CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.

Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.

“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).

Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.

Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.

The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.

All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.

The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m².

A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.

For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).

Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).

A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).

Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.

Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.

Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.

In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.

A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.

In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.

“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.

The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.

koakes@mdedge.com

CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.

Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.

“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).

Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.

Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.

The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.

All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.

The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m².

A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.

For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).

Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).

A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).

Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.

Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.

Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.

In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.

A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.

In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.

“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.

The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.

koakes@mdedge.com

CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.

Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.

“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).

Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.

Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.

The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.

All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.

The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m².

A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.

For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).

Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).

A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).

Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.

Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.

Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.

In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.

A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.

In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.

“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.

The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.

koakes@mdedge.com

ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.

M. Alexander Otto/MDedge News

Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.

About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.

The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.

Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.

The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.

There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.

Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.

In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.

Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.

Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.

The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.

The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”

The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.

Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.

The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.

The National Institutes of Health funded the work. The investigators had no relevant disclosures.

aotto@mdedge.com

SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.

ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.

M. Alexander Otto/MDedge News

Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.

About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.

The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.

Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.

The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.

There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.

Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.

In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.

Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.

Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.

The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.

The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”

The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.

Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.

The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.

The National Institutes of Health funded the work. The investigators had no relevant disclosures.

aotto@mdedge.com

SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.

ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.

M. Alexander Otto/MDedge News

Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.

About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.

The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.

Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.

The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.

There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.

Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.

In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.

Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.

Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.

The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.

The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”

The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.

Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.

The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.

The National Institutes of Health funded the work. The investigators had no relevant disclosures.

aotto@mdedge.com

SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.

To solve our most pressing national health issues, we must start locally, according to a Health Affairs blog post.

“For example, in [Mecklenburg County] North Carolina, African Americans face rates of cardiovascular disease 22% higher than their white counterparts do. To fight this, an organization called Village HeartBEAT joined forces with more than 60 faith-based groups to reach more than 20,000 people – connecting them with health resources to reduce their cardiovascular risk. As a direct result, rates of smoking decreased from 17.4% to 13.9%, and obesity rates fell from 70% to 64.7%.”

Mecklenburg County is a winner of the Healthiest Cities & Counties Challenge, a collaboration between the Aetna Foundation, the American Public Health Association, and the National Association of Counties, which has awarded more than $1.5 million in grants and prizes over the last 2 years.

Reference

1. Graham G, Benjamin G. “Winning Local Solutions to Our Most Pressing Public Health Needs.” Health Affairs. https://www.healthaffairs.org/do/10.1377/hblog20190423.202497/full/. Published April 25, 2019.

To solve our most pressing national health issues, we must start locally, according to a Health Affairs blog post.

“For example, in [Mecklenburg County] North Carolina, African Americans face rates of cardiovascular disease 22% higher than their white counterparts do. To fight this, an organization called Village HeartBEAT joined forces with more than 60 faith-based groups to reach more than 20,000 people – connecting them with health resources to reduce their cardiovascular risk. As a direct result, rates of smoking decreased from 17.4% to 13.9%, and obesity rates fell from 70% to 64.7%.”

Mecklenburg County is a winner of the Healthiest Cities & Counties Challenge, a collaboration between the Aetna Foundation, the American Public Health Association, and the National Association of Counties, which has awarded more than $1.5 million in grants and prizes over the last 2 years.

Reference

1. Graham G, Benjamin G. “Winning Local Solutions to Our Most Pressing Public Health Needs.” Health Affairs. https://www.healthaffairs.org/do/10.1377/hblog20190423.202497/full/. Published April 25, 2019.

To solve our most pressing national health issues, we must start locally, according to a Health Affairs blog post.

“For example, in [Mecklenburg County] North Carolina, African Americans face rates of cardiovascular disease 22% higher than their white counterparts do. To fight this, an organization called Village HeartBEAT joined forces with more than 60 faith-based groups to reach more than 20,000 people – connecting them with health resources to reduce their cardiovascular risk. As a direct result, rates of smoking decreased from 17.4% to 13.9%, and obesity rates fell from 70% to 64.7%.”

Mecklenburg County is a winner of the Healthiest Cities & Counties Challenge, a collaboration between the Aetna Foundation, the American Public Health Association, and the National Association of Counties, which has awarded more than $1.5 million in grants and prizes over the last 2 years.

