreValve. In the process the transcatheter aortic valve replacement (TAVR) procedures available to American patients on a routine basis became smaller – meaning more likely to use transfemoral approaches, less likely to cause substantial paravalvular leak, less likely to cause stroke, and in the case of the Evolut system also became repositionable and less likely to result in the need for a pacemaker.

With approvals of these two latest-generation devices, in both cases based on follow-up data of only 30 days, “we have really expanded the types of patients who can be treated with TAVR in the U.S., and we can do it with better products and get better outcomes. I am thrilled this technology will be available to patients,” said Dr. Jeffrey J. Popma, a lead investigator for the Evolut U.S. pivotal trial and professor of medicine at Harvard University in Boston.

Mitchel L. Zoler/Frontline Medical News

The pair of approvals were also notable as clear demonstration that the FDA was willing to base its decisions on 30-day follow-up data, a step closer to the approval model it applies to heart valves placed using open surgery. Perhaps most attention-grabbing of all, the FDA based its approval of the Evolut system on data from a total of 151 patients, with 60 coming from the ex-U.S. trial designed to secure a CE mark in Europe, and the other 91 patients the first ones enrolled in what was designed to be the U.S. pivotal trial for Evolut, with a planned enrollment of 250 patients that had almost fully filled by mid-June.

“This was a really good week for the FDA,” said Dr. Popma. “The FDA approved devices with reasonable assurance of safety and efficacy but without the burden of requiring 1 or more years follow-up. We are seeing a changed FDA,” he declared in an interview.

Although the full dataset for all 151 patients that the FDA used to approve the self-expanding Evolut system has not yet been released, investigators from the U.S. trial say data from their first 91 patients looked similar to the 60 patients in the CE trial, the results of which appeared in a poster in March at the annual scientific sessions of the American College of Cardiology.

The CE trial enrolled 60 symptomatic extreme- or high-risk patients at six centers in Australia, New Zealand, and the United Kingdom, who averaged 83 years old and had an average Society of Thoracic Surgeons predicted mortality estimate of 7%. Fifty-nine of the 60 patients (98%) had their TAVR done via the transfemoral route, and during 30-day follow-up no patients died and none had a stroke. The researchers identified a moderate or severe paravalvular leak in 3% of patients after 30 days, and 12% of patients had a new need for a pacemaker. By comparison, in the CoreValve pivotal trial for the first-generation version of this self-expanding valve, death occurred in 3% of patients after 30 days, major strokes in 4%, moderate or severe paravalvular leaks occurred in 9%, and 20% of patients by that point had required placement of a new pacemaker (N. Engl. J. Med. 2014;370:1790-8).

The striking reductions in more severe paravalvular leaks and in the need for a pacemaker likely related at least in part to the ability to reposition the Evolut valve during placement as long as the valve was not more than 80% deployed and as long as retrieval was not attempted more than three times.

Repositioning is “huge” said Dr. Mathew R. Williams, chief of adult cardiac surgery and director of interventional cardiology at New York University, and one of two lead investigators on the U.S. CoreValve Evolut R pivotal trial. “We don’t need to use it most of the time, but having that ability reduces stress and helps make the operator more comfortable,” he said in an interview. The more optimized positioning allowed by the recapture feature likely helped minimize both paravalvular leaks and the valve’s ability to trigger an arrhythmia and need for pacing. In the CE trial the operator used the repositioning function in 15 patients (25%) for a total of 22 repositioning events.

Like Dr. Popma, Dr. Williams welcomed the June 17 approval of the Sapien 3 TAVR system, based on 30-day outcomes from all 583 patients enrolled in the U.S. pivotal trial. Results from that study became public last March in a late-breaker report at the American College of Cardiology meeting.

Mitchel L. Zoler/Frontline Medical News

Sapien 3 treatment of high-risk, symptomatic patients, who averaged 83 years old and had a STS predicted mortality rate of 8.6%, resulted in a 2% mortality rate, a 1.5% stroke rate, a 3% rate of moderate or severe paravalvular leaks, and 13% of patients had a new need for a pacemaker, Dr. Susheel Kodali reported when he presented these data in March. Trial investigators were able to place the Sapien 3 aortic valve via a transfemoral approach in 491 of the 583 patients (84%) enrolled in the study. The adverse outcomes with Sapien 3 contrasted with rates for the prior Sapien XT TAVR system of 3.5% for 30-day mortality, 4.3% for strokes, and a 24% rate of moderate or severe paravalvular leak, said Dr. Kodali, director of the heart valve program at Columbia University in New York.

