Layla Richards, the first

person treated with UCART19

Photo courtesy of GOSH

A hospital in the UK has reported success with the first-in-human use of an allogeneic chimeric antigen receptor (CAR) T-cell treatment.

The therapy, UCART19, helped treat an aggressive case of acute lymphoblastic leukemia (ALL) in an infant named Layla Richards.

Chemotherapy, a first transplant, and blinatumomab all failed to treat Layla’s disease. But UCART19 provided a bridge to a second transplant, and Layla

is now free of leukemia.

“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Waseem Qasim, MBBS, PhD, a professor at University College London’s Institute of Child Health and a consultant immunologist at Great Ormond Street Hospital (GOSH) in London, where Layla was treated.

“But this is a landmark in the use of new gene-engineering technology, and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukemia and other cancers.”

Layla’s history

Layla was born in June 2014 and, at 14 weeks old, was diagnosed with CD19+ ALL (t[11;19] rearrangement). Doctors at GOSH described her leukemia as “one of the most aggressive forms of the disease we have ever seen.”

Layla underwent several rounds of chemotherapy at GOSH and then received a transplant from a mismatched, unrelated donor. Seven weeks later, her leukemia had returned.

A second round of chemotherapy wasn’t an option, so Layla went on to receive blinatumomab. This, too, ultimately failed.

Layla’s family was unwilling to accept palliative care, so her doctors mentioned the possibility of using UCART19.

“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new UCART19 cells?’” Dr Qasim said.

“The treatment was highly experimental, and we had to get special permissions, but she appeared ideally suited for this type of approach.”

UCART19 treatment

Before Layla received UCART19, investigators from GOSH, University College London, and the biotech company Cellectis had been developing off-the-shelf banks of the cells for use in clinical trials.

UCART19 consists of donor T cells modified using transcription activator-like effector nucleases (TALEN). Like some other CAR T-cell products, UCART19 is designed to target CD19+ cancer cells.

But UCART19 cells are also programmed to be insensitive to alemtuzumab. That way, a patient can receive the drug to prevent rejection of HLA-mismatched cells.

Before receiving UCART19, Layla was given vincristine, dexamethasone, and asparaginase, followed by fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose (4.5 x 10⁶/kg) of UCART19.

After this, Layla spent several months in isolation to protect her from infections while her immune system was extremely weak. Within weeks of receiving UCART19, Layla demonstrated an immune response in the form of a rash.

The rash worsened, but, aside from that, Layla appeared to be well. To date, she has shown no signs of cytokine release syndrome.

She did, however, show signs of molecular and cytogenetic remission. Once she was deemed leukemia-free, Layla underwent a second transplant. One month later, she was well enough to go home. Today, Layla is still free of ALL.

More details on Layla’s story and UCART19 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 2046). Clinical trials of UCART19 (funded by Cellectis) are set to begin early next year.

Layla Richards, the first

person treated with UCART19

Photo courtesy of GOSH

A hospital in the UK has reported success with the first-in-human use of an allogeneic chimeric antigen receptor (CAR) T-cell treatment.

The therapy, UCART19, helped treat an aggressive case of acute lymphoblastic leukemia (ALL) in an infant named Layla Richards.

Chemotherapy, a first transplant, and blinatumomab all failed to treat Layla’s disease. But UCART19 provided a bridge to a second transplant, and Layla

is now free of leukemia.

“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Waseem Qasim, MBBS, PhD, a professor at University College London’s Institute of Child Health and a consultant immunologist at Great Ormond Street Hospital (GOSH) in London, where Layla was treated.

“But this is a landmark in the use of new gene-engineering technology, and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukemia and other cancers.”

Layla’s history

Layla was born in June 2014 and, at 14 weeks old, was diagnosed with CD19+ ALL (t[11;19] rearrangement). Doctors at GOSH described her leukemia as “one of the most aggressive forms of the disease we have ever seen.”

Layla underwent several rounds of chemotherapy at GOSH and then received a transplant from a mismatched, unrelated donor. Seven weeks later, her leukemia had returned.

A second round of chemotherapy wasn’t an option, so Layla went on to receive blinatumomab. This, too, ultimately failed.

Layla’s family was unwilling to accept palliative care, so her doctors mentioned the possibility of using UCART19.

“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new UCART19 cells?’” Dr Qasim said.

“The treatment was highly experimental, and we had to get special permissions, but she appeared ideally suited for this type of approach.”

UCART19 treatment

Before Layla received UCART19, investigators from GOSH, University College London, and the biotech company Cellectis had been developing off-the-shelf banks of the cells for use in clinical trials.

UCART19 consists of donor T cells modified using transcription activator-like effector nucleases (TALEN). Like some other CAR T-cell products, UCART19 is designed to target CD19+ cancer cells.

But UCART19 cells are also programmed to be insensitive to alemtuzumab. That way, a patient can receive the drug to prevent rejection of HLA-mismatched cells.

Before receiving UCART19, Layla was given vincristine, dexamethasone, and asparaginase, followed by fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose (4.5 x 10⁶/kg) of UCART19.

After this, Layla spent several months in isolation to protect her from infections while her immune system was extremely weak. Within weeks of receiving UCART19, Layla demonstrated an immune response in the form of a rash.

The rash worsened, but, aside from that, Layla appeared to be well. To date, she has shown no signs of cytokine release syndrome.

She did, however, show signs of molecular and cytogenetic remission. Once she was deemed leukemia-free, Layla underwent a second transplant. One month later, she was well enough to go home. Today, Layla is still free of ALL.

More details on Layla’s story and UCART19 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 2046). Clinical trials of UCART19 (funded by Cellectis) are set to begin early next year.

Layla Richards, the first

person treated with UCART19

Photo courtesy of GOSH

A hospital in the UK has reported success with the first-in-human use of an allogeneic chimeric antigen receptor (CAR) T-cell treatment.

The therapy, UCART19, helped treat an aggressive case of acute lymphoblastic leukemia (ALL) in an infant named Layla Richards.

Chemotherapy, a first transplant, and blinatumomab all failed to treat Layla’s disease. But UCART19 provided a bridge to a second transplant, and Layla

is now free of leukemia.

“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Waseem Qasim, MBBS, PhD, a professor at University College London’s Institute of Child Health and a consultant immunologist at Great Ormond Street Hospital (GOSH) in London, where Layla was treated.

“But this is a landmark in the use of new gene-engineering technology, and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukemia and other cancers.”

Layla’s history

Layla was born in June 2014 and, at 14 weeks old, was diagnosed with CD19+ ALL (t[11;19] rearrangement). Doctors at GOSH described her leukemia as “one of the most aggressive forms of the disease we have ever seen.”

Layla underwent several rounds of chemotherapy at GOSH and then received a transplant from a mismatched, unrelated donor. Seven weeks later, her leukemia had returned.

A second round of chemotherapy wasn’t an option, so Layla went on to receive blinatumomab. This, too, ultimately failed.

Layla’s family was unwilling to accept palliative care, so her doctors mentioned the possibility of using UCART19.

“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new UCART19 cells?’” Dr Qasim said.

“The treatment was highly experimental, and we had to get special permissions, but she appeared ideally suited for this type of approach.”

UCART19 treatment

Before Layla received UCART19, investigators from GOSH, University College London, and the biotech company Cellectis had been developing off-the-shelf banks of the cells for use in clinical trials.

UCART19 consists of donor T cells modified using transcription activator-like effector nucleases (TALEN). Like some other CAR T-cell products, UCART19 is designed to target CD19+ cancer cells.

But UCART19 cells are also programmed to be insensitive to alemtuzumab. That way, a patient can receive the drug to prevent rejection of HLA-mismatched cells.

Before receiving UCART19, Layla was given vincristine, dexamethasone, and asparaginase, followed by fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose (4.5 x 10⁶/kg) of UCART19.

After this, Layla spent several months in isolation to protect her from infections while her immune system was extremely weak. Within weeks of receiving UCART19, Layla demonstrated an immune response in the form of a rash.

The rash worsened, but, aside from that, Layla appeared to be well. To date, she has shown no signs of cytokine release syndrome.

She did, however, show signs of molecular and cytogenetic remission. Once she was deemed leukemia-free, Layla underwent a second transplant. One month later, she was well enough to go home. Today, Layla is still free of ALL.

More details on Layla’s story and UCART19 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 2046). Clinical trials of UCART19 (funded by Cellectis) are set to begin early next year.

John Dick, PhD

University Health Network

Results of a study published in Science challenge traditional ideas about how blood is made.

The findings suggest hematopoiesis does not occur through a gradual process consisting of multipotent, oligopotent, and unilineage progenitor stages.

Rather, hematopoietic stem cells (HSCs) mature into different types of blood cells quickly, and the process differs between early human development (fetal liver HSCs) and adulthood (HSCs from bone marrow).

The research indicates “that the whole classic ‘textbook’ view we thought we knew doesn’t actually even exist,” said study investigator John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

He and his colleagues mapped the lineage potential of nearly 3000 single cells from 33 different populations of HSCs obtained from human blood samples taken at various life stages and ages.

The team’s discoveries build on research published in Science in 2011. In that paper, Dr Dick and his colleagues described isolating an HSC in its purest form—as a single cell capable of regenerating the entire blood system.

“Four years ago, when we isolated the pure stem cell, we realized we had also uncovered populations of stem-cell like ‘daughter’ cells that we thought at the time were other types of stem cells,” Dr Dick said.

“When we burrowed further to study these ‘daughters,’ we discovered they were actually already mature blood lineages. In other words, lineages that had broken off almost immediately from the stem cell compartment and had not developed downstream through the slow, gradual ‘textbook’ process.”

“So in human blood formation, everything begins with the stem cell, which is the executive decision-maker quickly driving the process that replenishes blood at a daily rate that exceeds 300 billion cells.”

The investigators believe this work could help advance the manufacture of blood cells in the lab, and it should aid the study of blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases—from anemia . . . to leukemia,” Dr Dick said. “Think of it as moving from the old world of black-and-white television into the new world of high-definition.”

John Dick, PhD

University Health Network

Results of a study published in Science challenge traditional ideas about how blood is made.

The findings suggest hematopoiesis does not occur through a gradual process consisting of multipotent, oligopotent, and unilineage progenitor stages.

Rather, hematopoietic stem cells (HSCs) mature into different types of blood cells quickly, and the process differs between early human development (fetal liver HSCs) and adulthood (HSCs from bone marrow).

The research indicates “that the whole classic ‘textbook’ view we thought we knew doesn’t actually even exist,” said study investigator John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

He and his colleagues mapped the lineage potential of nearly 3000 single cells from 33 different populations of HSCs obtained from human blood samples taken at various life stages and ages.

The team’s discoveries build on research published in Science in 2011. In that paper, Dr Dick and his colleagues described isolating an HSC in its purest form—as a single cell capable of regenerating the entire blood system.

“Four years ago, when we isolated the pure stem cell, we realized we had also uncovered populations of stem-cell like ‘daughter’ cells that we thought at the time were other types of stem cells,” Dr Dick said.

“When we burrowed further to study these ‘daughters,’ we discovered they were actually already mature blood lineages. In other words, lineages that had broken off almost immediately from the stem cell compartment and had not developed downstream through the slow, gradual ‘textbook’ process.”

“So in human blood formation, everything begins with the stem cell, which is the executive decision-maker quickly driving the process that replenishes blood at a daily rate that exceeds 300 billion cells.”

The investigators believe this work could help advance the manufacture of blood cells in the lab, and it should aid the study of blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases—from anemia . . . to leukemia,” Dr Dick said. “Think of it as moving from the old world of black-and-white television into the new world of high-definition.”

John Dick, PhD

University Health Network

Results of a study published in Science challenge traditional ideas about how blood is made.

The findings suggest hematopoiesis does not occur through a gradual process consisting of multipotent, oligopotent, and unilineage progenitor stages.

Rather, hematopoietic stem cells (HSCs) mature into different types of blood cells quickly, and the process differs between early human development (fetal liver HSCs) and adulthood (HSCs from bone marrow).

The research indicates “that the whole classic ‘textbook’ view we thought we knew doesn’t actually even exist,” said study investigator John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

He and his colleagues mapped the lineage potential of nearly 3000 single cells from 33 different populations of HSCs obtained from human blood samples taken at various life stages and ages.

The team’s discoveries build on research published in Science in 2011. In that paper, Dr Dick and his colleagues described isolating an HSC in its purest form—as a single cell capable of regenerating the entire blood system.

“Four years ago, when we isolated the pure stem cell, we realized we had also uncovered populations of stem-cell like ‘daughter’ cells that we thought at the time were other types of stem cells,” Dr Dick said.

“When we burrowed further to study these ‘daughters,’ we discovered they were actually already mature blood lineages. In other words, lineages that had broken off almost immediately from the stem cell compartment and had not developed downstream through the slow, gradual ‘textbook’ process.”

“So in human blood formation, everything begins with the stem cell, which is the executive decision-maker quickly driving the process that replenishes blood at a daily rate that exceeds 300 billion cells.”

The investigators believe this work could help advance the manufacture of blood cells in the lab, and it should aid the study of blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases—from anemia . . . to leukemia,” Dr Dick said. “Think of it as moving from the old world of black-and-white television into the new world of high-definition.”

Only four short-term, randomized trials have addressed the safety, efficacy, and tolerability of cannabinoids for treating rheumatic diseases, and all have methodologic weaknesses and a high risk of bias, according to a qualitative review of data published since 1946.

“There is low-quality evidence suggesting that cannabinoids may be associated with improvements in pain and sleep quality in rheumatoid arthritis and fibromyalgia. Clinical positive effects for the studies assessed in this review must be balanced by the reported adverse events,” wrote Dr. Mary-Ann Fitzcharles of McGill University, Montreal, and her colleagues (Arthritis Care Res. 2015 Nov 9. doi: 10.1002/acr.22727).

©Thinkstock.com

The four randomized clinical trials, ranging in duration from 2 to 8 weeks, included one with 58 rheumatoid arthritis patients, two with a total of 71 fibromyalgia patients, and one with 74 osteoarthritis patients. Three trials met their respective primary endpoints and found a statistically significant effect of cannabinoids on pain (in two studies), sleep (in two studies), and improved quality of life (in one study). The investigators noted a high incidence (generally observed in 25%-50% of subjects) of mild to moderate side effects (dizziness, drowsiness, nausea, dry mouth) and many methodologic weaknesses in the evaluated data. The study that tested a fatty acid amide hydrolase inhibitor in osteoarthritis patients was stopped early due to futility. The other three completed studies were associated with an overall high risk of bias.

One of the two fibromyalgia studies was a randomized, double-blind, placebo-controlled trial conducted in 2008 that assessed nabilone in 40 fibromyalgia patients. Nabilone treatment led to significant decreases in the visual analog scale for pain (–2.04, P less than .02) at 4 weeks. A second fibromyalgia trial from 2010 compared amitriptyline to nabilone in 31 subjects and found the latter agent to be superior on the primary endpoint of difference in score on the Insomnia Severity Index (difference = 3.2; 95% confidence interval, 1.2-5.3). A 2006 rheumatoid arthritis trial found that cannabis-based Sativex demonstrated a clinically meaningful advantage over placebo for the primary endpoint of morning pain on movement (difference of –0.95, 95% CI, –1.83 to –0.02; P = .044). No trials assessed herbal cannabis.

“It is not currently possible to recommend this category of treatments as therapy for patients with rheumatic diseases. Any conclusions based on these studies remain tenuous and call for larger, well controlled clinical trials to better understand potential benefits and risks as pertaining to rheumatic conditions,” Dr. Fitzcharles and her coauthors wrote.

No relevant financial disclosures were reported.

rhnews@frontlinemedcom.com

Only four short-term, randomized trials have addressed the safety, efficacy, and tolerability of cannabinoids for treating rheumatic diseases, and all have methodologic weaknesses and a high risk of bias, according to a qualitative review of data published since 1946.

“There is low-quality evidence suggesting that cannabinoids may be associated with improvements in pain and sleep quality in rheumatoid arthritis and fibromyalgia. Clinical positive effects for the studies assessed in this review must be balanced by the reported adverse events,” wrote Dr. Mary-Ann Fitzcharles of McGill University, Montreal, and her colleagues (Arthritis Care Res. 2015 Nov 9. doi: 10.1002/acr.22727).

©Thinkstock.com

The four randomized clinical trials, ranging in duration from 2 to 8 weeks, included one with 58 rheumatoid arthritis patients, two with a total of 71 fibromyalgia patients, and one with 74 osteoarthritis patients. Three trials met their respective primary endpoints and found a statistically significant effect of cannabinoids on pain (in two studies), sleep (in two studies), and improved quality of life (in one study). The investigators noted a high incidence (generally observed in 25%-50% of subjects) of mild to moderate side effects (dizziness, drowsiness, nausea, dry mouth) and many methodologic weaknesses in the evaluated data. The study that tested a fatty acid amide hydrolase inhibitor in osteoarthritis patients was stopped early due to futility. The other three completed studies were associated with an overall high risk of bias.

One of the two fibromyalgia studies was a randomized, double-blind, placebo-controlled trial conducted in 2008 that assessed nabilone in 40 fibromyalgia patients. Nabilone treatment led to significant decreases in the visual analog scale for pain (–2.04, P less than .02) at 4 weeks. A second fibromyalgia trial from 2010 compared amitriptyline to nabilone in 31 subjects and found the latter agent to be superior on the primary endpoint of difference in score on the Insomnia Severity Index (difference = 3.2; 95% confidence interval, 1.2-5.3). A 2006 rheumatoid arthritis trial found that cannabis-based Sativex demonstrated a clinically meaningful advantage over placebo for the primary endpoint of morning pain on movement (difference of –0.95, 95% CI, –1.83 to –0.02; P = .044). No trials assessed herbal cannabis.

“It is not currently possible to recommend this category of treatments as therapy for patients with rheumatic diseases. Any conclusions based on these studies remain tenuous and call for larger, well controlled clinical trials to better understand potential benefits and risks as pertaining to rheumatic conditions,” Dr. Fitzcharles and her coauthors wrote.

No relevant financial disclosures were reported.

rhnews@frontlinemedcom.com

Only four short-term, randomized trials have addressed the safety, efficacy, and tolerability of cannabinoids for treating rheumatic diseases, and all have methodologic weaknesses and a high risk of bias, according to a qualitative review of data published since 1946.

“There is low-quality evidence suggesting that cannabinoids may be associated with improvements in pain and sleep quality in rheumatoid arthritis and fibromyalgia. Clinical positive effects for the studies assessed in this review must be balanced by the reported adverse events,” wrote Dr. Mary-Ann Fitzcharles of McGill University, Montreal, and her colleagues (Arthritis Care Res. 2015 Nov 9. doi: 10.1002/acr.22727).

©Thinkstock.com

The four randomized clinical trials, ranging in duration from 2 to 8 weeks, included one with 58 rheumatoid arthritis patients, two with a total of 71 fibromyalgia patients, and one with 74 osteoarthritis patients. Three trials met their respective primary endpoints and found a statistically significant effect of cannabinoids on pain (in two studies), sleep (in two studies), and improved quality of life (in one study). The investigators noted a high incidence (generally observed in 25%-50% of subjects) of mild to moderate side effects (dizziness, drowsiness, nausea, dry mouth) and many methodologic weaknesses in the evaluated data. The study that tested a fatty acid amide hydrolase inhibitor in osteoarthritis patients was stopped early due to futility. The other three completed studies were associated with an overall high risk of bias.

One of the two fibromyalgia studies was a randomized, double-blind, placebo-controlled trial conducted in 2008 that assessed nabilone in 40 fibromyalgia patients. Nabilone treatment led to significant decreases in the visual analog scale for pain (–2.04, P less than .02) at 4 weeks. A second fibromyalgia trial from 2010 compared amitriptyline to nabilone in 31 subjects and found the latter agent to be superior on the primary endpoint of difference in score on the Insomnia Severity Index (difference = 3.2; 95% confidence interval, 1.2-5.3). A 2006 rheumatoid arthritis trial found that cannabis-based Sativex demonstrated a clinically meaningful advantage over placebo for the primary endpoint of morning pain on movement (difference of –0.95, 95% CI, –1.83 to –0.02; P = .044). No trials assessed herbal cannabis.

“It is not currently possible to recommend this category of treatments as therapy for patients with rheumatic diseases. Any conclusions based on these studies remain tenuous and call for larger, well controlled clinical trials to better understand potential benefits and risks as pertaining to rheumatic conditions,” Dr. Fitzcharles and her coauthors wrote.

No relevant financial disclosures were reported.

rhnews@frontlinemedcom.com

Regular corticosteroid injections over 2 years were relatively safe for osteoarthritic knees in a trial from Tufts Medical Center in Boston, but they did not slow the progression of joint damage or improve patient outcomes.

The findings come at a time when the role of intra-articular steroid shots is up for debate. They are widely used for knee osteoarthritis (OA) in the hopes of reducing cartilage damage from synovitis, but there’s also concern that they might actually harm cartilage and periarticular bone.

The investigators, led by Dr. Timothy McAlindon, chief of rheumatology at Tufts Medical Center, sought to bring some data to the table. “Our objective was to test the potential for disease modification of synovitic knee OA by triamcinolone hexacetonide [THA] in a clinical trial with comprehensive measurement of effects on cartilage and subchondral bone using MRI and DXA [dual-energy x-ray absorptiometry],” they said.

The investigators randomized 140 patients with symptomatic knee OA (Kellgren-Lawrence grade 2 or 3) and synovitis on ultrasound to either 40 mg THA or saline knee injections every 3 months for 2 years. Randomization was blocked and stratified by gender and Kellgren-Lawrence grade. Patients had clinical assessments at each visit and annual MRIs and DXA knee and hip scans.

There were no significant between-group differences over the course of the study in mean changes on Western Ontario and McMaster Universities Arthritis Index pain (–2.2 for THA vs. –2.8 for placebo; P = .3) and function scores (–7.1 for THA vs. –9.2 for placebo; P = .4), and no differences in chair stand (–1.1 for THA vs. –1.6 for placebo; P = .8) or walk time tests (–0.5 for THA vs. –0.03 for placebo; P = .5).

There were no significant differences on MRI or DXA, except that the steroid group had greater cartilage loss and the placebo group greater progression of fibrillation.

“The greater rate of loss of cartilage thickness ... in the treated group was small in magnitude and of uncertain clinical significance,” said Dr. McAlindon.

The mean body mass index in the study was 31.2 kg/m². Just over half the subjects were women, and about two-thirds were white. More than 90% of patients in both groups completed the study.

The work was funded by the National Institutes of Health. The investigators have no relevant disclosures.

aotto@frontlinemedcom.com

Regular corticosteroid injections over 2 years were relatively safe for osteoarthritic knees in a trial from Tufts Medical Center in Boston, but they did not slow the progression of joint damage or improve patient outcomes.

The findings come at a time when the role of intra-articular steroid shots is up for debate. They are widely used for knee osteoarthritis (OA) in the hopes of reducing cartilage damage from synovitis, but there’s also concern that they might actually harm cartilage and periarticular bone.

The investigators, led by Dr. Timothy McAlindon, chief of rheumatology at Tufts Medical Center, sought to bring some data to the table. “Our objective was to test the potential for disease modification of synovitic knee OA by triamcinolone hexacetonide [THA] in a clinical trial with comprehensive measurement of effects on cartilage and subchondral bone using MRI and DXA [dual-energy x-ray absorptiometry],” they said.

The investigators randomized 140 patients with symptomatic knee OA (Kellgren-Lawrence grade 2 or 3) and synovitis on ultrasound to either 40 mg THA or saline knee injections every 3 months for 2 years. Randomization was blocked and stratified by gender and Kellgren-Lawrence grade. Patients had clinical assessments at each visit and annual MRIs and DXA knee and hip scans.

There were no significant between-group differences over the course of the study in mean changes on Western Ontario and McMaster Universities Arthritis Index pain (–2.2 for THA vs. –2.8 for placebo; P = .3) and function scores (–7.1 for THA vs. –9.2 for placebo; P = .4), and no differences in chair stand (–1.1 for THA vs. –1.6 for placebo; P = .8) or walk time tests (–0.5 for THA vs. –0.03 for placebo; P = .5).

There were no significant differences on MRI or DXA, except that the steroid group had greater cartilage loss and the placebo group greater progression of fibrillation.

“The greater rate of loss of cartilage thickness ... in the treated group was small in magnitude and of uncertain clinical significance,” said Dr. McAlindon.

The mean body mass index in the study was 31.2 kg/m². Just over half the subjects were women, and about two-thirds were white. More than 90% of patients in both groups completed the study.

The work was funded by the National Institutes of Health. The investigators have no relevant disclosures.

aotto@frontlinemedcom.com

Regular corticosteroid injections over 2 years were relatively safe for osteoarthritic knees in a trial from Tufts Medical Center in Boston, but they did not slow the progression of joint damage or improve patient outcomes.

The findings come at a time when the role of intra-articular steroid shots is up for debate. They are widely used for knee osteoarthritis (OA) in the hopes of reducing cartilage damage from synovitis, but there’s also concern that they might actually harm cartilage and periarticular bone.

The investigators, led by Dr. Timothy McAlindon, chief of rheumatology at Tufts Medical Center, sought to bring some data to the table. “Our objective was to test the potential for disease modification of synovitic knee OA by triamcinolone hexacetonide [THA] in a clinical trial with comprehensive measurement of effects on cartilage and subchondral bone using MRI and DXA [dual-energy x-ray absorptiometry],” they said.

The investigators randomized 140 patients with symptomatic knee OA (Kellgren-Lawrence grade 2 or 3) and synovitis on ultrasound to either 40 mg THA or saline knee injections every 3 months for 2 years. Randomization was blocked and stratified by gender and Kellgren-Lawrence grade. Patients had clinical assessments at each visit and annual MRIs and DXA knee and hip scans.

There were no significant between-group differences over the course of the study in mean changes on Western Ontario and McMaster Universities Arthritis Index pain (–2.2 for THA vs. –2.8 for placebo; P = .3) and function scores (–7.1 for THA vs. –9.2 for placebo; P = .4), and no differences in chair stand (–1.1 for THA vs. –1.6 for placebo; P = .8) or walk time tests (–0.5 for THA vs. –0.03 for placebo; P = .5).

There were no significant differences on MRI or DXA, except that the steroid group had greater cartilage loss and the placebo group greater progression of fibrillation.

“The greater rate of loss of cartilage thickness ... in the treated group was small in magnitude and of uncertain clinical significance,” said Dr. McAlindon.

The mean body mass index in the study was 31.2 kg/m². Just over half the subjects were women, and about two-thirds were white. More than 90% of patients in both groups completed the study.

The work was funded by the National Institutes of Health. The investigators have no relevant disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – Neither fish oil nor aspirin can be recommended for prevention of primary arteriovenous fistula failure in patients with advanced renal disease, a randomized trial showed.

“AVF failure increases patient morbidity and health provider costs,” Dr. Ashley B. Irish said during a press briefing at a meeting sponsored by the American Society of Nephrology. “Therefore, therapies to reduce AVF failure may reduce patient outcomes and reduce costs. But it remains uncertain whether targeting antiplatelet agents to affect thrombosis is going to improve the numbers of AVFs you can actually use.”

In a randomized trial known as Fish Oils and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED), Dr. Irish and his associates set out to determine whether omega-3 polyunsaturated fatty acids (fish oil) can reduce new AVF access failure at 12 months. The secondary outcome was to determine if aspirin would have the same effect.

Doug Brunk/Frontline Medical News

The intervention consisted of 12 weeks of fish oil 4 g or placebo (olive oil) divided in two doses. A subset of patients were randomized to aspirin 100 mg or matching placebo in addition to fish oil or placebo in a factorial design, said Dr, Irish, of the department of nephrology at Fiona Stanley Hospital, Perth, Australia. AVF failure was defined as AVF thrombosis and/or abandonment and/or cannulation formation.

The study was carried out at centers in Australia, Malaysia, and the United Kingdom, and included 567 patients with stage 4 or stage 5 chronic kidney disease who were either on dialysis or who were expected to start within 12 months. Their mean age was 55 years, 63% were male, 46% had diabetes, but only 16% were on vascular dialysis. “So, these patients were a little bit healthier than you might expect in usual populations of people on dialysis,” Dr. Irish said.

The researchers found that fish oil had no effect on preventing AVF failure. In fact, 47% of patients who received fish oil had a failed AVF at 12 months, compared with 47% of those who received placebo (relative risk after adjusting for aspirin use was 1.03).

“So, nearly half of all patients in this trial had no usable AVF at 12 months after surgery,” Dr. Irish said. “It didn’t matter whether you were old or young, had vascular disease, or were diabetic or not. Fish oil didn’t help.”

Aspirin didn’t work, either. In fact, 45% of those who received aspirin had a failed AVF at 12 months, compared with 43% of those who received placebo (RR, 1.05).

Dr. Irish noted that the proportion of serious adverse events was low and similar between patients who received fish oil and those who received or aspirin. “The treatment was safe; it just didn’t work,” he said.

“This study and others have shown that trying to prevent AVFs from clotting or promoting their development by inhibiting platelets and blood vessel changes is not effective,” Dr. Irish explained. “The focus might need to shift to other strategies, such as preserving blood vessels from damage, surgical techniques, and modification of vessel walls by infrared and other pharmacological treatments.”

Dr. Irish characterized the study results as “disappointing, because these therapies are cheap, safe, and readily available. But it’s not a waste of time, because now we know that this avenue of approach in research is not going to lead us anywhere. It’s time to move on. This information will help us inform practice and plan new trials.”

The researchers reported having no financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – Neither fish oil nor aspirin can be recommended for prevention of primary arteriovenous fistula failure in patients with advanced renal disease, a randomized trial showed.

“AVF failure increases patient morbidity and health provider costs,” Dr. Ashley B. Irish said during a press briefing at a meeting sponsored by the American Society of Nephrology. “Therefore, therapies to reduce AVF failure may reduce patient outcomes and reduce costs. But it remains uncertain whether targeting antiplatelet agents to affect thrombosis is going to improve the numbers of AVFs you can actually use.”

In a randomized trial known as Fish Oils and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED), Dr. Irish and his associates set out to determine whether omega-3 polyunsaturated fatty acids (fish oil) can reduce new AVF access failure at 12 months. The secondary outcome was to determine if aspirin would have the same effect.

Doug Brunk/Frontline Medical News

The intervention consisted of 12 weeks of fish oil 4 g or placebo (olive oil) divided in two doses. A subset of patients were randomized to aspirin 100 mg or matching placebo in addition to fish oil or placebo in a factorial design, said Dr, Irish, of the department of nephrology at Fiona Stanley Hospital, Perth, Australia. AVF failure was defined as AVF thrombosis and/or abandonment and/or cannulation formation.

The study was carried out at centers in Australia, Malaysia, and the United Kingdom, and included 567 patients with stage 4 or stage 5 chronic kidney disease who were either on dialysis or who were expected to start within 12 months. Their mean age was 55 years, 63% were male, 46% had diabetes, but only 16% were on vascular dialysis. “So, these patients were a little bit healthier than you might expect in usual populations of people on dialysis,” Dr. Irish said.

The researchers found that fish oil had no effect on preventing AVF failure. In fact, 47% of patients who received fish oil had a failed AVF at 12 months, compared with 47% of those who received placebo (relative risk after adjusting for aspirin use was 1.03).

“So, nearly half of all patients in this trial had no usable AVF at 12 months after surgery,” Dr. Irish said. “It didn’t matter whether you were old or young, had vascular disease, or were diabetic or not. Fish oil didn’t help.”

Aspirin didn’t work, either. In fact, 45% of those who received aspirin had a failed AVF at 12 months, compared with 43% of those who received placebo (RR, 1.05).

Dr. Irish noted that the proportion of serious adverse events was low and similar between patients who received fish oil and those who received or aspirin. “The treatment was safe; it just didn’t work,” he said.

“This study and others have shown that trying to prevent AVFs from clotting or promoting their development by inhibiting platelets and blood vessel changes is not effective,” Dr. Irish explained. “The focus might need to shift to other strategies, such as preserving blood vessels from damage, surgical techniques, and modification of vessel walls by infrared and other pharmacological treatments.”

Dr. Irish characterized the study results as “disappointing, because these therapies are cheap, safe, and readily available. But it’s not a waste of time, because now we know that this avenue of approach in research is not going to lead us anywhere. It’s time to move on. This information will help us inform practice and plan new trials.”

The researchers reported having no financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – Neither fish oil nor aspirin can be recommended for prevention of primary arteriovenous fistula failure in patients with advanced renal disease, a randomized trial showed.

“AVF failure increases patient morbidity and health provider costs,” Dr. Ashley B. Irish said during a press briefing at a meeting sponsored by the American Society of Nephrology. “Therefore, therapies to reduce AVF failure may reduce patient outcomes and reduce costs. But it remains uncertain whether targeting antiplatelet agents to affect thrombosis is going to improve the numbers of AVFs you can actually use.”

In a randomized trial known as Fish Oils and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED), Dr. Irish and his associates set out to determine whether omega-3 polyunsaturated fatty acids (fish oil) can reduce new AVF access failure at 12 months. The secondary outcome was to determine if aspirin would have the same effect.

Doug Brunk/Frontline Medical News

The intervention consisted of 12 weeks of fish oil 4 g or placebo (olive oil) divided in two doses. A subset of patients were randomized to aspirin 100 mg or matching placebo in addition to fish oil or placebo in a factorial design, said Dr, Irish, of the department of nephrology at Fiona Stanley Hospital, Perth, Australia. AVF failure was defined as AVF thrombosis and/or abandonment and/or cannulation formation.

The study was carried out at centers in Australia, Malaysia, and the United Kingdom, and included 567 patients with stage 4 or stage 5 chronic kidney disease who were either on dialysis or who were expected to start within 12 months. Their mean age was 55 years, 63% were male, 46% had diabetes, but only 16% were on vascular dialysis. “So, these patients were a little bit healthier than you might expect in usual populations of people on dialysis,” Dr. Irish said.

The researchers found that fish oil had no effect on preventing AVF failure. In fact, 47% of patients who received fish oil had a failed AVF at 12 months, compared with 47% of those who received placebo (relative risk after adjusting for aspirin use was 1.03).

“So, nearly half of all patients in this trial had no usable AVF at 12 months after surgery,” Dr. Irish said. “It didn’t matter whether you were old or young, had vascular disease, or were diabetic or not. Fish oil didn’t help.”

Aspirin didn’t work, either. In fact, 45% of those who received aspirin had a failed AVF at 12 months, compared with 43% of those who received placebo (RR, 1.05).

Dr. Irish noted that the proportion of serious adverse events was low and similar between patients who received fish oil and those who received or aspirin. “The treatment was safe; it just didn’t work,” he said.

“This study and others have shown that trying to prevent AVFs from clotting or promoting their development by inhibiting platelets and blood vessel changes is not effective,” Dr. Irish explained. “The focus might need to shift to other strategies, such as preserving blood vessels from damage, surgical techniques, and modification of vessel walls by infrared and other pharmacological treatments.”

Dr. Irish characterized the study results as “disappointing, because these therapies are cheap, safe, and readily available. But it’s not a waste of time, because now we know that this avenue of approach in research is not going to lead us anywhere. It’s time to move on. This information will help us inform practice and plan new trials.”

The researchers reported having no financial disclosures.

dbrunk@frontlinemedcom.com

CHICAGO – Access to equal care decreases but does not eliminate the survival disparities between black and white patients with rectal cancer, according to investigators from the University of Cincinnati, Ohio.

After rigorous propensity score matching of thousands of black and white patients for patient, disease, and treatment characteristics, median survival was 109.6 months among white patients and 85.8 months among black patients (J Am Coll Surg. 2015 Nov [doi: 10.1016/j.jamcollsurg.2015.07.056]).

“Blacks have worse outcomes, but we don’t have a clear explanation,” explained investigator and surgery resident Dr. Meghan Nolan. For now, the findings suggest that it might be a good idea to start screening black patients before age 50 years, perhaps even as early as age 40 years.

“We are urging people to screen at a lower age in black patients,” Dr. Nolan said at the annual clinical congress of the American College of Surgeons.

Racial disparities in rectal cancer are well known. The investigators wanted to see if they simply are because of unequal access to care, so they analyzed 178,414 white and 18,385 black patients in the National Cancer Data Base from 1998 to 2006.

Mean 5-year survival for blacks was 50.7%, compared with 56.2% for whites, and black patients were more likely to present with stage IV disease. Such findings aren’t new, the investigators noted.

To account for the difference in late-stage presentation, the investigators limited their analysis to patients with stage I-III rectal cancer. But even then, 5-year survival was 66.7% among whites and 58.7% among blacks.

That might have had something to do with the fact 85% of white patients, but only 78% of black patients, had surgery for those potentially curable lower-stage tumors. Among those who didn’t undergo surgery, patient refusal was slightly more common among black patients than white patients, which suggests that “cultural factors may be playing a role” in the surgery disparity, Dr. Nolan said.

The investigators controlled for the different surgery rates by limiting their analysis to stage I-III patients who had appropriate operations. The survival gap narrowed but did not disappear: 65.8% of white patients were alive at 5 years, compared with 61% of black patients. Blacks were also more likely to have positive margins on pathology. “I’m not sure why. That was a surprise,” Dr. Nolan said.

The propensity score matching led the team to conclude that there’s more at work than differences in access to care. A total of 7,569 pairs of black and white patients were matched for age at diagnosis, gender, insurance coverage, income, education, facility type, tumor stage, Charlson-Deyo score, surgical management, margin status, and other potential confounders.

Every matched patient completed their recommended therapy, and there was no statistical difference between matched black and white patients who received appropriate, stage-specific chemoradiation. Still, the survival differences persisted.

Dr. Nolan had no relevant disclosures.

aotto@frontlinemedcom.com

CHICAGO – Access to equal care decreases but does not eliminate the survival disparities between black and white patients with rectal cancer, according to investigators from the University of Cincinnati, Ohio.

After rigorous propensity score matching of thousands of black and white patients for patient, disease, and treatment characteristics, median survival was 109.6 months among white patients and 85.8 months among black patients (J Am Coll Surg. 2015 Nov [doi: 10.1016/j.jamcollsurg.2015.07.056]).

“Blacks have worse outcomes, but we don’t have a clear explanation,” explained investigator and surgery resident Dr. Meghan Nolan. For now, the findings suggest that it might be a good idea to start screening black patients before age 50 years, perhaps even as early as age 40 years.

“We are urging people to screen at a lower age in black patients,” Dr. Nolan said at the annual clinical congress of the American College of Surgeons.

Racial disparities in rectal cancer are well known. The investigators wanted to see if they simply are because of unequal access to care, so they analyzed 178,414 white and 18,385 black patients in the National Cancer Data Base from 1998 to 2006.

Mean 5-year survival for blacks was 50.7%, compared with 56.2% for whites, and black patients were more likely to present with stage IV disease. Such findings aren’t new, the investigators noted.

To account for the difference in late-stage presentation, the investigators limited their analysis to patients with stage I-III rectal cancer. But even then, 5-year survival was 66.7% among whites and 58.7% among blacks.

That might have had something to do with the fact 85% of white patients, but only 78% of black patients, had surgery for those potentially curable lower-stage tumors. Among those who didn’t undergo surgery, patient refusal was slightly more common among black patients than white patients, which suggests that “cultural factors may be playing a role” in the surgery disparity, Dr. Nolan said.

The investigators controlled for the different surgery rates by limiting their analysis to stage I-III patients who had appropriate operations. The survival gap narrowed but did not disappear: 65.8% of white patients were alive at 5 years, compared with 61% of black patients. Blacks were also more likely to have positive margins on pathology. “I’m not sure why. That was a surprise,” Dr. Nolan said.

The propensity score matching led the team to conclude that there’s more at work than differences in access to care. A total of 7,569 pairs of black and white patients were matched for age at diagnosis, gender, insurance coverage, income, education, facility type, tumor stage, Charlson-Deyo score, surgical management, margin status, and other potential confounders.

Every matched patient completed their recommended therapy, and there was no statistical difference between matched black and white patients who received appropriate, stage-specific chemoradiation. Still, the survival differences persisted.

Dr. Nolan had no relevant disclosures.

aotto@frontlinemedcom.com

CHICAGO – Access to equal care decreases but does not eliminate the survival disparities between black and white patients with rectal cancer, according to investigators from the University of Cincinnati, Ohio.

After rigorous propensity score matching of thousands of black and white patients for patient, disease, and treatment characteristics, median survival was 109.6 months among white patients and 85.8 months among black patients (J Am Coll Surg. 2015 Nov [doi: 10.1016/j.jamcollsurg.2015.07.056]).

“Blacks have worse outcomes, but we don’t have a clear explanation,” explained investigator and surgery resident Dr. Meghan Nolan. For now, the findings suggest that it might be a good idea to start screening black patients before age 50 years, perhaps even as early as age 40 years.

“We are urging people to screen at a lower age in black patients,” Dr. Nolan said at the annual clinical congress of the American College of Surgeons.

Racial disparities in rectal cancer are well known. The investigators wanted to see if they simply are because of unequal access to care, so they analyzed 178,414 white and 18,385 black patients in the National Cancer Data Base from 1998 to 2006.

Mean 5-year survival for blacks was 50.7%, compared with 56.2% for whites, and black patients were more likely to present with stage IV disease. Such findings aren’t new, the investigators noted.

To account for the difference in late-stage presentation, the investigators limited their analysis to patients with stage I-III rectal cancer. But even then, 5-year survival was 66.7% among whites and 58.7% among blacks.

That might have had something to do with the fact 85% of white patients, but only 78% of black patients, had surgery for those potentially curable lower-stage tumors. Among those who didn’t undergo surgery, patient refusal was slightly more common among black patients than white patients, which suggests that “cultural factors may be playing a role” in the surgery disparity, Dr. Nolan said.

The investigators controlled for the different surgery rates by limiting their analysis to stage I-III patients who had appropriate operations. The survival gap narrowed but did not disappear: 65.8% of white patients were alive at 5 years, compared with 61% of black patients. Blacks were also more likely to have positive margins on pathology. “I’m not sure why. That was a surprise,” Dr. Nolan said.

The propensity score matching led the team to conclude that there’s more at work than differences in access to care. A total of 7,569 pairs of black and white patients were matched for age at diagnosis, gender, insurance coverage, income, education, facility type, tumor stage, Charlson-Deyo score, surgical management, margin status, and other potential confounders.

Every matched patient completed their recommended therapy, and there was no statistical difference between matched black and white patients who received appropriate, stage-specific chemoradiation. Still, the survival differences persisted.

Dr. Nolan had no relevant disclosures.

aotto@frontlinemedcom.com

Most adults who survived out-of-hospital cardiac arrests remained neurologically intact, even if cardiopulmonary resuscitation lasted longer than has been recommended, authors of a retrospective observational study reported at the American Heart Association scientific sessions.

Dr. Jefferson Williams of the Wake County Department of Emergency Medical Services in Raleigh, N.C., and his associates studied 3,814 adults who had a cardiac arrest outside the hospital between 2005 and 2014. Only 12% of patients survived, but 84% of survivors had a cerebral performance category of 1 or 2, including 10% who underwent more than 35 minutes of CPR before reaching the hospital.

Neurologically intact survival was associated with having an initial shockable rhythm, a bystander-witnessed arrest, and return of spontaneous circulation in the field rather than in the hospital. Age, basic airway management, and therapeutic hypothermia phase also predicted survival with intact brain function, but duration of CPR did not.

Dr. Williams had no disclosures. The senior author disclosed research funding from the Medtronic Foundation.

Most adults who survived out-of-hospital cardiac arrests remained neurologically intact, even if cardiopulmonary resuscitation lasted longer than has been recommended, authors of a retrospective observational study reported at the American Heart Association scientific sessions.

Dr. Jefferson Williams of the Wake County Department of Emergency Medical Services in Raleigh, N.C., and his associates studied 3,814 adults who had a cardiac arrest outside the hospital between 2005 and 2014. Only 12% of patients survived, but 84% of survivors had a cerebral performance category of 1 or 2, including 10% who underwent more than 35 minutes of CPR before reaching the hospital.

Neurologically intact survival was associated with having an initial shockable rhythm, a bystander-witnessed arrest, and return of spontaneous circulation in the field rather than in the hospital. Age, basic airway management, and therapeutic hypothermia phase also predicted survival with intact brain function, but duration of CPR did not.

Dr. Williams had no disclosures. The senior author disclosed research funding from the Medtronic Foundation.

Most adults who survived out-of-hospital cardiac arrests remained neurologically intact, even if cardiopulmonary resuscitation lasted longer than has been recommended, authors of a retrospective observational study reported at the American Heart Association scientific sessions.

Dr. Jefferson Williams of the Wake County Department of Emergency Medical Services in Raleigh, N.C., and his associates studied 3,814 adults who had a cardiac arrest outside the hospital between 2005 and 2014. Only 12% of patients survived, but 84% of survivors had a cerebral performance category of 1 or 2, including 10% who underwent more than 35 minutes of CPR before reaching the hospital.

Neurologically intact survival was associated with having an initial shockable rhythm, a bystander-witnessed arrest, and return of spontaneous circulation in the field rather than in the hospital. Age, basic airway management, and therapeutic hypothermia phase also predicted survival with intact brain function, but duration of CPR did not.

Dr. Williams had no disclosures. The senior author disclosed research funding from the Medtronic Foundation.

Box of clopidogrel (Plavix)

A review conducted by the US Food and Drug Administration (FDA) indicates that long-term use of the antiplatelet drug clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with, or at risk for, heart disease.

In addition, the FDA said there is no evidence to suggest that clopidogrel increases the risk of cancer or death from cancer.

These findings contradict those of the Dual Antiplatelet Therapy (DAPT) trial, the study that prompted the FDA’s review.

In this trial, researchers compared 12 months of DAPT (either clopidogrel or prasugrel plus aspirin) to 30 months of DAPT in patients who had a drug-eluting coronary stent.

Compared to patients taking clopidogrel for 12 months, patients who received clopidogrel for 30 months had lower rates of heart attacks and stent thrombosis but higher rates of death, primarily from cancer or trauma.

To investigate these findings, the FDA examined data from the DAPT trial and performed trial-level meta-analyses of other large, long-term trials.

The trials had a clopidogrel-plus-aspirin arm (long-term treatment was 12 months or longer) and a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less). They also had a planned follow-up of at least 1 year.

All-cause death

In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs 1.5% for 12 months). But there was no increased risk for prasugrel plus aspirin (1.6% for 30 months vs 1.6% for 12 months).

The FDA’s initial meta-analysis on mortality included 12 trials (56,799 patients). The incidence of all-cause mortality was 6.7% for the long-term clopidogrel-plus-aspirin arm and 6.6% for the comparator arm, resulting in a Mantel Haenszel Risk Difference (MH RD) of 0.04% (95% CI, -0.35%-0.44%).

The FDA also conducted a meta-analysis of 9 of the 12 trials (45,374 patients), which enrolled patients with coronary artery disease or patients at risk of coronary artery disease. This analysis showed no difference in the risk of all-cause mortality—MH RD of -0.07% (95% CI, -0.43%-0.29%).

Cancer and death in DAPT

In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel, when considering cancers reported after enrollment (from month 0 to 33 of the study).

The FDA performed several analyses of the cancer adverse event data, and the relative risk of cancer for the 30-month vs 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis.

Similar analyses for the prasugrel group revealed relative risks of cancer-related adverse events ranging from 1.4 to 1.6.

The FDA noted that, although there was no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm, the risk of cancer-related death was higher than in the 12-month arm—0.7% and 0.2%, respectively.

For prasugrel, there was a trend toward a higher risk of cancer adverse events in the 30-month arm than in the 12-month arm, but the risk of cancer death was identical in both arms—0.4% vs 0.4%.

The FDA said these findings are difficult to reconcile.

Meta-analyses of cancer and death

The FDA performed 2 trial-level meta-analyses to investigate the role of clopidogrel in cancer and cancer death.

The first was an analysis of cancer-related adverse events from 4 trials (37,835 patients) that compared long-term clopidogrel and aspirin to either aspirin alone or short-term clopidogrel plus aspirin.

The incidence of cancer adverse events was 4.2% for the long-term clopidogrel-plus-aspirin arm and 4.0% for the comparator arm (MH RD of 0.19%; 95% CI, -0.2%-0.59%).

The FDA conducted the second meta-analysis to assess cancer-related death. The analysis included 5 trials (40,855 patients).

The incidence of cancer death was 0.9% for the long-term clopidogrel-plus-aspirin arm and 1.1% for the comparator arm (MH RD of -0.14%; 95% CI, -0.33%-0.06%).

The FDA said that, taken together, the results of this review do not suggest an increased risk of cancer adverse events, cancer-related death, or all-cause mortality with long-term clopidogrel therapy.

More details can be found in the FDA’s Drug Safety Communication on this topic.

Box of clopidogrel (Plavix)

A review conducted by the US Food and Drug Administration (FDA) indicates that long-term use of the antiplatelet drug clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with, or at risk for, heart disease.

In addition, the FDA said there is no evidence to suggest that clopidogrel increases the risk of cancer or death from cancer.

These findings contradict those of the Dual Antiplatelet Therapy (DAPT) trial, the study that prompted the FDA’s review.

In this trial, researchers compared 12 months of DAPT (either clopidogrel or prasugrel plus aspirin) to 30 months of DAPT in patients who had a drug-eluting coronary stent.

Compared to patients taking clopidogrel for 12 months, patients who received clopidogrel for 30 months had lower rates of heart attacks and stent thrombosis but higher rates of death, primarily from cancer or trauma.

To investigate these findings, the FDA examined data from the DAPT trial and performed trial-level meta-analyses of other large, long-term trials.

The trials had a clopidogrel-plus-aspirin arm (long-term treatment was 12 months or longer) and a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less). They also had a planned follow-up of at least 1 year.

All-cause death

In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs 1.5% for 12 months). But there was no increased risk for prasugrel plus aspirin (1.6% for 30 months vs 1.6% for 12 months).

The FDA’s initial meta-analysis on mortality included 12 trials (56,799 patients). The incidence of all-cause mortality was 6.7% for the long-term clopidogrel-plus-aspirin arm and 6.6% for the comparator arm, resulting in a Mantel Haenszel Risk Difference (MH RD) of 0.04% (95% CI, -0.35%-0.44%).

The FDA also conducted a meta-analysis of 9 of the 12 trials (45,374 patients), which enrolled patients with coronary artery disease or patients at risk of coronary artery disease. This analysis showed no difference in the risk of all-cause mortality—MH RD of -0.07% (95% CI, -0.43%-0.29%).

Cancer and death in DAPT

In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel, when considering cancers reported after enrollment (from month 0 to 33 of the study).

The FDA performed several analyses of the cancer adverse event data, and the relative risk of cancer for the 30-month vs 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis.

Similar analyses for the prasugrel group revealed relative risks of cancer-related adverse events ranging from 1.4 to 1.6.

The FDA noted that, although there was no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm, the risk of cancer-related death was higher than in the 12-month arm—0.7% and 0.2%, respectively.

For prasugrel, there was a trend toward a higher risk of cancer adverse events in the 30-month arm than in the 12-month arm, but the risk of cancer death was identical in both arms—0.4% vs 0.4%.

The FDA said these findings are difficult to reconcile.

Meta-analyses of cancer and death

The FDA performed 2 trial-level meta-analyses to investigate the role of clopidogrel in cancer and cancer death.

The first was an analysis of cancer-related adverse events from 4 trials (37,835 patients) that compared long-term clopidogrel and aspirin to either aspirin alone or short-term clopidogrel plus aspirin.

The incidence of cancer adverse events was 4.2% for the long-term clopidogrel-plus-aspirin arm and 4.0% for the comparator arm (MH RD of 0.19%; 95% CI, -0.2%-0.59%).

The FDA conducted the second meta-analysis to assess cancer-related death. The analysis included 5 trials (40,855 patients).

The incidence of cancer death was 0.9% for the long-term clopidogrel-plus-aspirin arm and 1.1% for the comparator arm (MH RD of -0.14%; 95% CI, -0.33%-0.06%).

The FDA said that, taken together, the results of this review do not suggest an increased risk of cancer adverse events, cancer-related death, or all-cause mortality with long-term clopidogrel therapy.

More details can be found in the FDA’s Drug Safety Communication on this topic.

Box of clopidogrel (Plavix)

A review conducted by the US Food and Drug Administration (FDA) indicates that long-term use of the antiplatelet drug clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with, or at risk for, heart disease.

In addition, the FDA said there is no evidence to suggest that clopidogrel increases the risk of cancer or death from cancer.

These findings contradict those of the Dual Antiplatelet Therapy (DAPT) trial, the study that prompted the FDA’s review.

In this trial, researchers compared 12 months of DAPT (either clopidogrel or prasugrel plus aspirin) to 30 months of DAPT in patients who had a drug-eluting coronary stent.

Compared to patients taking clopidogrel for 12 months, patients who received clopidogrel for 30 months had lower rates of heart attacks and stent thrombosis but higher rates of death, primarily from cancer or trauma.

To investigate these findings, the FDA examined data from the DAPT trial and performed trial-level meta-analyses of other large, long-term trials.

The trials had a clopidogrel-plus-aspirin arm (long-term treatment was 12 months or longer) and a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less). They also had a planned follow-up of at least 1 year.

All-cause death

In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs 1.5% for 12 months). But there was no increased risk for prasugrel plus aspirin (1.6% for 30 months vs 1.6% for 12 months).

The FDA’s initial meta-analysis on mortality included 12 trials (56,799 patients). The incidence of all-cause mortality was 6.7% for the long-term clopidogrel-plus-aspirin arm and 6.6% for the comparator arm, resulting in a Mantel Haenszel Risk Difference (MH RD) of 0.04% (95% CI, -0.35%-0.44%).

The FDA also conducted a meta-analysis of 9 of the 12 trials (45,374 patients), which enrolled patients with coronary artery disease or patients at risk of coronary artery disease. This analysis showed no difference in the risk of all-cause mortality—MH RD of -0.07% (95% CI, -0.43%-0.29%).

Cancer and death in DAPT

In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel, when considering cancers reported after enrollment (from month 0 to 33 of the study).

The FDA performed several analyses of the cancer adverse event data, and the relative risk of cancer for the 30-month vs 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis.

Similar analyses for the prasugrel group revealed relative risks of cancer-related adverse events ranging from 1.4 to 1.6.

The FDA noted that, although there was no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm, the risk of cancer-related death was higher than in the 12-month arm—0.7% and 0.2%, respectively.

For prasugrel, there was a trend toward a higher risk of cancer adverse events in the 30-month arm than in the 12-month arm, but the risk of cancer death was identical in both arms—0.4% vs 0.4%.

The FDA said these findings are difficult to reconcile.

Meta-analyses of cancer and death

The FDA performed 2 trial-level meta-analyses to investigate the role of clopidogrel in cancer and cancer death.

The first was an analysis of cancer-related adverse events from 4 trials (37,835 patients) that compared long-term clopidogrel and aspirin to either aspirin alone or short-term clopidogrel plus aspirin.

The incidence of cancer adverse events was 4.2% for the long-term clopidogrel-plus-aspirin arm and 4.0% for the comparator arm (MH RD of 0.19%; 95% CI, -0.2%-0.59%).

The FDA conducted the second meta-analysis to assess cancer-related death. The analysis included 5 trials (40,855 patients).

The incidence of cancer death was 0.9% for the long-term clopidogrel-plus-aspirin arm and 1.1% for the comparator arm (MH RD of -0.14%; 95% CI, -0.33%-0.06%).

The FDA said that, taken together, the results of this review do not suggest an increased risk of cancer adverse events, cancer-related death, or all-cause mortality with long-term clopidogrel therapy.

More details can be found in the FDA’s Drug Safety Communication on this topic.

LAS VEGAS – The addition of field treatment to targeted lesion treatment may offer patients the best outcomes when addressing actinic keratoses (AKs), said Dr. David M. Pariser, professor of dermatology at Eastern Virginia Medical School, Norfolk, Virginia.

Speaking at the Skin Disease Education Foundation’s annual Las Vegas dermatology seminar, Dr. Pariser said that the rationale for treating AKs stems from the fact that not all AKs will transform to squamous cell carcinoma (SCC). “We don’t know which ones will and which ones won’t.” Though treatment can be guided by a shared decision-making approach, a personal history of multiple skin cancers is an obvious reason for concern, as is any drug-related or disease-related immunosuppression, he added.

Available treatments for AKs include cryosurgery, curettage, and electrodessication; photodynamic therapy (PDT); and topical agents, including 5-fluorouracil (5-FU), diclofenac, imiquimod, and ingenol mebutate.

“Cryosurgery is what most of us do for most AKs,” said Dr. Pariser, observing that this is a bread-and-butter procedure that is part of the backbone of most dermatology practices. Cryosurgery, curettage, and electrodessication are all used to treat discrete lesions, especially for higher-grade AKs.

However, Dr. Pariser noted that many AKs occur in a “field of cancerization.” This is a larger area of photodamaged skin; the skin may not appear grossly abnormal, but deranged areas will be diffusely evident with fluorescence detection, “indicating that all of this area was damaged,” he said.

PDT and topical agents effectively provide field treatment, and do not just address discrete lesions, although field treatment is technically an off-label use for these modalities, he added.

Lower concentrations and shorter courses of topical agents may be effective and better tolerated by patients, Dr. Pariser said. In clinical trials, for example, the efficacy of imiquimod 2.5% and 3.75% has been comparable to the stronger 5% formulation. Treatment cycles lasting 2 rather than 3 weeks have also shown similar efficacy. The greater palatability of these regimens to patients may increase real-world adherence as well.

Cure rates for PDT range from 67% to 92% for both the blue light–aminolevulinic acid modality and the red light–methyl aminolevulinate more commonly used in Europe. These modalities also treat a broad field, offer cure rates comparable to other topical modalities, and result in less scarring than destructive modalities, Dr. Pariser said.

The pain of PDT may be understandably off-putting for some patients, he commented. In the United States, investigators are experimenting with shorter incubation times for the ALA topical solutions. One study found comparable reductions in the number of AKs by the end of the study period for 1 versus 2 or 3 hours of incubation, and a 2-hour incubation period with spot treatment only was also similarly effective. Clearance rates ranged from about 70%-80%, and all were highly statistically significant, compared with the vehicle-only arm. However, “a second treatment at week 8 seems to be necessary for improved efficacy,” Dr. Pariser said.

Another treatment strategy currently being investigated is “painless PDT,” where the agent is applied and the field is illuminated immediately. Photo-bleaching degrades the protoporphyrins as they are produced, dramatically reducing patient discomfort. Efficacy is promising, he added.

In Europe, “daylight PDT” is being explored – the photosensitizing agent is applied, and the patient simply goes about his or her daily business in normal daylight. This is a nearly painless therapy and shows promise for efficacy. However, said Dr. Pariser, the realities of practice economics make it very unlikely that daylight PDT will catch on in the United States, since the daylight exposure does not represent a billable procedure.

Dr. Pariser reiterated that regardless of the modality, “field therapy has better long-term efficacy rates and better sustained clearance no matter which one of the agents we use, and combination therapy [of lesional and field treatment] seems to be the most effective.”

Dr. Pariser disclosed that he is an investigator and consultant for DUSA Pharmaceuticals, Photocure, and LEO Pharma, and that he discussed off-label uses of drugs and devices.

SDEF and this news organization are owned by the same parent company.

koakes@frontlinemedcom.com

On Twitter @karioakes

LAS VEGAS – The addition of field treatment to targeted lesion treatment may offer patients the best outcomes when addressing actinic keratoses (AKs), said Dr. David M. Pariser, professor of dermatology at Eastern Virginia Medical School, Norfolk, Virginia.

Speaking at the Skin Disease Education Foundation’s annual Las Vegas dermatology seminar, Dr. Pariser said that the rationale for treating AKs stems from the fact that not all AKs will transform to squamous cell carcinoma (SCC). “We don’t know which ones will and which ones won’t.” Though treatment can be guided by a shared decision-making approach, a personal history of multiple skin cancers is an obvious reason for concern, as is any drug-related or disease-related immunosuppression, he added.

Available treatments for AKs include cryosurgery, curettage, and electrodessication; photodynamic therapy (PDT); and topical agents, including 5-fluorouracil (5-FU), diclofenac, imiquimod, and ingenol mebutate.

“Cryosurgery is what most of us do for most AKs,” said Dr. Pariser, observing that this is a bread-and-butter procedure that is part of the backbone of most dermatology practices. Cryosurgery, curettage, and electrodessication are all used to treat discrete lesions, especially for higher-grade AKs.

However, Dr. Pariser noted that many AKs occur in a “field of cancerization.” This is a larger area of photodamaged skin; the skin may not appear grossly abnormal, but deranged areas will be diffusely evident with fluorescence detection, “indicating that all of this area was damaged,” he said.

PDT and topical agents effectively provide field treatment, and do not just address discrete lesions, although field treatment is technically an off-label use for these modalities, he added.

Lower concentrations and shorter courses of topical agents may be effective and better tolerated by patients, Dr. Pariser said. In clinical trials, for example, the efficacy of imiquimod 2.5% and 3.75% has been comparable to the stronger 5% formulation. Treatment cycles lasting 2 rather than 3 weeks have also shown similar efficacy. The greater palatability of these regimens to patients may increase real-world adherence as well.

Cure rates for PDT range from 67% to 92% for both the blue light–aminolevulinic acid modality and the red light–methyl aminolevulinate more commonly used in Europe. These modalities also treat a broad field, offer cure rates comparable to other topical modalities, and result in less scarring than destructive modalities, Dr. Pariser said.

The pain of PDT may be understandably off-putting for some patients, he commented. In the United States, investigators are experimenting with shorter incubation times for the ALA topical solutions. One study found comparable reductions in the number of AKs by the end of the study period for 1 versus 2 or 3 hours of incubation, and a 2-hour incubation period with spot treatment only was also similarly effective. Clearance rates ranged from about 70%-80%, and all were highly statistically significant, compared with the vehicle-only arm. However, “a second treatment at week 8 seems to be necessary for improved efficacy,” Dr. Pariser said.

Another treatment strategy currently being investigated is “painless PDT,” where the agent is applied and the field is illuminated immediately. Photo-bleaching degrades the protoporphyrins as they are produced, dramatically reducing patient discomfort. Efficacy is promising, he added.

In Europe, “daylight PDT” is being explored – the photosensitizing agent is applied, and the patient simply goes about his or her daily business in normal daylight. This is a nearly painless therapy and shows promise for efficacy. However, said Dr. Pariser, the realities of practice economics make it very unlikely that daylight PDT will catch on in the United States, since the daylight exposure does not represent a billable procedure.

Dr. Pariser reiterated that regardless of the modality, “field therapy has better long-term efficacy rates and better sustained clearance no matter which one of the agents we use, and combination therapy [of lesional and field treatment] seems to be the most effective.”

Dr. Pariser disclosed that he is an investigator and consultant for DUSA Pharmaceuticals, Photocure, and LEO Pharma, and that he discussed off-label uses of drugs and devices.

SDEF and this news organization are owned by the same parent company.

koakes@frontlinemedcom.com

On Twitter @karioakes

LAS VEGAS – The addition of field treatment to targeted lesion treatment may offer patients the best outcomes when addressing actinic keratoses (AKs), said Dr. David M. Pariser, professor of dermatology at Eastern Virginia Medical School, Norfolk, Virginia.

Speaking at the Skin Disease Education Foundation’s annual Las Vegas dermatology seminar, Dr. Pariser said that the rationale for treating AKs stems from the fact that not all AKs will transform to squamous cell carcinoma (SCC). “We don’t know which ones will and which ones won’t.” Though treatment can be guided by a shared decision-making approach, a personal history of multiple skin cancers is an obvious reason for concern, as is any drug-related or disease-related immunosuppression, he added.

Available treatments for AKs include cryosurgery, curettage, and electrodessication; photodynamic therapy (PDT); and topical agents, including 5-fluorouracil (5-FU), diclofenac, imiquimod, and ingenol mebutate.

“Cryosurgery is what most of us do for most AKs,” said Dr. Pariser, observing that this is a bread-and-butter procedure that is part of the backbone of most dermatology practices. Cryosurgery, curettage, and electrodessication are all used to treat discrete lesions, especially for higher-grade AKs.

However, Dr. Pariser noted that many AKs occur in a “field of cancerization.” This is a larger area of photodamaged skin; the skin may not appear grossly abnormal, but deranged areas will be diffusely evident with fluorescence detection, “indicating that all of this area was damaged,” he said.

PDT and topical agents effectively provide field treatment, and do not just address discrete lesions, although field treatment is technically an off-label use for these modalities, he added.

Lower concentrations and shorter courses of topical agents may be effective and better tolerated by patients, Dr. Pariser said. In clinical trials, for example, the efficacy of imiquimod 2.5% and 3.75% has been comparable to the stronger 5% formulation. Treatment cycles lasting 2 rather than 3 weeks have also shown similar efficacy. The greater palatability of these regimens to patients may increase real-world adherence as well.

Cure rates for PDT range from 67% to 92% for both the blue light–aminolevulinic acid modality and the red light–methyl aminolevulinate more commonly used in Europe. These modalities also treat a broad field, offer cure rates comparable to other topical modalities, and result in less scarring than destructive modalities, Dr. Pariser said.

The pain of PDT may be understandably off-putting for some patients, he commented. In the United States, investigators are experimenting with shorter incubation times for the ALA topical solutions. One study found comparable reductions in the number of AKs by the end of the study period for 1 versus 2 or 3 hours of incubation, and a 2-hour incubation period with spot treatment only was also similarly effective. Clearance rates ranged from about 70%-80%, and all were highly statistically significant, compared with the vehicle-only arm. However, “a second treatment at week 8 seems to be necessary for improved efficacy,” Dr. Pariser said.

Another treatment strategy currently being investigated is “painless PDT,” where the agent is applied and the field is illuminated immediately. Photo-bleaching degrades the protoporphyrins as they are produced, dramatically reducing patient discomfort. Efficacy is promising, he added.

In Europe, “daylight PDT” is being explored – the photosensitizing agent is applied, and the patient simply goes about his or her daily business in normal daylight. This is a nearly painless therapy and shows promise for efficacy. However, said Dr. Pariser, the realities of practice economics make it very unlikely that daylight PDT will catch on in the United States, since the daylight exposure does not represent a billable procedure.

Dr. Pariser reiterated that regardless of the modality, “field therapy has better long-term efficacy rates and better sustained clearance no matter which one of the agents we use, and combination therapy [of lesional and field treatment] seems to be the most effective.”

Dr. Pariser disclosed that he is an investigator and consultant for DUSA Pharmaceuticals, Photocure, and LEO Pharma, and that he discussed off-label uses of drugs and devices.

SDEF and this news organization are owned by the same parent company.

koakes@frontlinemedcom.com

On Twitter @karioakes