Reference

1. Graham G, Benjamin G. “Winning Local Solutions to Our Most Pressing Public Health Needs.” Health Affairs. https://www.healthaffairs.org/do/10.1377/hblog20190423.202497/full/. Published April 25, 2019.

The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.

Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.

“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.

To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).

The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.

If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.

The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.

“The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.

Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.

Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.

“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”

The authors reported no relevant conflicts of interest.

SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.

The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.

Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.

“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.

To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).

The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.

If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.

The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.

“The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.

Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.

Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.

“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”

The authors reported no relevant conflicts of interest.

SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.

The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.

Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.

“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.

To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).

The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.

If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.

The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.

“The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.

Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.

Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.

“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”

The authors reported no relevant conflicts of interest.

SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.

ORLANDO – While the benefit of daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) continues to improve with longer follow-up of the GRIFFIN trial, even early adopters may want to wait for additional data before declaring the combination a first-line standard for transplant-eligible multiple myeloma, according to an investigator on the trial.

Andrew D. Bowser/MDedge News

D-RVd has significantly improved both response rates and depth of response, compared with RVd alone, Peter M. Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, N.C., reported at the annual meeting of the American Society of Hematology.

Additionally, rates of response and minimal residual disease (MRD) negativity with D-RVd have increased with longer follow-up beyond posttransplant consolidation, in the ongoing randomized phase 2 trial, Dr. Voorhees said.

“Those of you that are early adopters have good ammunition based on this result, but I would argue that we do need to confirm that the increased MRD-negative rate that we’re seeing translates into a sustained improvement in MRD negativity,” said Dr. Voorhees while presenting the updated results.

Most importantly, it needs to be confirmed that improved depth of response with D-RVd translates into an improvement in progression-free survival, not only in GRIFFIN, he said, but in PERSEUS, a large, randomized European phase 3 trial of subcutaneous daratumumab plus RVd versus RVd alone.

In the GRIFFIN trial, a total of 207 patients with transplant-eligible newly diagnosed multiple myeloma were randomized to intravenous daratumumab plus RVd versus RVd alone, with a primary endpoint of stringent complete response (sCR) by the end of consolidation.

Primary findings, presented in September at the 17th International Myeloma Workshop (IMW) meeting in Boston, indicated an sCR of 42.4% for D-RVd versus 32.0% for RVd at a median follow-up of 13.5 months, a difference that Dr. Voorhees said was statistically significant as defined by the protocol (1-sided P = .068), with an odds ratio of 1.57 (95% confidence interval, 0.87-2.82) in favor of the D-RVd arm.

With longer follow-up data, which Dr. Voorhees reported at ASH, the responses have “deepened over time” in both arms of the study, though he said the daratumumab arm continues to perform better. The sCR with 22.1 months of follow-up was 62.6% for D-RVd versus 45.4% for RVd.

The rates of MRD negativity at this clinical cutoff were 51.0% versus 20.4% for the D-RVd and RVd arms, respectively (P less than .0001), while the 24-month PFS rates were 95.8% for D-RVd and 89.8% for RVd. “Suffice it to say that both groups of patients are doing incredibly well at 2 years,” Dr. Voorhees said.

Rates of grade 3 and 4 neutropenia and thrombocytopenia were higher in the D-RVd arm, and there were more infections, though this was largely driven by an increased incidence of grade 1 or 2 upper respiratory tract infections, according to Dr. Voorhees.

Daratumumab did not impact time to engraftment, with a median CD34+ cell yield of 8.2 x 10⁶ cells/kg for D-RVd and 9.4 x 10⁶ cells/kg for RVd, a difference that Dr. Voorhees said was “not of clinical significance.”

Dr. Voorhees reported disclosures related to Takeda, Oncopeptides, Novartis, GSK, Janssen, Celgene, BMS, Adaptive Biotechnologies, Amgen, and TeneBio.

SOURCE: Voorhees PM et al. ASH 2019, Abstract 691.

ORLANDO – While the benefit of daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) continues to improve with longer follow-up of the GRIFFIN trial, even early adopters may want to wait for additional data before declaring the combination a first-line standard for transplant-eligible multiple myeloma, according to an investigator on the trial.

Andrew D. Bowser/MDedge News

D-RVd has significantly improved both response rates and depth of response, compared with RVd alone, Peter M. Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, N.C., reported at the annual meeting of the American Society of Hematology.

Additionally, rates of response and minimal residual disease (MRD) negativity with D-RVd have increased with longer follow-up beyond posttransplant consolidation, in the ongoing randomized phase 2 trial, Dr. Voorhees said.

“Those of you that are early adopters have good ammunition based on this result, but I would argue that we do need to confirm that the increased MRD-negative rate that we’re seeing translates into a sustained improvement in MRD negativity,” said Dr. Voorhees while presenting the updated results.

Most importantly, it needs to be confirmed that improved depth of response with D-RVd translates into an improvement in progression-free survival, not only in GRIFFIN, he said, but in PERSEUS, a large, randomized European phase 3 trial of subcutaneous daratumumab plus RVd versus RVd alone.

In the GRIFFIN trial, a total of 207 patients with transplant-eligible newly diagnosed multiple myeloma were randomized to intravenous daratumumab plus RVd versus RVd alone, with a primary endpoint of stringent complete response (sCR) by the end of consolidation.

Primary findings, presented in September at the 17th International Myeloma Workshop (IMW) meeting in Boston, indicated an sCR of 42.4% for D-RVd versus 32.0% for RVd at a median follow-up of 13.5 months, a difference that Dr. Voorhees said was statistically significant as defined by the protocol (1-sided P = .068), with an odds ratio of 1.57 (95% confidence interval, 0.87-2.82) in favor of the D-RVd arm.

With longer follow-up data, which Dr. Voorhees reported at ASH, the responses have “deepened over time” in both arms of the study, though he said the daratumumab arm continues to perform better. The sCR with 22.1 months of follow-up was 62.6% for D-RVd versus 45.4% for RVd.

The rates of MRD negativity at this clinical cutoff were 51.0% versus 20.4% for the D-RVd and RVd arms, respectively (P less than .0001), while the 24-month PFS rates were 95.8% for D-RVd and 89.8% for RVd. “Suffice it to say that both groups of patients are doing incredibly well at 2 years,” Dr. Voorhees said.

Rates of grade 3 and 4 neutropenia and thrombocytopenia were higher in the D-RVd arm, and there were more infections, though this was largely driven by an increased incidence of grade 1 or 2 upper respiratory tract infections, according to Dr. Voorhees.

Daratumumab did not impact time to engraftment, with a median CD34+ cell yield of 8.2 x 10⁶ cells/kg for D-RVd and 9.4 x 10⁶ cells/kg for RVd, a difference that Dr. Voorhees said was “not of clinical significance.”

Dr. Voorhees reported disclosures related to Takeda, Oncopeptides, Novartis, GSK, Janssen, Celgene, BMS, Adaptive Biotechnologies, Amgen, and TeneBio.

SOURCE: Voorhees PM et al. ASH 2019, Abstract 691.

ORLANDO – While the benefit of daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) continues to improve with longer follow-up of the GRIFFIN trial, even early adopters may want to wait for additional data before declaring the combination a first-line standard for transplant-eligible multiple myeloma, according to an investigator on the trial.

Andrew D. Bowser/MDedge News

D-RVd has significantly improved both response rates and depth of response, compared with RVd alone, Peter M. Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, N.C., reported at the annual meeting of the American Society of Hematology.

Additionally, rates of response and minimal residual disease (MRD) negativity with D-RVd have increased with longer follow-up beyond posttransplant consolidation, in the ongoing randomized phase 2 trial, Dr. Voorhees said.

“Those of you that are early adopters have good ammunition based on this result, but I would argue that we do need to confirm that the increased MRD-negative rate that we’re seeing translates into a sustained improvement in MRD negativity,” said Dr. Voorhees while presenting the updated results.

Most importantly, it needs to be confirmed that improved depth of response with D-RVd translates into an improvement in progression-free survival, not only in GRIFFIN, he said, but in PERSEUS, a large, randomized European phase 3 trial of subcutaneous daratumumab plus RVd versus RVd alone.

In the GRIFFIN trial, a total of 207 patients with transplant-eligible newly diagnosed multiple myeloma were randomized to intravenous daratumumab plus RVd versus RVd alone, with a primary endpoint of stringent complete response (sCR) by the end of consolidation.

Primary findings, presented in September at the 17th International Myeloma Workshop (IMW) meeting in Boston, indicated an sCR of 42.4% for D-RVd versus 32.0% for RVd at a median follow-up of 13.5 months, a difference that Dr. Voorhees said was statistically significant as defined by the protocol (1-sided P = .068), with an odds ratio of 1.57 (95% confidence interval, 0.87-2.82) in favor of the D-RVd arm.

With longer follow-up data, which Dr. Voorhees reported at ASH, the responses have “deepened over time” in both arms of the study, though he said the daratumumab arm continues to perform better. The sCR with 22.1 months of follow-up was 62.6% for D-RVd versus 45.4% for RVd.

The rates of MRD negativity at this clinical cutoff were 51.0% versus 20.4% for the D-RVd and RVd arms, respectively (P less than .0001), while the 24-month PFS rates were 95.8% for D-RVd and 89.8% for RVd. “Suffice it to say that both groups of patients are doing incredibly well at 2 years,” Dr. Voorhees said.

Rates of grade 3 and 4 neutropenia and thrombocytopenia were higher in the D-RVd arm, and there were more infections, though this was largely driven by an increased incidence of grade 1 or 2 upper respiratory tract infections, according to Dr. Voorhees.

Daratumumab did not impact time to engraftment, with a median CD34+ cell yield of 8.2 x 10⁶ cells/kg for D-RVd and 9.4 x 10⁶ cells/kg for RVd, a difference that Dr. Voorhees said was “not of clinical significance.”

Dr. Voorhees reported disclosures related to Takeda, Oncopeptides, Novartis, GSK, Janssen, Celgene, BMS, Adaptive Biotechnologies, Amgen, and TeneBio.

SOURCE: Voorhees PM et al. ASH 2019, Abstract 691.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

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“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

The Food and Drug Administration has approved enzalutamide (Xtandi) for patients with metastatic castration-sensitive prostate cancer (mCSPC).

The drug was previously approved for patients with castration-resistant prostate cancer.

Approval was based on radiographic progression-free survival (rPFS) improvement in ARCHES, a trial of 1,150 patients with mCSPC randomized to receive either enzalutamide or placebo daily. All patients received a gonadotropin-releasing hormone analogue or had a prior bilateral orchiectomy.

Median rPFS was not reached in the enzalutamide, arm compared with 19.4 months (95% confidence interval, 16.6 to not reached) in the placebo arm (HR 0.39; 95% CI, 0.30-0.50; P less than .0001), the FDA said in a statement.

The most common adverse reactions in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.

The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily with or without food, the FDA said.

lnikolaides@mdedge.com





 

The Food and Drug Administration has approved enzalutamide (Xtandi) for patients with metastatic castration-sensitive prostate cancer (mCSPC).

The drug was previously approved for patients with castration-resistant prostate cancer.

Approval was based on radiographic progression-free survival (rPFS) improvement in ARCHES, a trial of 1,150 patients with mCSPC randomized to receive either enzalutamide or placebo daily. All patients received a gonadotropin-releasing hormone analogue or had a prior bilateral orchiectomy.

Median rPFS was not reached in the enzalutamide, arm compared with 19.4 months (95% confidence interval, 16.6 to not reached) in the placebo arm (HR 0.39; 95% CI, 0.30-0.50; P less than .0001), the FDA said in a statement.

The most common adverse reactions in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.

The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily with or without food, the FDA said.

lnikolaides@mdedge.com





 

The Food and Drug Administration has approved enzalutamide (Xtandi) for patients with metastatic castration-sensitive prostate cancer (mCSPC).

The drug was previously approved for patients with castration-resistant prostate cancer.

Approval was based on radiographic progression-free survival (rPFS) improvement in ARCHES, a trial of 1,150 patients with mCSPC randomized to receive either enzalutamide or placebo daily. All patients received a gonadotropin-releasing hormone analogue or had a prior bilateral orchiectomy.

Median rPFS was not reached in the enzalutamide, arm compared with 19.4 months (95% confidence interval, 16.6 to not reached) in the placebo arm (HR 0.39; 95% CI, 0.30-0.50; P less than .0001), the FDA said in a statement.

The most common adverse reactions in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.

The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily with or without food, the FDA said.

lnikolaides@mdedge.com





 

PHILADELPHIA – Use of the Impella ventricular-assist device in patients with cardiogenic shock having percutaneous coronary interventions (PCI) has increased rapidly since its approval in 2008, but two studies comparing it with intra-aortic balloon pumps in PCI patients have raised questions about the safety, effectiveness, and cost of the ventricular-assist device, according to results of two studies presented at the American Heart Association scientific sessions.

The results of an observational analysis of 48,306 patients and a national real-world study of 28,304 patients may not be telling the complete story of the utility of ventricular assist in patients requiring mechanical circulatory support (MCS), one interventional cardiologist said in an interview. “It’s concerning; it’s sobering,” said Ranya N. Sweis, MD, of Northwestern University, Chicago. However, the data didn’t parse out patients who would have been routed to palliative care and otherwise wouldn’t have been candidates for PCI without MCS.

“What I take from it is that we need to get more randomized data,” she said. “Who are the patients that were doing worse? Who are the patients who really needed the Impella support for the PCI after cardiogenic shock?”

In the observational study, Amit P. Amin, MD, of Washington University, St. Louis, said that the use of MCS devices increased steadily to 32% of all PCI patients receiving MCS from 2008 to 2016 while use of intra-aortic balloon pump (IABP) declined, but that Impella was less likely to be used in critically ill patients. The study analyzed patients in the Premier Healthcare Database who had PCI with MCS at 432 hospitals from 2004 to 2016.

Outcomes in what Dr. Amin called “the Impella era,” showed significantly higher risks for death, acute kidney injury, and stroke, with odds ratios of 1.17, 1.91 and 3.34, respectively (P less than .001 for all). In the patient-level comparison of Impella versus IABP, Impella had a 24% higher risk of death (P less than .0001), 10% for bleeding (P = .0445), 8% for acute kidney injury (P = .0521) and 34% for stroke (P less than .0001). The findings were published simultaneously with the presentation (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044007)

“The total length of stay, as well as the ICU length of stay, were actually lower with Impella use, by approximately a half day to 1 day,” Dr. Amin said. “Despite that, the total costs were approximately $15,000.”

Yet, the study found wide variation in the use of Impella among hospitals, some doing no cases with the device and others all of them, Dr. Amin said. The risk analysis also found wide variations in outcomes across hospitals using Impella. “We saw a 2.5-fold variation in bleeding across hospitals and a 1.5-fold variation in acute kidney injury, stroke and death,” he noted. The study found less variation in hospital stays and total cost of Impella, “perhaps related to the uniformly high device acquisition costs.”

“These data underscore the need for defining the appropriate use of mechanical circulatory support in patients undergoing PCI,” Dr. Amin said.

Dr. Sweis wasn’t surprised by the cost findings. “New technology is going to cost more,” she said in an interview. “I’m actually surprised that the cost wasn’t more significantly different just knowing the cost of some of these devices.

Patients who require MCS represent a small portion of PCI cases: 2%, according to Dr. Sweis. “It’s not like all PCI has increased because of MCS, and there’s a potential improvement in the length of stay so there are going to be cost savings that way.”

The national real-world study that Sanket S. Dhruva, MD, MHS, of the University of California San Francisco, reported on focused on Impella and IABP in PCI patients with acute MI complicated by cardiogenic shock (CS). The study used outcomes of patients with AMI-CS who had PCI from October 2015 to December 2017 in the National Cardiovascular Data Registry’s CathPCI and Chest Pain–MI registries. An estimated 4%-12% of AMIs present with CS.

Most patients in the study population had medical therapy only, but this study focused on the 1,768 who had Impella only and the 8,471 who had IABP only. The rates of in-hospital death and bleeding were 34.1% 16% in the IABP group, and 45% and 31.3% in the Impella group, Dr. Dhruva said. In this study population, the rate of Impella use increased from 3.5% in 2015 to 8.7% by the end of 2017 (P less than .001).

Dr. Dhruva acknowledged a number of limitations to the study findings, including residual confounding. However, the “robust propensity match” of 95% of the Impella-only patients and the results were consistent across multiple sensitivity analyses. “There may have been questions about the clinical severity of AMI-CS patients in the NCDR Registry,” he said. “However, the registry definition is similar to that used in the trials.”

The trial also failed to distinguish between the different types of Impella devices, but the results mostly pertain to the Impella 2.5 and CP because the 5.0 device requires a surgical cutdown, and the study excluded patients who received multiple devices.

“Better evidence and guidance are needed regarding the optimal management of patients with AMI-CS as well as the role of mechanical circulatory support devices in general and Impella in particular,” he said, adding that Impella has been on the U.S. market since 2008, but with limited randomized clinical trial evidence in cardiogenic shock.

The study population of patient’s with CS is “only a piece of the puzzle,” Dr. Sweis said. “We know that there are sick hearts that aren’t in shock right now, but you’re going to do triple-vessel intervention and use atherectomy. Those patients would not do very well during the procedure itself and it may not even be offered to them if there weren’t support.”

Impella is not going away, Dr. Sweis said. “It provides an option that a patient wouldn’t otherwise have. This is really stressing to me that we need to get rid of that variability in the safety related to these devices.”

Dr. Amin disclosed financial relationships with Terumo and GE Healthcare. Dr. Dhruva had no financial relationships to disclose. The study was supported in part by a Center of Excellence in Regulatory Science and Innovation grant from the Food and Drug Administration and the American College of Cardiology’s National Cardiovascular Data Registry.

PHILADELPHIA – Use of the Impella ventricular-assist device in patients with cardiogenic shock having percutaneous coronary interventions (PCI) has increased rapidly since its approval in 2008, but two studies comparing it with intra-aortic balloon pumps in PCI patients have raised questions about the safety, effectiveness, and cost of the ventricular-assist device, according to results of two studies presented at the American Heart Association scientific sessions.

The results of an observational analysis of 48,306 patients and a national real-world study of 28,304 patients may not be telling the complete story of the utility of ventricular assist in patients requiring mechanical circulatory support (MCS), one interventional cardiologist said in an interview. “It’s concerning; it’s sobering,” said Ranya N. Sweis, MD, of Northwestern University, Chicago. However, the data didn’t parse out patients who would have been routed to palliative care and otherwise wouldn’t have been candidates for PCI without MCS.

“What I take from it is that we need to get more randomized data,” she said. “Who are the patients that were doing worse? Who are the patients who really needed the Impella support for the PCI after cardiogenic shock?”

In the observational study, Amit P. Amin, MD, of Washington University, St. Louis, said that the use of MCS devices increased steadily to 32% of all PCI patients receiving MCS from 2008 to 2016 while use of intra-aortic balloon pump (IABP) declined, but that Impella was less likely to be used in critically ill patients. The study analyzed patients in the Premier Healthcare Database who had PCI with MCS at 432 hospitals from 2004 to 2016.

Outcomes in what Dr. Amin called “the Impella era,” showed significantly higher risks for death, acute kidney injury, and stroke, with odds ratios of 1.17, 1.91 and 3.34, respectively (P less than .001 for all). In the patient-level comparison of Impella versus IABP, Impella had a 24% higher risk of death (P less than .0001), 10% for bleeding (P = .0445), 8% for acute kidney injury (P = .0521) and 34% for stroke (P less than .0001). The findings were published simultaneously with the presentation (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044007)

“The total length of stay, as well as the ICU length of stay, were actually lower with Impella use, by approximately a half day to 1 day,” Dr. Amin said. “Despite that, the total costs were approximately $15,000.”

Yet, the study found wide variation in the use of Impella among hospitals, some doing no cases with the device and others all of them, Dr. Amin said. The risk analysis also found wide variations in outcomes across hospitals using Impella. “We saw a 2.5-fold variation in bleeding across hospitals and a 1.5-fold variation in acute kidney injury, stroke and death,” he noted. The study found less variation in hospital stays and total cost of Impella, “perhaps related to the uniformly high device acquisition costs.”

“These data underscore the need for defining the appropriate use of mechanical circulatory support in patients undergoing PCI,” Dr. Amin said.

Dr. Sweis wasn’t surprised by the cost findings. “New technology is going to cost more,” she said in an interview. “I’m actually surprised that the cost wasn’t more significantly different just knowing the cost of some of these devices.

Patients who require MCS represent a small portion of PCI cases: 2%, according to Dr. Sweis. “It’s not like all PCI has increased because of MCS, and there’s a potential improvement in the length of stay so there are going to be cost savings that way.”

The national real-world study that Sanket S. Dhruva, MD, MHS, of the University of California San Francisco, reported on focused on Impella and IABP in PCI patients with acute MI complicated by cardiogenic shock (CS). The study used outcomes of patients with AMI-CS who had PCI from October 2015 to December 2017 in the National Cardiovascular Data Registry’s CathPCI and Chest Pain–MI registries. An estimated 4%-12% of AMIs present with CS.

Most patients in the study population had medical therapy only, but this study focused on the 1,768 who had Impella only and the 8,471 who had IABP only. The rates of in-hospital death and bleeding were 34.1% 16% in the IABP group, and 45% and 31.3% in the Impella group, Dr. Dhruva said. In this study population, the rate of Impella use increased from 3.5% in 2015 to 8.7% by the end of 2017 (P less than .001).

Dr. Dhruva acknowledged a number of limitations to the study findings, including residual confounding. However, the “robust propensity match” of 95% of the Impella-only patients and the results were consistent across multiple sensitivity analyses. “There may have been questions about the clinical severity of AMI-CS patients in the NCDR Registry,” he said. “However, the registry definition is similar to that used in the trials.”

The trial also failed to distinguish between the different types of Impella devices, but the results mostly pertain to the Impella 2.5 and CP because the 5.0 device requires a surgical cutdown, and the study excluded patients who received multiple devices.

“Better evidence and guidance are needed regarding the optimal management of patients with AMI-CS as well as the role of mechanical circulatory support devices in general and Impella in particular,” he said, adding that Impella has been on the U.S. market since 2008, but with limited randomized clinical trial evidence in cardiogenic shock.

The study population of patient’s with CS is “only a piece of the puzzle,” Dr. Sweis said. “We know that there are sick hearts that aren’t in shock right now, but you’re going to do triple-vessel intervention and use atherectomy. Those patients would not do very well during the procedure itself and it may not even be offered to them if there weren’t support.”

Impella is not going away, Dr. Sweis said. “It provides an option that a patient wouldn’t otherwise have. This is really stressing to me that we need to get rid of that variability in the safety related to these devices.”

Dr. Amin disclosed financial relationships with Terumo and GE Healthcare. Dr. Dhruva had no financial relationships to disclose. The study was supported in part by a Center of Excellence in Regulatory Science and Innovation grant from the Food and Drug Administration and the American College of Cardiology’s National Cardiovascular Data Registry.

PHILADELPHIA – Use of the Impella ventricular-assist device in patients with cardiogenic shock having percutaneous coronary interventions (PCI) has increased rapidly since its approval in 2008, but two studies comparing it with intra-aortic balloon pumps in PCI patients have raised questions about the safety, effectiveness, and cost of the ventricular-assist device, according to results of two studies presented at the American Heart Association scientific sessions.

The results of an observational analysis of 48,306 patients and a national real-world study of 28,304 patients may not be telling the complete story of the utility of ventricular assist in patients requiring mechanical circulatory support (MCS), one interventional cardiologist said in an interview. “It’s concerning; it’s sobering,” said Ranya N. Sweis, MD, of Northwestern University, Chicago. However, the data didn’t parse out patients who would have been routed to palliative care and otherwise wouldn’t have been candidates for PCI without MCS.

“What I take from it is that we need to get more randomized data,” she said. “Who are the patients that were doing worse? Who are the patients who really needed the Impella support for the PCI after cardiogenic shock?”

In the observational study, Amit P. Amin, MD, of Washington University, St. Louis, said that the use of MCS devices increased steadily to 32% of all PCI patients receiving MCS from 2008 to 2016 while use of intra-aortic balloon pump (IABP) declined, but that Impella was less likely to be used in critically ill patients. The study analyzed patients in the Premier Healthcare Database who had PCI with MCS at 432 hospitals from 2004 to 2016.

Outcomes in what Dr. Amin called “the Impella era,” showed significantly higher risks for death, acute kidney injury, and stroke, with odds ratios of 1.17, 1.91 and 3.34, respectively (P less than .001 for all). In the patient-level comparison of Impella versus IABP, Impella had a 24% higher risk of death (P less than .0001), 10% for bleeding (P = .0445), 8% for acute kidney injury (P = .0521) and 34% for stroke (P less than .0001). The findings were published simultaneously with the presentation (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044007)

“The total length of stay, as well as the ICU length of stay, were actually lower with Impella use, by approximately a half day to 1 day,” Dr. Amin said. “Despite that, the total costs were approximately $15,000.”

Yet, the study found wide variation in the use of Impella among hospitals, some doing no cases with the device and others all of them, Dr. Amin said. The risk analysis also found wide variations in outcomes across hospitals using Impella. “We saw a 2.5-fold variation in bleeding across hospitals and a 1.5-fold variation in acute kidney injury, stroke and death,” he noted. The study found less variation in hospital stays and total cost of Impella, “perhaps related to the uniformly high device acquisition costs.”

“These data underscore the need for defining the appropriate use of mechanical circulatory support in patients undergoing PCI,” Dr. Amin said.

Dr. Sweis wasn’t surprised by the cost findings. “New technology is going to cost more,” she said in an interview. “I’m actually surprised that the cost wasn’t more significantly different just knowing the cost of some of these devices.

Patients who require MCS represent a small portion of PCI cases: 2%, according to Dr. Sweis. “It’s not like all PCI has increased because of MCS, and there’s a potential improvement in the length of stay so there are going to be cost savings that way.”

The national real-world study that Sanket S. Dhruva, MD, MHS, of the University of California San Francisco, reported on focused on Impella and IABP in PCI patients with acute MI complicated by cardiogenic shock (CS). The study used outcomes of patients with AMI-CS who had PCI from October 2015 to December 2017 in the National Cardiovascular Data Registry’s CathPCI and Chest Pain–MI registries. An estimated 4%-12% of AMIs present with CS.

Most patients in the study population had medical therapy only, but this study focused on the 1,768 who had Impella only and the 8,471 who had IABP only. The rates of in-hospital death and bleeding were 34.1% 16% in the IABP group, and 45% and 31.3% in the Impella group, Dr. Dhruva said. In this study population, the rate of Impella use increased from 3.5% in 2015 to 8.7% by the end of 2017 (P less than .001).

Dr. Dhruva acknowledged a number of limitations to the study findings, including residual confounding. However, the “robust propensity match” of 95% of the Impella-only patients and the results were consistent across multiple sensitivity analyses. “There may have been questions about the clinical severity of AMI-CS patients in the NCDR Registry,” he said. “However, the registry definition is similar to that used in the trials.”

The trial also failed to distinguish between the different types of Impella devices, but the results mostly pertain to the Impella 2.5 and CP because the 5.0 device requires a surgical cutdown, and the study excluded patients who received multiple devices.

“Better evidence and guidance are needed regarding the optimal management of patients with AMI-CS as well as the role of mechanical circulatory support devices in general and Impella in particular,” he said, adding that Impella has been on the U.S. market since 2008, but with limited randomized clinical trial evidence in cardiogenic shock.

The study population of patient’s with CS is “only a piece of the puzzle,” Dr. Sweis said. “We know that there are sick hearts that aren’t in shock right now, but you’re going to do triple-vessel intervention and use atherectomy. Those patients would not do very well during the procedure itself and it may not even be offered to them if there weren’t support.”

Impella is not going away, Dr. Sweis said. “It provides an option that a patient wouldn’t otherwise have. This is really stressing to me that we need to get rid of that variability in the safety related to these devices.”

Dr. Amin disclosed financial relationships with Terumo and GE Healthcare. Dr. Dhruva had no financial relationships to disclose. The study was supported in part by a Center of Excellence in Regulatory Science and Innovation grant from the Food and Drug Administration and the American College of Cardiology’s National Cardiovascular Data Registry.

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

dbrunk@mdedge.com

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

dbrunk@mdedge.com

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

dbrunk@mdedge.com

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

jremaly@mdedge.com

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

jremaly@mdedge.com

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

jremaly@mdedge.com