While the Sapien 3 and Evolut systems appeared to produce roughly similar outcomes for parameters like 30-day mortality, stroke, and paravalvular leak rates, with both systems outperforming what they displaced, the Evolut has two important differences, compared with Sapien 3. First, the Evolut is slightly smaller, with the ability to traverse arteries as narrow as 5 mm, whereas the minimum vessel size for Sapien 3 passage is 5.5 mm; second, Evolute is repositionable, while Sapien 3 is not.

The CoreValve Evolut R trials were sponsored by Medtronic. Dr. Popma has received research grants from and served as a speaker on behalf of Medtronic. He has also been a speaker for Abbott Vascular, Boston Scientific, Covidien, Cook Medical, and Direct Flow Medical and has received research support from five other companies. Dr. Williams has been a consultant to and received research support from Medtronic and has also been a consultant to Edwards and Direct Flow Medical. The Sapien 3 trial was sponsored by Edwards. Dr. Kodali has received research support from Edwards, has an equity interest in Thubrikar Aortic Valve, has received honoraria from St. Jude, and has served on the steering committee for trials sponsored by Claret Medical and Meril.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The nature of U.S. transcatheter aortic valve replacement (TAVR) shifted dramatically in mid-June when the Food and Drug Administration, in two separate actions timed just days apart, approved marketing of next-generation models for the only two transcatheter aortic valve replacement systems on the U.S. market.

For inoperable or high-risk patients in came the Edwards Sapien 3 and the CoreValve Evolut R systems, and out went the Sapien XT and the original CoreValve. In the process the transcatheter aortic valve replacement (TAVR) procedures available to American patients on a routine basis became smaller – meaning more likely to use transfemoral approaches, less likely to cause substantial paravalvular leak, less likely to cause stroke, and in the case of the Evolut system also became repositionable and less likely to result in the need for a pacemaker.

With approvals of these two latest-generation devices, in both cases based on follow-up data of only 30 days, “we have really expanded the types of patients who can be treated with TAVR in the U.S., and we can do it with better products and get better outcomes. I am thrilled this technology will be available to patients,” said Dr. Jeffrey J. Popma, a lead investigator for the Evolut U.S. pivotal trial and professor of medicine at Harvard University in Boston.

Mitchel L. Zoler/Frontline Medical News

The pair of approvals were also notable as clear demonstration that the FDA was willing to base its decisions on 30-day follow-up data, a step closer to the approval model it applies to heart valves placed using open surgery. Perhaps most attention-grabbing of all, the FDA based its approval of the Evolut system on data from a total of 151 patients, with 60 coming from the ex-U.S. trial designed to secure a CE mark in Europe, and the other 91 patients the first ones enrolled in what was designed to be the U.S. pivotal trial for Evolut, with a planned enrollment of 250 patients that had almost fully filled by mid-June.

“This was a really good week for the FDA,” said Dr. Popma. “The FDA approved devices with reasonable assurance of safety and efficacy but without the burden of requiring 1 or more years follow-up. We are seeing a changed FDA,” he declared in an interview.

Although the full dataset for all 151 patients that the FDA used to approve the self-expanding Evolut system has not yet been released, investigators from the U.S. trial say data from their first 91 patients looked similar to the 60 patients in the CE trial, the results of which appeared in a poster in March at the annual scientific sessions of the American College of Cardiology.

The CE trial enrolled 60 symptomatic extreme- or high-risk patients at six centers in Australia, New Zealand, and the United Kingdom, who averaged 83 years old and had an average Society of Thoracic Surgeons predicted mortality estimate of 7%. Fifty-nine of the 60 patients (98%) had their TAVR done via the transfemoral route, and during 30-day follow-up no patients died and none had a stroke. The researchers identified a moderate or severe paravalvular leak in 3% of patients after 30 days, and 12% of patients had a new need for a pacemaker. By comparison, in the CoreValve pivotal trial for the first-generation version of this self-expanding valve, death occurred in 3% of patients after 30 days, major strokes in 4%, moderate or severe paravalvular leaks occurred in 9%, and 20% of patients by that point had required placement of a new pacemaker (N. Engl. J. Med. 2014;370:1790-8).

The striking reductions in more severe paravalvular leaks and in the need for a pacemaker likely related at least in part to the ability to reposition the Evolut valve during placement as long as the valve was not more than 80% deployed and as long as retrieval was not attempted more than three times.

Repositioning is “huge” said Dr. Mathew R. Williams, chief of adult cardiac surgery and director of interventional cardiology at New York University, and one of two lead investigators on the U.S. CoreValve Evolut R pivotal trial. “We don’t need to use it most of the time, but having that ability reduces stress and helps make the operator more comfortable,” he said in an interview. The more optimized positioning allowed by the recapture feature likely helped minimize both paravalvular leaks and the valve’s ability to trigger an arrhythmia and need for pacing. In the CE trial the operator used the repositioning function in 15 patients (25%) for a total of 22 repositioning events.

Like Dr. Popma, Dr. Williams welcomed the June 17 approval of the Sapien 3 TAVR system, based on 30-day outcomes from all 583 patients enrolled in the U.S. pivotal trial. Results from that study became public last March in a late-breaker report at the American College of Cardiology meeting.

Mitchel L. Zoler/Frontline Medical News

Sapien 3 treatment of high-risk, symptomatic patients, who averaged 83 years old and had a STS predicted mortality rate of 8.6%, resulted in a 2% mortality rate, a 1.5% stroke rate, a 3% rate of moderate or severe paravalvular leaks, and 13% of patients had a new need for a pacemaker, Dr. Susheel Kodali reported when he presented these data in March. Trial investigators were able to place the Sapien 3 aortic valve via a transfemoral approach in 491 of the 583 patients (84%) enrolled in the study. The adverse outcomes with Sapien 3 contrasted with rates for the prior Sapien XT TAVR system of 3.5% for 30-day mortality, 4.3% for strokes, and a 24% rate of moderate or severe paravalvular leak, said Dr. Kodali, director of the heart valve program at Columbia University in New York.

While the Sapien 3 and Evolut systems appeared to produce roughly similar outcomes for parameters like 30-day mortality, stroke, and paravalvular leak rates, with both systems outperforming what they displaced, the Evolut has two important differences, compared with Sapien 3. First, the Evolut is slightly smaller, with the ability to traverse arteries as narrow as 5 mm, whereas the minimum vessel size for Sapien 3 passage is 5.5 mm; second, Evolute is repositionable, while Sapien 3 is not.

The CoreValve Evolut R trials were sponsored by Medtronic. Dr. Popma has received research grants from and served as a speaker on behalf of Medtronic. He has also been a speaker for Abbott Vascular, Boston Scientific, Covidien, Cook Medical, and Direct Flow Medical and has received research support from five other companies. Dr. Williams has been a consultant to and received research support from Medtronic and has also been a consultant to Edwards and Direct Flow Medical. The Sapien 3 trial was sponsored by Edwards. Dr. Kodali has received research support from Edwards, has an equity interest in Thubrikar Aortic Valve, has received honoraria from St. Jude, and has served on the steering committee for trials sponsored by Claret Medical and Meril.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The nature of U.S. transcatheter aortic valve replacement (TAVR) shifted dramatically in mid-June when the Food and Drug Administration, in two separate actions timed just days apart, approved marketing of next-generation models for the only two transcatheter aortic valve replacement systems on the U.S. market.

For inoperable or high-risk patients in came the Edwards Sapien 3 and the CoreValve Evolut R systems, and out went the Sapien XT and the original CoreValve. In the process the transcatheter aortic valve replacement (TAVR) procedures available to American patients on a routine basis became smaller – meaning more likely to use transfemoral approaches, less likely to cause substantial paravalvular leak, less likely to cause stroke, and in the case of the Evolut system also became repositionable and less likely to result in the need for a pacemaker.

With approvals of these two latest-generation devices, in both cases based on follow-up data of only 30 days, “we have really expanded the types of patients who can be treated with TAVR in the U.S., and we can do it with better products and get better outcomes. I am thrilled this technology will be available to patients,” said Dr. Jeffrey J. Popma, a lead investigator for the Evolut U.S. pivotal trial and professor of medicine at Harvard University in Boston.

Mitchel L. Zoler/Frontline Medical News

The pair of approvals were also notable as clear demonstration that the FDA was willing to base its decisions on 30-day follow-up data, a step closer to the approval model it applies to heart valves placed using open surgery. Perhaps most attention-grabbing of all, the FDA based its approval of the Evolut system on data from a total of 151 patients, with 60 coming from the ex-U.S. trial designed to secure a CE mark in Europe, and the other 91 patients the first ones enrolled in what was designed to be the U.S. pivotal trial for Evolut, with a planned enrollment of 250 patients that had almost fully filled by mid-June.

“This was a really good week for the FDA,” said Dr. Popma. “The FDA approved devices with reasonable assurance of safety and efficacy but without the burden of requiring 1 or more years follow-up. We are seeing a changed FDA,” he declared in an interview.

Although the full dataset for all 151 patients that the FDA used to approve the self-expanding Evolut system has not yet been released, investigators from the U.S. trial say data from their first 91 patients looked similar to the 60 patients in the CE trial, the results of which appeared in a poster in March at the annual scientific sessions of the American College of Cardiology.

The CE trial enrolled 60 symptomatic extreme- or high-risk patients at six centers in Australia, New Zealand, and the United Kingdom, who averaged 83 years old and had an average Society of Thoracic Surgeons predicted mortality estimate of 7%. Fifty-nine of the 60 patients (98%) had their TAVR done via the transfemoral route, and during 30-day follow-up no patients died and none had a stroke. The researchers identified a moderate or severe paravalvular leak in 3% of patients after 30 days, and 12% of patients had a new need for a pacemaker. By comparison, in the CoreValve pivotal trial for the first-generation version of this self-expanding valve, death occurred in 3% of patients after 30 days, major strokes in 4%, moderate or severe paravalvular leaks occurred in 9%, and 20% of patients by that point had required placement of a new pacemaker (N. Engl. J. Med. 2014;370:1790-8).

The striking reductions in more severe paravalvular leaks and in the need for a pacemaker likely related at least in part to the ability to reposition the Evolut valve during placement as long as the valve was not more than 80% deployed and as long as retrieval was not attempted more than three times.

Repositioning is “huge” said Dr. Mathew R. Williams, chief of adult cardiac surgery and director of interventional cardiology at New York University, and one of two lead investigators on the U.S. CoreValve Evolut R pivotal trial. “We don’t need to use it most of the time, but having that ability reduces stress and helps make the operator more comfortable,” he said in an interview. The more optimized positioning allowed by the recapture feature likely helped minimize both paravalvular leaks and the valve’s ability to trigger an arrhythmia and need for pacing. In the CE trial the operator used the repositioning function in 15 patients (25%) for a total of 22 repositioning events.

Like Dr. Popma, Dr. Williams welcomed the June 17 approval of the Sapien 3 TAVR system, based on 30-day outcomes from all 583 patients enrolled in the U.S. pivotal trial. Results from that study became public last March in a late-breaker report at the American College of Cardiology meeting.

Mitchel L. Zoler/Frontline Medical News

Sapien 3 treatment of high-risk, symptomatic patients, who averaged 83 years old and had a STS predicted mortality rate of 8.6%, resulted in a 2% mortality rate, a 1.5% stroke rate, a 3% rate of moderate or severe paravalvular leaks, and 13% of patients had a new need for a pacemaker, Dr. Susheel Kodali reported when he presented these data in March. Trial investigators were able to place the Sapien 3 aortic valve via a transfemoral approach in 491 of the 583 patients (84%) enrolled in the study. The adverse outcomes with Sapien 3 contrasted with rates for the prior Sapien XT TAVR system of 3.5% for 30-day mortality, 4.3% for strokes, and a 24% rate of moderate or severe paravalvular leak, said Dr. Kodali, director of the heart valve program at Columbia University in New York.

While the Sapien 3 and Evolut systems appeared to produce roughly similar outcomes for parameters like 30-day mortality, stroke, and paravalvular leak rates, with both systems outperforming what they displaced, the Evolut has two important differences, compared with Sapien 3. First, the Evolut is slightly smaller, with the ability to traverse arteries as narrow as 5 mm, whereas the minimum vessel size for Sapien 3 passage is 5.5 mm; second, Evolute is repositionable, while Sapien 3 is not.

The CoreValve Evolut R trials were sponsored by Medtronic. Dr. Popma has received research grants from and served as a speaker on behalf of Medtronic. He has also been a speaker for Abbott Vascular, Boston Scientific, Covidien, Cook Medical, and Direct Flow Medical and has received research support from five other companies. Dr. Williams has been a consultant to and received research support from Medtronic and has also been a consultant to Edwards and Direct Flow Medical. The Sapien 3 trial was sponsored by Edwards. Dr. Kodali has received research support from Edwards, has an equity interest in Thubrikar Aortic Valve, has received honoraria from St. Jude, and has served on the steering committee for trials sponsored by Claret Medical and Meril.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler