Amputation in diabetes is less likely when critical limb ischemia is approached in a multidisciplinary way, according to the coauthor of clinical recommendations issued earlier this year. But to ensure optimal patient outcomes, just who should be on the interdisciplinary care team, how should it be coordinated, and what algorithms are best?

To help navigate these concerns, Joseph L. Mills, MD, professor and chief of vascular surgery and endovascular therapy at Baylor College of Medicine in Houston, will discuss “the toe and flow” model of care on Sunday morning, Sept. 18, as part of the presymposium Addressing Core Questions in Critical Limb Ischemia session.

“This model of care combines podiatrists and orthopedists with vascular specialists who provide advanced open surgery and endovascular therapy, to provide best treatment for patients,” said Dr. Mills, who coauthored the Society for Vascular Surgery Threatened Limb Classification (Wound, Ischemia, and foot Infection), or “WIfI,” as well as a clinical guideline on management of the diabetic foot, released earlier this year by the SVS in collaboration with the American Podiatric Medical Association, and the Society for Vascular Medicine.

Every 20 seconds, somewhere in the world a person with diabetes undergoes leg amputation as a result of the disease, according to Dr. Mills. Not only are the resulting costs of care unmanageable, fragmented diabetic foot care compromises a patient’s quality and longevity of life, he said.

The unfortunate path to amputation in diabetes most commonly begins with a simple neuropathic foot ulcer, often made worse by peripheral artery disease. The wound eventually moves through acute and chronic stages of neuropathy, vasculopathy, and infection, until amputation is necessary. Offering appropriate intervention at any point in this trajectory, or avoiding it altogether, means the ideal care team should include specialists with expertise in these disciplines. Beyond the core team members of a vascular surgeon, podiatrist, and orthopedic specialist, Dr. Mills said that other interdisciplinary team configurations might include a diabetologist, orthopedist, plastic surgeon, infectious disease specialist, general surgeon, and pedorthist/prosthetist.

“Learning how to build ‘toe and flow’ teams into your local environment can help improve outcomes in this challenging patient population,” Dr. Mills said. “Methods and flow diagrams concerning how this can be done will be a major focus of the talk.”

Dr. Mills will cover how patient responsibilities should be divided between team members across varying levels of clinical care, ranging from basic clinics to centers of excellence. The talk will also address aftercare, as well as how to facilitate effective communication between team members and patients.

“Enthusiasm for this model is the key ingredient to helping reduce the number of amputations in your patients,” he said.

[email protected]

On Twitter @whitneymcknight

Amputation in diabetes is less likely when critical limb ischemia is approached in a multidisciplinary way, according to the coauthor of clinical recommendations issued earlier this year. But to ensure optimal patient outcomes, just who should be on the interdisciplinary care team, how should it be coordinated, and what algorithms are best?

To help navigate these concerns, Joseph L. Mills, MD, professor and chief of vascular surgery and endovascular therapy at Baylor College of Medicine in Houston, will discuss “the toe and flow” model of care on Sunday morning, Sept. 18, as part of the presymposium Addressing Core Questions in Critical Limb Ischemia session.

“This model of care combines podiatrists and orthopedists with vascular specialists who provide advanced open surgery and endovascular therapy, to provide best treatment for patients,” said Dr. Mills, who coauthored the Society for Vascular Surgery Threatened Limb Classification (Wound, Ischemia, and foot Infection), or “WIfI,” as well as a clinical guideline on management of the diabetic foot, released earlier this year by the SVS in collaboration with the American Podiatric Medical Association, and the Society for Vascular Medicine.

Every 20 seconds, somewhere in the world a person with diabetes undergoes leg amputation as a result of the disease, according to Dr. Mills. Not only are the resulting costs of care unmanageable, fragmented diabetic foot care compromises a patient’s quality and longevity of life, he said.

The unfortunate path to amputation in diabetes most commonly begins with a simple neuropathic foot ulcer, often made worse by peripheral artery disease. The wound eventually moves through acute and chronic stages of neuropathy, vasculopathy, and infection, until amputation is necessary. Offering appropriate intervention at any point in this trajectory, or avoiding it altogether, means the ideal care team should include specialists with expertise in these disciplines. Beyond the core team members of a vascular surgeon, podiatrist, and orthopedic specialist, Dr. Mills said that other interdisciplinary team configurations might include a diabetologist, orthopedist, plastic surgeon, infectious disease specialist, general surgeon, and pedorthist/prosthetist.

“Learning how to build ‘toe and flow’ teams into your local environment can help improve outcomes in this challenging patient population,” Dr. Mills said. “Methods and flow diagrams concerning how this can be done will be a major focus of the talk.”

Dr. Mills will cover how patient responsibilities should be divided between team members across varying levels of clinical care, ranging from basic clinics to centers of excellence. The talk will also address aftercare, as well as how to facilitate effective communication between team members and patients.

“Enthusiasm for this model is the key ingredient to helping reduce the number of amputations in your patients,” he said.

[email protected]

On Twitter @whitneymcknight

Amputation in diabetes is less likely when critical limb ischemia is approached in a multidisciplinary way, according to the coauthor of clinical recommendations issued earlier this year. But to ensure optimal patient outcomes, just who should be on the interdisciplinary care team, how should it be coordinated, and what algorithms are best?

To help navigate these concerns, Joseph L. Mills, MD, professor and chief of vascular surgery and endovascular therapy at Baylor College of Medicine in Houston, will discuss “the toe and flow” model of care on Sunday morning, Sept. 18, as part of the presymposium Addressing Core Questions in Critical Limb Ischemia session.

“This model of care combines podiatrists and orthopedists with vascular specialists who provide advanced open surgery and endovascular therapy, to provide best treatment for patients,” said Dr. Mills, who coauthored the Society for Vascular Surgery Threatened Limb Classification (Wound, Ischemia, and foot Infection), or “WIfI,” as well as a clinical guideline on management of the diabetic foot, released earlier this year by the SVS in collaboration with the American Podiatric Medical Association, and the Society for Vascular Medicine.

Every 20 seconds, somewhere in the world a person with diabetes undergoes leg amputation as a result of the disease, according to Dr. Mills. Not only are the resulting costs of care unmanageable, fragmented diabetic foot care compromises a patient’s quality and longevity of life, he said.

The unfortunate path to amputation in diabetes most commonly begins with a simple neuropathic foot ulcer, often made worse by peripheral artery disease. The wound eventually moves through acute and chronic stages of neuropathy, vasculopathy, and infection, until amputation is necessary. Offering appropriate intervention at any point in this trajectory, or avoiding it altogether, means the ideal care team should include specialists with expertise in these disciplines. Beyond the core team members of a vascular surgeon, podiatrist, and orthopedic specialist, Dr. Mills said that other interdisciplinary team configurations might include a diabetologist, orthopedist, plastic surgeon, infectious disease specialist, general surgeon, and pedorthist/prosthetist.

“Learning how to build ‘toe and flow’ teams into your local environment can help improve outcomes in this challenging patient population,” Dr. Mills said. “Methods and flow diagrams concerning how this can be done will be a major focus of the talk.”

Dr. Mills will cover how patient responsibilities should be divided between team members across varying levels of clinical care, ranging from basic clinics to centers of excellence. The talk will also address aftercare, as well as how to facilitate effective communication between team members and patients.

“Enthusiasm for this model is the key ingredient to helping reduce the number of amputations in your patients,” he said.

[email protected]

On Twitter @whitneymcknight

SAN FRANCISCO – Frontal cortical thinning was common in late-life depression but generally did not predict executive dysfunction, according to magnetic resonance imaging studies of 157 adults.

The only exception was the left middle fronto-orbital gyrus. Thinning there predicted significantly worse performance on tests of executive function and processing speed, said Krista Farley of the late-life depression program at the University of California, San Francisco. Based on this limited finding, “further investigation of the etiology of executive dysfunction in late-life depression is warranted,” Ms. Farley said in a poster presented at the 2016 congress of the International Psychogeriatric Association.

©Jana Bla?ková/Thinkstock

About 5%-10% of community-dwelling older adults meet criteria for major depressive disorder, which is even more common in acute care and long-term care settings, and is often refractory to pharmacotherapy. Although late-life depression has been linked to cortical atrophy and executive dysfunction, it was unknown whether those two aspects of the disorder were related, Ms. Farley said.

The study by Ms. Farley and her associates of adults aged 65 years and older included 65 normal controls and 92 patients who met DSM-IV criteria for major depressive disorder, scored at least 19 on the Hamilton Depression Rating Scale, and had no evidence of dementia, having scored at least 25 on the Mini–Mental State Examination. Using T1– and T2–weighted structural MRI scans, the researchers measured the cortical thickness of six individual regions of the frontal lobe as well as the anterior cingulate gyrus. The patient and control groups resembled one another in terms of education, IQ, and age, but 71% of patients with late-life depression were female, compared with only 50% of controls.

Patients with late-life depression had significantly more thinning of the middle frontal gyrus, the inferior frontal gyrus, and the middle fronto-orbital gyrus, compared with controls, even after the investigators adjusted for age and sex (P less than .05 for all comparisons). Analyzing the left and right brain hemispheres separately localized the differences to the left hemisphere and additionally implicated the left lateral frontal orbital gyrus (mean thickness in patients, 3.2 mm; standard deviation, 0.2; versus 3.4 mm [SD = 0.31] in controls; P = .03).

Patients with late-life depression also scored significantly lower than controls on the Symbol Digit Modalities Test for information processing speed (P = .001) and the Stroop test of executive function (P = .002). The thickness of the left middle fronto-orbital gyrus was significantly inversely correlated with performance on both tests, with P values of .01 and .03, respectively. “The negative association with focal frontal regions was unexpected and deserves further investigation,” Ms. Farley said. But because cortical thinning in other locations did not predict cognitive performance, “cortical abnormalities may have a limited role in the manifestation of cognitive dysfunction in this vulnerable patient population,” Ms. Farley concluded.

The National Institutes of Health and the Leon J. Epstein Psychiatry Fund at the University of California, San Francisco, supported the work. Ms. Farley had no relevant financial disclosures.

SAN FRANCISCO – Frontal cortical thinning was common in late-life depression but generally did not predict executive dysfunction, according to magnetic resonance imaging studies of 157 adults.

The only exception was the left middle fronto-orbital gyrus. Thinning there predicted significantly worse performance on tests of executive function and processing speed, said Krista Farley of the late-life depression program at the University of California, San Francisco. Based on this limited finding, “further investigation of the etiology of executive dysfunction in late-life depression is warranted,” Ms. Farley said in a poster presented at the 2016 congress of the International Psychogeriatric Association.

©Jana Bla?ková/Thinkstock

About 5%-10% of community-dwelling older adults meet criteria for major depressive disorder, which is even more common in acute care and long-term care settings, and is often refractory to pharmacotherapy. Although late-life depression has been linked to cortical atrophy and executive dysfunction, it was unknown whether those two aspects of the disorder were related, Ms. Farley said.

The study by Ms. Farley and her associates of adults aged 65 years and older included 65 normal controls and 92 patients who met DSM-IV criteria for major depressive disorder, scored at least 19 on the Hamilton Depression Rating Scale, and had no evidence of dementia, having scored at least 25 on the Mini–Mental State Examination. Using T1– and T2–weighted structural MRI scans, the researchers measured the cortical thickness of six individual regions of the frontal lobe as well as the anterior cingulate gyrus. The patient and control groups resembled one another in terms of education, IQ, and age, but 71% of patients with late-life depression were female, compared with only 50% of controls.

Patients with late-life depression had significantly more thinning of the middle frontal gyrus, the inferior frontal gyrus, and the middle fronto-orbital gyrus, compared with controls, even after the investigators adjusted for age and sex (P less than .05 for all comparisons). Analyzing the left and right brain hemispheres separately localized the differences to the left hemisphere and additionally implicated the left lateral frontal orbital gyrus (mean thickness in patients, 3.2 mm; standard deviation, 0.2; versus 3.4 mm [SD = 0.31] in controls; P = .03).

Patients with late-life depression also scored significantly lower than controls on the Symbol Digit Modalities Test for information processing speed (P = .001) and the Stroop test of executive function (P = .002). The thickness of the left middle fronto-orbital gyrus was significantly inversely correlated with performance on both tests, with P values of .01 and .03, respectively. “The negative association with focal frontal regions was unexpected and deserves further investigation,” Ms. Farley said. But because cortical thinning in other locations did not predict cognitive performance, “cortical abnormalities may have a limited role in the manifestation of cognitive dysfunction in this vulnerable patient population,” Ms. Farley concluded.

The National Institutes of Health and the Leon J. Epstein Psychiatry Fund at the University of California, San Francisco, supported the work. Ms. Farley had no relevant financial disclosures.

SAN FRANCISCO – Frontal cortical thinning was common in late-life depression but generally did not predict executive dysfunction, according to magnetic resonance imaging studies of 157 adults.

The only exception was the left middle fronto-orbital gyrus. Thinning there predicted significantly worse performance on tests of executive function and processing speed, said Krista Farley of the late-life depression program at the University of California, San Francisco. Based on this limited finding, “further investigation of the etiology of executive dysfunction in late-life depression is warranted,” Ms. Farley said in a poster presented at the 2016 congress of the International Psychogeriatric Association.

©Jana Bla?ková/Thinkstock

About 5%-10% of community-dwelling older adults meet criteria for major depressive disorder, which is even more common in acute care and long-term care settings, and is often refractory to pharmacotherapy. Although late-life depression has been linked to cortical atrophy and executive dysfunction, it was unknown whether those two aspects of the disorder were related, Ms. Farley said.

The study by Ms. Farley and her associates of adults aged 65 years and older included 65 normal controls and 92 patients who met DSM-IV criteria for major depressive disorder, scored at least 19 on the Hamilton Depression Rating Scale, and had no evidence of dementia, having scored at least 25 on the Mini–Mental State Examination. Using T1– and T2–weighted structural MRI scans, the researchers measured the cortical thickness of six individual regions of the frontal lobe as well as the anterior cingulate gyrus. The patient and control groups resembled one another in terms of education, IQ, and age, but 71% of patients with late-life depression were female, compared with only 50% of controls.

Patients with late-life depression had significantly more thinning of the middle frontal gyrus, the inferior frontal gyrus, and the middle fronto-orbital gyrus, compared with controls, even after the investigators adjusted for age and sex (P less than .05 for all comparisons). Analyzing the left and right brain hemispheres separately localized the differences to the left hemisphere and additionally implicated the left lateral frontal orbital gyrus (mean thickness in patients, 3.2 mm; standard deviation, 0.2; versus 3.4 mm [SD = 0.31] in controls; P = .03).

Patients with late-life depression also scored significantly lower than controls on the Symbol Digit Modalities Test for information processing speed (P = .001) and the Stroop test of executive function (P = .002). The thickness of the left middle fronto-orbital gyrus was significantly inversely correlated with performance on both tests, with P values of .01 and .03, respectively. “The negative association with focal frontal regions was unexpected and deserves further investigation,” Ms. Farley said. But because cortical thinning in other locations did not predict cognitive performance, “cortical abnormalities may have a limited role in the manifestation of cognitive dysfunction in this vulnerable patient population,” Ms. Farley concluded.

The National Institutes of Health and the Leon J. Epstein Psychiatry Fund at the University of California, San Francisco, supported the work. Ms. Farley had no relevant financial disclosures.

MUNICH – Once-weekly dulaglutide paired with insulin glargine plus metformin allowed 69% of patients with poorly controlled type 2 diabetes to achieve a hemoglobin A_1c of 7% or lower.

Over the 28-week study, 51% of the group reached an HbA_1c of 6.5% or lower – significantly better than the 17% who achieved this goal on insulin glargine with or without metformin, Paolo Pozzilli, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

Michele G. Sullivan/Frontline Medical News

The combination was safe, with just one incident of severe hypoglycemia, and well tolerated, said Dr. Pozzilli of the University Campus Bio-Medico, Rome. Nausea – the most troublesome side effect of any glucagonlike peptide receptor agonist occurred in 12% of those taking the drug. Diarrhea occurred in 11% and vomiting in 6%. All of the gastrointestinal side effects were significantly more common than they were in the placebo group.

“I would say that the combination treatment of dulaglutide and insulin glargine – with or without metformin – is a reasonable, well-tolerated, and effective option for patients with type 2 diabetes who are not hitting their treatment goals,” he said.

Dr. Pozzilli reported results of Lily’s AWARD-9 trial. The placebo-controlled trial comprised 300 patients with poorly controlled type 2 diabetes (HbA_1c, 7%-10.5%), despite being on insulin glargine and metformin. They were randomized to weekly subcutaneous placebo or 1.5 mg dulaglutide injections, in addition to their usual medications. There was no up titration on the study drug – patients started out with the full dose immediately. The study’s completion rate was high, with 92% of the investigational group and 87% of the control group finishing the 28-week treatment.

The group was typical for poorly controlled type 2 patients. Their mean age was 60 years; about 60% were men; and almost all were white. The mean body mass index was 32 kg/m². The mean disease duration was 13 years, and the mean HbA_1c was 8.4%. Their mean fasting plasma glucose was 8.7 mmol/L.

The effect of dual therapy was quickly evident, with HbA_1c levels beginning to drop within 2 weeks. By 12 weeks, the separation between groups was statistically significant (dulaglutide HbA_1c about 7%, placebo about 8%). By 28 weeks, the combination group had reached a mean HbA_1c of 6.92%, compared with 7.69% in the placebo group. The response curve of the combination group appeared to be on a continuing decline when the study ended. The final measure represented an HbA_1c decrease of 1.44% for the combination group and 0.67% for the placebo group.

By 28 weeks, 69% of the dulaglutide group and 35% of the placebo group had achieved an HbA_1c of 7% or lower – a significant difference. Half of the dulaglutide group (51%) achieved a measure of 6.5% or lower, compared with 17% of the placebo group – also a significant difference.

The addition of dulaglutide moderated the need to increase the insulin that occurred over the study period. By 28 weeks, those taking dulaglutide had increased their insulin by a mean of 0.14 U/kg, compared with an increase of 0.27 U/kg in the placebo group. This difference was also statistically significant.

Patients in the combination group lost significantly more weight as well (mean 1.91 kg vs. a gain of 0.5 kg in the placebo group). Weight loss was quickly evident; by 4 weeks, patients had lost more than 1 kg. This “encouraging sign might help boost patient compliance,” Dr. Pozzilli said.

The side-effect profile was acceptable, compared with placebo. Hypoglycemia occurred in about 55% of those taking dulaglutide and 51% of those taking the placebo; it was symptomatic in 35% and 30%, respectively. Nocturnal hypoglycemia occurred in 28% and 29%, respectively. There was one case of severe hypoglycemia, which occurred in the dulaglutide group.

In addition to the GI side effects, there was one injection site reaction in the dulaglutide group. There were no cases of pancreatitis or pancreatic cancer.

The study was sponsored by Eli Lilly. Dr. Pozzilli is on the company’s speakers’ bureau and receives research grant money from it.

[email protected]

MUNICH – Once-weekly dulaglutide paired with insulin glargine plus metformin allowed 69% of patients with poorly controlled type 2 diabetes to achieve a hemoglobin A_1c of 7% or lower.

Over the 28-week study, 51% of the group reached an HbA_1c of 6.5% or lower – significantly better than the 17% who achieved this goal on insulin glargine with or without metformin, Paolo Pozzilli, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

Michele G. Sullivan/Frontline Medical News

The combination was safe, with just one incident of severe hypoglycemia, and well tolerated, said Dr. Pozzilli of the University Campus Bio-Medico, Rome. Nausea – the most troublesome side effect of any glucagonlike peptide receptor agonist occurred in 12% of those taking the drug. Diarrhea occurred in 11% and vomiting in 6%. All of the gastrointestinal side effects were significantly more common than they were in the placebo group.

“I would say that the combination treatment of dulaglutide and insulin glargine – with or without metformin – is a reasonable, well-tolerated, and effective option for patients with type 2 diabetes who are not hitting their treatment goals,” he said.

Dr. Pozzilli reported results of Lily’s AWARD-9 trial. The placebo-controlled trial comprised 300 patients with poorly controlled type 2 diabetes (HbA_1c, 7%-10.5%), despite being on insulin glargine and metformin. They were randomized to weekly subcutaneous placebo or 1.5 mg dulaglutide injections, in addition to their usual medications. There was no up titration on the study drug – patients started out with the full dose immediately. The study’s completion rate was high, with 92% of the investigational group and 87% of the control group finishing the 28-week treatment.

The group was typical for poorly controlled type 2 patients. Their mean age was 60 years; about 60% were men; and almost all were white. The mean body mass index was 32 kg/m². The mean disease duration was 13 years, and the mean HbA_1c was 8.4%. Their mean fasting plasma glucose was 8.7 mmol/L.

The effect of dual therapy was quickly evident, with HbA_1c levels beginning to drop within 2 weeks. By 12 weeks, the separation between groups was statistically significant (dulaglutide HbA_1c about 7%, placebo about 8%). By 28 weeks, the combination group had reached a mean HbA_1c of 6.92%, compared with 7.69% in the placebo group. The response curve of the combination group appeared to be on a continuing decline when the study ended. The final measure represented an HbA_1c decrease of 1.44% for the combination group and 0.67% for the placebo group.

By 28 weeks, 69% of the dulaglutide group and 35% of the placebo group had achieved an HbA_1c of 7% or lower – a significant difference. Half of the dulaglutide group (51%) achieved a measure of 6.5% or lower, compared with 17% of the placebo group – also a significant difference.

The addition of dulaglutide moderated the need to increase the insulin that occurred over the study period. By 28 weeks, those taking dulaglutide had increased their insulin by a mean of 0.14 U/kg, compared with an increase of 0.27 U/kg in the placebo group. This difference was also statistically significant.

Patients in the combination group lost significantly more weight as well (mean 1.91 kg vs. a gain of 0.5 kg in the placebo group). Weight loss was quickly evident; by 4 weeks, patients had lost more than 1 kg. This “encouraging sign might help boost patient compliance,” Dr. Pozzilli said.

The side-effect profile was acceptable, compared with placebo. Hypoglycemia occurred in about 55% of those taking dulaglutide and 51% of those taking the placebo; it was symptomatic in 35% and 30%, respectively. Nocturnal hypoglycemia occurred in 28% and 29%, respectively. There was one case of severe hypoglycemia, which occurred in the dulaglutide group.

In addition to the GI side effects, there was one injection site reaction in the dulaglutide group. There were no cases of pancreatitis or pancreatic cancer.

The study was sponsored by Eli Lilly. Dr. Pozzilli is on the company’s speakers’ bureau and receives research grant money from it.

[email protected]

MUNICH – Once-weekly dulaglutide paired with insulin glargine plus metformin allowed 69% of patients with poorly controlled type 2 diabetes to achieve a hemoglobin A_1c of 7% or lower.

Over the 28-week study, 51% of the group reached an HbA_1c of 6.5% or lower – significantly better than the 17% who achieved this goal on insulin glargine with or without metformin, Paolo Pozzilli, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

Michele G. Sullivan/Frontline Medical News

The combination was safe, with just one incident of severe hypoglycemia, and well tolerated, said Dr. Pozzilli of the University Campus Bio-Medico, Rome. Nausea – the most troublesome side effect of any glucagonlike peptide receptor agonist occurred in 12% of those taking the drug. Diarrhea occurred in 11% and vomiting in 6%. All of the gastrointestinal side effects were significantly more common than they were in the placebo group.

“I would say that the combination treatment of dulaglutide and insulin glargine – with or without metformin – is a reasonable, well-tolerated, and effective option for patients with type 2 diabetes who are not hitting their treatment goals,” he said.

Dr. Pozzilli reported results of Lily’s AWARD-9 trial. The placebo-controlled trial comprised 300 patients with poorly controlled type 2 diabetes (HbA_1c, 7%-10.5%), despite being on insulin glargine and metformin. They were randomized to weekly subcutaneous placebo or 1.5 mg dulaglutide injections, in addition to their usual medications. There was no up titration on the study drug – patients started out with the full dose immediately. The study’s completion rate was high, with 92% of the investigational group and 87% of the control group finishing the 28-week treatment.

The group was typical for poorly controlled type 2 patients. Their mean age was 60 years; about 60% were men; and almost all were white. The mean body mass index was 32 kg/m². The mean disease duration was 13 years, and the mean HbA_1c was 8.4%. Their mean fasting plasma glucose was 8.7 mmol/L.

The effect of dual therapy was quickly evident, with HbA_1c levels beginning to drop within 2 weeks. By 12 weeks, the separation between groups was statistically significant (dulaglutide HbA_1c about 7%, placebo about 8%). By 28 weeks, the combination group had reached a mean HbA_1c of 6.92%, compared with 7.69% in the placebo group. The response curve of the combination group appeared to be on a continuing decline when the study ended. The final measure represented an HbA_1c decrease of 1.44% for the combination group and 0.67% for the placebo group.

By 28 weeks, 69% of the dulaglutide group and 35% of the placebo group had achieved an HbA_1c of 7% or lower – a significant difference. Half of the dulaglutide group (51%) achieved a measure of 6.5% or lower, compared with 17% of the placebo group – also a significant difference.

The addition of dulaglutide moderated the need to increase the insulin that occurred over the study period. By 28 weeks, those taking dulaglutide had increased their insulin by a mean of 0.14 U/kg, compared with an increase of 0.27 U/kg in the placebo group. This difference was also statistically significant.

Patients in the combination group lost significantly more weight as well (mean 1.91 kg vs. a gain of 0.5 kg in the placebo group). Weight loss was quickly evident; by 4 weeks, patients had lost more than 1 kg. This “encouraging sign might help boost patient compliance,” Dr. Pozzilli said.

The side-effect profile was acceptable, compared with placebo. Hypoglycemia occurred in about 55% of those taking dulaglutide and 51% of those taking the placebo; it was symptomatic in 35% and 30%, respectively. Nocturnal hypoglycemia occurred in 28% and 29%, respectively. There was one case of severe hypoglycemia, which occurred in the dulaglutide group.

In addition to the GI side effects, there was one injection site reaction in the dulaglutide group. There were no cases of pancreatitis or pancreatic cancer.

The study was sponsored by Eli Lilly. Dr. Pozzilli is on the company’s speakers’ bureau and receives research grant money from it.

[email protected]

Primary care practitioners’ use of a seven-item checklist may reduce the number of pediatric patients with respiratory tract infections who are prescribed unnecessary antibiotics, a prognostic cohort study suggests.

The study revealed short illness (a duration of illness of 3 days or less), temperature (a body temperature of 37.8°C or greater at presentation), age (being under 2 years), intercostal or subcostal recession, wheeze on auscultation, asthma, and vomiting (moderate or severe in the previous 24 hours) were each independently associated with hospital admission (P less than .01 for all associations).

©Devonyu/thinkstockphotos.com

The checklist includes these seven characteristics or risk variables (short illness, temperature, age, recession, wheeze, asthma, and vomiting [mnemonic STARWAVe]). To use the checklist, a primary care practitioner would assign one point for the presence of each item in a patient then add up all of the points to determine that patient’s risk level for future hospital admission for respiratory tract infection. A score of 1 point or less, observed in 5,593 (67%) cases would be considered indicative of a very low rate of risk for hospitalization (0.3%, 0.2%-0.4%). A score of 2 or 3 points, found for 2,520 (30%) children, would be considered as a normal level of risk (1.5%, 1.0%-1.9%), and a score of 4 or more points, seen in 204 (3%) children, would signify a high risk level (11.8%, 7.3%-16.2%).

Of the 8,394 children assessed, 78 (0.9%; 95% confidence interval, 0.7%-1.2%) were admitted to a hospital. Most were admitted on days 2-7 (33, 42%) and on days 8-30 (30, 39%) following recruitment. Only 15 (19%) were admitted on the day of recruitment (day 1).

“Many clinicians report that they prescribe antibiotics just in case, to mitigate perceived risk of future hospital admission and complications, and that failing to provide a prescription for a child who subsequently becomes seriously unwell is professionally unacceptable. If primary care clinicians could identify children at low (or very low) risk of such future complications, the reduced clinical uncertainty could lead to a reduced use of antibiotics in these groups of patients,” wrote first author Alastair Hay, MD, from the Centre for Academic Primary Care in the School of Social and Community Medicine at the University of Bristol (England), and his colleagues.

These researchers conducted the study based on a structured, blinded review of the medical records from children aged between 3 months and 16 years presenting with acute cough (less than or equal to 28 days) and respiratory tract infection treated by 519 general practitioners in 247 practices in England between July 2011 and June 2013. The primary study outcome was hospital admission for respiratory tract infection within 30 days.

Additionally, a multivariable model was employed to detect factors associated with increased risk of hospital admission. As measured by receiver operating characteristic curve analysis, the accuracy of the STARWAVe score checklist in predicting risk groups and associated risk of hospitalization was found to be high (0.81; 95% CI, 0.77-0.86). The suggested probability of hospital admission for children who did not have any of the seven characteristics included in the checklist was found to be exceptionally low (0.14%).

Significantly associated parent-reported variables included both moderate or severe vomiting and severe fever, each in the previous 24 hours. Significant clinician-reported variables included intercostal or subcostal recession and wheeze on auscultation.

“The main value of our results is to reduce clinical uncertainty and antibiotic use in children least likely to benefit from them, namely those at very low risk of future hospital admission,” Dr. Hay and his associates noted in The Lancet Respiratory Medicine (Lancet Respir Med. 2016 Sep 1. doi: 10.1016/S2213-2600(16)30223-5).

Funding for this study was provided by the National Institute for Health Research and sponsored by the University of Bristol. Only one of the study’s authors, Dr. Peter Muir, reported ties to industry sources.

Primary care practitioners’ use of a seven-item checklist may reduce the number of pediatric patients with respiratory tract infections who are prescribed unnecessary antibiotics, a prognostic cohort study suggests.

The study revealed short illness (a duration of illness of 3 days or less), temperature (a body temperature of 37.8°C or greater at presentation), age (being under 2 years), intercostal or subcostal recession, wheeze on auscultation, asthma, and vomiting (moderate or severe in the previous 24 hours) were each independently associated with hospital admission (P less than .01 for all associations).

©Devonyu/thinkstockphotos.com

The checklist includes these seven characteristics or risk variables (short illness, temperature, age, recession, wheeze, asthma, and vomiting [mnemonic STARWAVe]). To use the checklist, a primary care practitioner would assign one point for the presence of each item in a patient then add up all of the points to determine that patient’s risk level for future hospital admission for respiratory tract infection. A score of 1 point or less, observed in 5,593 (67%) cases would be considered indicative of a very low rate of risk for hospitalization (0.3%, 0.2%-0.4%). A score of 2 or 3 points, found for 2,520 (30%) children, would be considered as a normal level of risk (1.5%, 1.0%-1.9%), and a score of 4 or more points, seen in 204 (3%) children, would signify a high risk level (11.8%, 7.3%-16.2%).

Of the 8,394 children assessed, 78 (0.9%; 95% confidence interval, 0.7%-1.2%) were admitted to a hospital. Most were admitted on days 2-7 (33, 42%) and on days 8-30 (30, 39%) following recruitment. Only 15 (19%) were admitted on the day of recruitment (day 1).

“Many clinicians report that they prescribe antibiotics just in case, to mitigate perceived risk of future hospital admission and complications, and that failing to provide a prescription for a child who subsequently becomes seriously unwell is professionally unacceptable. If primary care clinicians could identify children at low (or very low) risk of such future complications, the reduced clinical uncertainty could lead to a reduced use of antibiotics in these groups of patients,” wrote first author Alastair Hay, MD, from the Centre for Academic Primary Care in the School of Social and Community Medicine at the University of Bristol (England), and his colleagues.

These researchers conducted the study based on a structured, blinded review of the medical records from children aged between 3 months and 16 years presenting with acute cough (less than or equal to 28 days) and respiratory tract infection treated by 519 general practitioners in 247 practices in England between July 2011 and June 2013. The primary study outcome was hospital admission for respiratory tract infection within 30 days.

Additionally, a multivariable model was employed to detect factors associated with increased risk of hospital admission. As measured by receiver operating characteristic curve analysis, the accuracy of the STARWAVe score checklist in predicting risk groups and associated risk of hospitalization was found to be high (0.81; 95% CI, 0.77-0.86). The suggested probability of hospital admission for children who did not have any of the seven characteristics included in the checklist was found to be exceptionally low (0.14%).

Significantly associated parent-reported variables included both moderate or severe vomiting and severe fever, each in the previous 24 hours. Significant clinician-reported variables included intercostal or subcostal recession and wheeze on auscultation.

“The main value of our results is to reduce clinical uncertainty and antibiotic use in children least likely to benefit from them, namely those at very low risk of future hospital admission,” Dr. Hay and his associates noted in The Lancet Respiratory Medicine (Lancet Respir Med. 2016 Sep 1. doi: 10.1016/S2213-2600(16)30223-5).

Funding for this study was provided by the National Institute for Health Research and sponsored by the University of Bristol. Only one of the study’s authors, Dr. Peter Muir, reported ties to industry sources.

Primary care practitioners’ use of a seven-item checklist may reduce the number of pediatric patients with respiratory tract infections who are prescribed unnecessary antibiotics, a prognostic cohort study suggests.

The study revealed short illness (a duration of illness of 3 days or less), temperature (a body temperature of 37.8°C or greater at presentation), age (being under 2 years), intercostal or subcostal recession, wheeze on auscultation, asthma, and vomiting (moderate or severe in the previous 24 hours) were each independently associated with hospital admission (P less than .01 for all associations).

©Devonyu/thinkstockphotos.com

The checklist includes these seven characteristics or risk variables (short illness, temperature, age, recession, wheeze, asthma, and vomiting [mnemonic STARWAVe]). To use the checklist, a primary care practitioner would assign one point for the presence of each item in a patient then add up all of the points to determine that patient’s risk level for future hospital admission for respiratory tract infection. A score of 1 point or less, observed in 5,593 (67%) cases would be considered indicative of a very low rate of risk for hospitalization (0.3%, 0.2%-0.4%). A score of 2 or 3 points, found for 2,520 (30%) children, would be considered as a normal level of risk (1.5%, 1.0%-1.9%), and a score of 4 or more points, seen in 204 (3%) children, would signify a high risk level (11.8%, 7.3%-16.2%).

Of the 8,394 children assessed, 78 (0.9%; 95% confidence interval, 0.7%-1.2%) were admitted to a hospital. Most were admitted on days 2-7 (33, 42%) and on days 8-30 (30, 39%) following recruitment. Only 15 (19%) were admitted on the day of recruitment (day 1).

“Many clinicians report that they prescribe antibiotics just in case, to mitigate perceived risk of future hospital admission and complications, and that failing to provide a prescription for a child who subsequently becomes seriously unwell is professionally unacceptable. If primary care clinicians could identify children at low (or very low) risk of such future complications, the reduced clinical uncertainty could lead to a reduced use of antibiotics in these groups of patients,” wrote first author Alastair Hay, MD, from the Centre for Academic Primary Care in the School of Social and Community Medicine at the University of Bristol (England), and his colleagues.

These researchers conducted the study based on a structured, blinded review of the medical records from children aged between 3 months and 16 years presenting with acute cough (less than or equal to 28 days) and respiratory tract infection treated by 519 general practitioners in 247 practices in England between July 2011 and June 2013. The primary study outcome was hospital admission for respiratory tract infection within 30 days.

Additionally, a multivariable model was employed to detect factors associated with increased risk of hospital admission. As measured by receiver operating characteristic curve analysis, the accuracy of the STARWAVe score checklist in predicting risk groups and associated risk of hospitalization was found to be high (0.81; 95% CI, 0.77-0.86). The suggested probability of hospital admission for children who did not have any of the seven characteristics included in the checklist was found to be exceptionally low (0.14%).

Significantly associated parent-reported variables included both moderate or severe vomiting and severe fever, each in the previous 24 hours. Significant clinician-reported variables included intercostal or subcostal recession and wheeze on auscultation.

“The main value of our results is to reduce clinical uncertainty and antibiotic use in children least likely to benefit from them, namely those at very low risk of future hospital admission,” Dr. Hay and his associates noted in The Lancet Respiratory Medicine (Lancet Respir Med. 2016 Sep 1. doi: 10.1016/S2213-2600(16)30223-5).

Funding for this study was provided by the National Institute for Health Research and sponsored by the University of Bristol. Only one of the study’s authors, Dr. Peter Muir, reported ties to industry sources.

After years of relative neglect, compared with the attention given to aortic disease, studies and devices designed to expand and improve treatment of peripheral arterial disease are moving to the forefront.

At this year’s VIVA Vascular meeting, the majority of late-breaking clinical trials have a focus on peripheral arterial disease (PAD) and critical limb ischemia (CLI), emphasizing the tremendous growth of research in this area. The following are some of the latest trials for which results will be presented:

On Monday morning, Michael P. Murphy, MD, will present results from the MOBILE clinical trial, which examines the use of the MarrowStim™ PAD Kit for the treatment of CLI in subjects with severe PAD. The treatment involves removing bone marrow from the hips, which is then processed in the MarrowStim device to separate stem cells for delivery by injection to multiple sites in the affected leg.

A report on the 6-month results from the two-phase DISRUPT PAD study to assess the safety and performance of the Shockwave Lithoplasty® System in treating calcified peripheral vascular lesions will then be presented by Thomas Zeller, MD, principal investigator for the study. “Lithoplasty is a novel technology utilizing integrated lithotripsy emitters that generate mechanical pulse waves to disrupt both superficial and deep calcium normalizing vessel wall compliance prior to low-pressure balloon dilatation,” according to a company report.

In addition, results from the IN.PACT SFA randomized trial will be presented by Prakash Krishnan, MD, and data from the VIRTUS US Iliofemoral Stenting IDE Trial will be addressed by Stephen Black, MD, and Michael R. Jaff, DO, will present insights on the use of drug-coated balloon treatment for patients with intermittent claudication based on results from the IN.PACT Global full clinical cohort.

On Tuesday morning, Stefan Müller-Hülsbeck, MD, will present the 2-year results plus subgroup analysis of the Majestic Trial, which examined the efficacy benefit of using the Eluvia drug-eluting stent for treating lesions in the femoropopliteal arteries.

This will be followed by Antonio Micari, MD, PhD, who will present the 2-year results of from the SFA-Long Study, which examines the use of paclitaxel coated balloons for long femoropopliteal artery disease.

On Wednesday morning, the 3-Year Results of the Evaluation of the ESPRIT Bioresorbable Vascular Scaffold (ESPRIT BVS) in The Treatment of Patients with Occlusive Vascular Disease of the Superficial Femoral (SFA) or Common or External Iliac Arteries (ESPRIT I Trial) will be presented by Michael R. Jaff, DO.

This will be followed by a presentation of the 12-month results from the DANCE Trial Atherectomy Cohort by Chris D. Owens, MD, and John Laird, MD, discussing the 9-month results of the Prospective, Multicenter BOLSTER Trial, which examined the use of an expanded polytetrafluoroethylene balloon-expandable covered stent for obstructive lesions in the iliac artery.

In further research addressing the peripheral vascular system, Dr. Laird will also address the 24-month results from the TIGRIS randomized trial, assessing the use of a novel nitinol stent for long lesions in the SFA and the proximal popliteal artery.

Afterwards, Richard Saxon, MD, will discuss the PRISM Indigo Aspiration System as a potential frontline tool for vacuum-assisted aspiration thrombectomy in the periphery.

After years of relative neglect, compared with the attention given to aortic disease, studies and devices designed to expand and improve treatment of peripheral arterial disease are moving to the forefront.

At this year’s VIVA Vascular meeting, the majority of late-breaking clinical trials have a focus on peripheral arterial disease (PAD) and critical limb ischemia (CLI), emphasizing the tremendous growth of research in this area. The following are some of the latest trials for which results will be presented:

On Monday morning, Michael P. Murphy, MD, will present results from the MOBILE clinical trial, which examines the use of the MarrowStim™ PAD Kit for the treatment of CLI in subjects with severe PAD. The treatment involves removing bone marrow from the hips, which is then processed in the MarrowStim device to separate stem cells for delivery by injection to multiple sites in the affected leg.

A report on the 6-month results from the two-phase DISRUPT PAD study to assess the safety and performance of the Shockwave Lithoplasty® System in treating calcified peripheral vascular lesions will then be presented by Thomas Zeller, MD, principal investigator for the study. “Lithoplasty is a novel technology utilizing integrated lithotripsy emitters that generate mechanical pulse waves to disrupt both superficial and deep calcium normalizing vessel wall compliance prior to low-pressure balloon dilatation,” according to a company report.

In addition, results from the IN.PACT SFA randomized trial will be presented by Prakash Krishnan, MD, and data from the VIRTUS US Iliofemoral Stenting IDE Trial will be addressed by Stephen Black, MD, and Michael R. Jaff, DO, will present insights on the use of drug-coated balloon treatment for patients with intermittent claudication based on results from the IN.PACT Global full clinical cohort.

On Tuesday morning, Stefan Müller-Hülsbeck, MD, will present the 2-year results plus subgroup analysis of the Majestic Trial, which examined the efficacy benefit of using the Eluvia drug-eluting stent for treating lesions in the femoropopliteal arteries.

This will be followed by Antonio Micari, MD, PhD, who will present the 2-year results of from the SFA-Long Study, which examines the use of paclitaxel coated balloons for long femoropopliteal artery disease.

On Wednesday morning, the 3-Year Results of the Evaluation of the ESPRIT Bioresorbable Vascular Scaffold (ESPRIT BVS) in The Treatment of Patients with Occlusive Vascular Disease of the Superficial Femoral (SFA) or Common or External Iliac Arteries (ESPRIT I Trial) will be presented by Michael R. Jaff, DO.

This will be followed by a presentation of the 12-month results from the DANCE Trial Atherectomy Cohort by Chris D. Owens, MD, and John Laird, MD, discussing the 9-month results of the Prospective, Multicenter BOLSTER Trial, which examined the use of an expanded polytetrafluoroethylene balloon-expandable covered stent for obstructive lesions in the iliac artery.

In further research addressing the peripheral vascular system, Dr. Laird will also address the 24-month results from the TIGRIS randomized trial, assessing the use of a novel nitinol stent for long lesions in the SFA and the proximal popliteal artery.

Afterwards, Richard Saxon, MD, will discuss the PRISM Indigo Aspiration System as a potential frontline tool for vacuum-assisted aspiration thrombectomy in the periphery.

After years of relative neglect, compared with the attention given to aortic disease, studies and devices designed to expand and improve treatment of peripheral arterial disease are moving to the forefront.

At this year’s VIVA Vascular meeting, the majority of late-breaking clinical trials have a focus on peripheral arterial disease (PAD) and critical limb ischemia (CLI), emphasizing the tremendous growth of research in this area. The following are some of the latest trials for which results will be presented:

On Monday morning, Michael P. Murphy, MD, will present results from the MOBILE clinical trial, which examines the use of the MarrowStim™ PAD Kit for the treatment of CLI in subjects with severe PAD. The treatment involves removing bone marrow from the hips, which is then processed in the MarrowStim device to separate stem cells for delivery by injection to multiple sites in the affected leg.

A report on the 6-month results from the two-phase DISRUPT PAD study to assess the safety and performance of the Shockwave Lithoplasty® System in treating calcified peripheral vascular lesions will then be presented by Thomas Zeller, MD, principal investigator for the study. “Lithoplasty is a novel technology utilizing integrated lithotripsy emitters that generate mechanical pulse waves to disrupt both superficial and deep calcium normalizing vessel wall compliance prior to low-pressure balloon dilatation,” according to a company report.

In addition, results from the IN.PACT SFA randomized trial will be presented by Prakash Krishnan, MD, and data from the VIRTUS US Iliofemoral Stenting IDE Trial will be addressed by Stephen Black, MD, and Michael R. Jaff, DO, will present insights on the use of drug-coated balloon treatment for patients with intermittent claudication based on results from the IN.PACT Global full clinical cohort.

On Tuesday morning, Stefan Müller-Hülsbeck, MD, will present the 2-year results plus subgroup analysis of the Majestic Trial, which examined the efficacy benefit of using the Eluvia drug-eluting stent for treating lesions in the femoropopliteal arteries.

This will be followed by Antonio Micari, MD, PhD, who will present the 2-year results of from the SFA-Long Study, which examines the use of paclitaxel coated balloons for long femoropopliteal artery disease.

On Wednesday morning, the 3-Year Results of the Evaluation of the ESPRIT Bioresorbable Vascular Scaffold (ESPRIT BVS) in The Treatment of Patients with Occlusive Vascular Disease of the Superficial Femoral (SFA) or Common or External Iliac Arteries (ESPRIT I Trial) will be presented by Michael R. Jaff, DO.

This will be followed by a presentation of the 12-month results from the DANCE Trial Atherectomy Cohort by Chris D. Owens, MD, and John Laird, MD, discussing the 9-month results of the Prospective, Multicenter BOLSTER Trial, which examined the use of an expanded polytetrafluoroethylene balloon-expandable covered stent for obstructive lesions in the iliac artery.

In further research addressing the peripheral vascular system, Dr. Laird will also address the 24-month results from the TIGRIS randomized trial, assessing the use of a novel nitinol stent for long lesions in the SFA and the proximal popliteal artery.

Afterwards, Richard Saxon, MD, will discuss the PRISM Indigo Aspiration System as a potential frontline tool for vacuum-assisted aspiration thrombectomy in the periphery.

BOSTON – Smartphones coupled with the rapidly growing number of medical applications are the latest disruptive technologies reshaping the way physicians conduct business and interact with patients, according to Paul Alan Wetter, MD, founder and chairman of the Society of Laparoendoscopic Surgeons.

“The message really is to the physicians out there: We need to be prepared and understand as much about this as we can,” said Dr. Wetter, clinical professor emeritus at the University of Miami. “We don’t want to be, 5 years from now ... wondering what’s going, what is this change?”

In a video interview, Dr. Wetter explained how mobile devices and apps could potentially improve technology-based tools that doctors already use, such as electronic health records, by allowing patients to carry accurate and up-to-date medical information with them.

Dr. Wetter spoke at the annual Minimally Invasive Surgery Week, held by the Society of Laparoendoscopic Surgeons. He did not report any relevant financial disclosures.

[email protected]

BOSTON – Smartphones coupled with the rapidly growing number of medical applications are the latest disruptive technologies reshaping the way physicians conduct business and interact with patients, according to Paul Alan Wetter, MD, founder and chairman of the Society of Laparoendoscopic Surgeons.

“The message really is to the physicians out there: We need to be prepared and understand as much about this as we can,” said Dr. Wetter, clinical professor emeritus at the University of Miami. “We don’t want to be, 5 years from now ... wondering what’s going, what is this change?”

In a video interview, Dr. Wetter explained how mobile devices and apps could potentially improve technology-based tools that doctors already use, such as electronic health records, by allowing patients to carry accurate and up-to-date medical information with them.

Dr. Wetter spoke at the annual Minimally Invasive Surgery Week, held by the Society of Laparoendoscopic Surgeons. He did not report any relevant financial disclosures.

[email protected]

BOSTON – Smartphones coupled with the rapidly growing number of medical applications are the latest disruptive technologies reshaping the way physicians conduct business and interact with patients, according to Paul Alan Wetter, MD, founder and chairman of the Society of Laparoendoscopic Surgeons.

“The message really is to the physicians out there: We need to be prepared and understand as much about this as we can,” said Dr. Wetter, clinical professor emeritus at the University of Miami. “We don’t want to be, 5 years from now ... wondering what’s going, what is this change?”

In a video interview, Dr. Wetter explained how mobile devices and apps could potentially improve technology-based tools that doctors already use, such as electronic health records, by allowing patients to carry accurate and up-to-date medical information with them.

Dr. Wetter spoke at the annual Minimally Invasive Surgery Week, held by the Society of Laparoendoscopic Surgeons. He did not report any relevant financial disclosures.

[email protected]

FROM AN FDA ADVISORY PANEL MEETING

The majority of attendees at a joint meeting of two Food and Drug Administration advisory committees voted Sept. 14 to eliminate the black box warning about neuropsychiatric risks for the smoking cessation drug varenicline.

Panelists weighed the need for greater adoption of effective smoking cessation interventions against the possibility that varenicline (Chantix) might increase the risk of such serious adverse events (AEs) as aggression and suicidal behavior. In assessing findings of a clinical trial designed to sort out neuropsychiatric risk, they also had to wade through differing interpretations of the clinical trial data presented by the drug’s sponsor and the FDA.

Members of the Psychopharmacologic Drugs Advisory and the Drug Safety and Risk Management committees heard Chantix’s sponsor, Pfizer, present results of the postmarketing EAGLES trial. The global multisite trial compared varenicline with bupropion, also approved for smoking cessation, as well as with nicotine replacement therapy and placebo.

Of the 19 voting advisory committee members, 10 voted in favor of eliminating the boxed warning, while 4 members voted for a modification of the existing boxed warning, and 5 voted to retain the warning. The vote represents a reversal for the committees. In 2014, the joint panels recommended retaining the black box warning on the drug. The FDA usually follows the recommendations of its advisory panels, but the recommendations are not binding.

The boxed warning, which advises prescribers of the potential for “serious neuropsychiatric events,” arose from individual postmarketing reports of agitation, hostility, depressed mood, and suicidal ideation and behavior. Though postmarketing observational studies had not shown a consistent signal for increased risk of neuropsychiatric events, a plausible psychopharmacologic mechanism existed for the reports, and a clinical trial examining neuropsychiatric safety was designed to settle the question.

The primary objectives of EAGLES were to assess the risk of “clinically significant” AEs for individuals using varenicline, bupropion, nicotine replacement, or placebo, and to determine whether a past history of psychiatric disorders increased the risk of neuropsychiatric AEs when either prescription medication was used for smoking cessation.

A total of 8,000 patients were randomized 1:1:1:1 to receive varenicline, bupropion, nicotine replacement via patch, or placebo. The double blind, triple dummy design meant that all patients took pills and applied a patch daily. Each study arm was evenly divided so that half of the participants had a prior psychiatric diagnosis of a mood, anxiety, psychotic, or personality disorder. Overall, 70.7% of the psychiatric cohort had a mood disorder, and just under half were receiving a psychotropic medication at baseline.

The other half of patients in each study arm had no current or past psychiatric diagnoses. Approximately 80% of participants completed the trial overall.

The FDA and Pfizer worked together to develop a composite neuropsychiatric safety endpoint that broadly included the postmarketing AEs that had been reported for varenicline. The composite was designed to increase sensitivity, but only “moderate” or “severe” events were included in the analysis to increase specificity by minimizing inclusion of symptoms that might be attributable to nicotine withdrawal.

Results were similar across treatment arms for the primary composite endpoint, with higher incidence of events for the psychiatric cohort regardless of treatment, according to Pfizer’s analysis of the data. Since the study was not designed with a specific hypothesis, the results were not expressed in terms of statistical significance, but rather in risk differences with accompanying confidence intervals (CIs). The confidence interval crossed zero for all study drugs (including nicotine), except when varenicline was compared with placebo in the nonpsychiatric cohort (risk difference, 1.28; 95% CI, –2.40 to –0.15).

Overall, Pfizer found that about 2% of smokers without mental illness experienced neuropsychiatric AEs, compared with 5%-7% in the psychiatric cohort, regardless of treatment arm.

The FDA also found a small decrease in AEs for varenicline when compared with placebo in those without mental illness, and a higher incidence of neuropsychiatric events for those patients with mental illness who took varenicline and bupropion than those on placebo. In the FDA’s analysis, 6.5% of those on varenicline and 6.7% of those on bupropion met the primary composite AE endpoint. However, the FDA found that severe neuropsychiatric events and scoring on the Columbia Suicide Severity Rating Scale (C-SSRS), though lower for participants without mental illness, were similar across treatment arms in both cohorts.

Reporting problems also complicated the panel’s task. As the FDA conceived it, said Celia Winchell, MD, each AE was to be accompanied by a narrative that captured not just test scores and coded clinician assessments, but also the verbatim patient report and any other relevant data, such as the police report of a traffic accident, or family members’ appraisals of the event. Instead, she said, many of the reports appeared to have been automatically generated and were lacking in detail. Compared with other studies she’s reviewed, “The quality of the narratives that were submitted were unusually uninformative,” said Dr. Winchell, clinical team leader in the FDA’s Division of Anesthesia, Analgesia, and Addiction Products (DAAAP).

Clinical trials were run at 139 sites in 16 countries, treating a total of 8,058 patients. Despite Pfizer’s extensive efforts to standardize adverse event categorization and reporting, the FDA and some panelists remained concerned that language difficulty and cultural variation in interpreting neuropsychiatric symptoms may have resulted in miscategorization or underreporting of such events. In addition, Pfizer’s own surveillance revealed data reporting problems at two overseas sites that resulted in those sites’ data being eliminated from analysis.

All of the trial data, together with a review of several observational studies, had to be weighed against the individual and public health risks of smoking. Individuals with serious mental illness are significantly more likely to smoke heavily and to relapse after quitting compared with the general population. Yet, those individuals are less likely to be prescribed medication to help stop smoking, Anne Eden Evins, MD, director of the Center for Addiction Medicine at Massachusetts General Hospital, Boston, said in her testimony on Pfizer’s behalf.

“The implication of EAGLES is that we can offer treatment to all smokers, including those with stable mental illness,” she said. “It is imperative we find ways to increase use of the most effective smoking cessation treatment for our patients who try time and again to quit smoking.”

Many committee members agreed, providing anecdotal evidence that the current boxed warning deters both prescribers and patients from considering varenicline for smoking cessation in patients with mental illness.

For David Pickar, MD, who voted to remove the warning, the decision was easy. “I have no ambivalence, whatsoever,” he said. “The risk-benefit ratio to me is as clear as anything I have seen. I have never, ever, ever seen a schizophrenia patient on this drug,” said Dr. Pickar, a psychiatrist affiliated with the Uniformed Services University of the Health Sciences, Bethesda, Md.

However, many panelists were disturbed by the variability seen between sites during the clinical trials and by the lack of depth in Pfizer’s adverse events reporting. Said Rajesh Narendran, MD, professor of radiology and psychiatry at the University of Pittsburgh: “I don’t think the trial was conducted with the same cleanliness and elegance” of a trial for a new drug application. “I wasn’t fully reassured, and I think that removing the black box does send the wrong message that this is now a safe drug,” he said.

Although the joint committees’ chair, Ruth Murphey Parker, MD, voted for modification of the boxed warning, she agreed. “I also felt that removal of the black box would be a signal for safety,” she said.

Others who voted for modification felt that prescribers should talk to their patients about risks and benefits. Said Christianne Roumie, MD, professor of internal medicine and pediatrics at Vanderbilt University, Nashville, Tenn., and a staff physician at Veterans Affairs Tennessee Valley Healthcare System, also in Nashville: “As a clinician, I always have the discussion. This should be a conversation and not ... carte blanche.”

[email protected]

On Twitter @karioakes

FROM AN FDA ADVISORY PANEL MEETING

The majority of attendees at a joint meeting of two Food and Drug Administration advisory committees voted Sept. 14 to eliminate the black box warning about neuropsychiatric risks for the smoking cessation drug varenicline.

Panelists weighed the need for greater adoption of effective smoking cessation interventions against the possibility that varenicline (Chantix) might increase the risk of such serious adverse events (AEs) as aggression and suicidal behavior. In assessing findings of a clinical trial designed to sort out neuropsychiatric risk, they also had to wade through differing interpretations of the clinical trial data presented by the drug’s sponsor and the FDA.

Members of the Psychopharmacologic Drugs Advisory and the Drug Safety and Risk Management committees heard Chantix’s sponsor, Pfizer, present results of the postmarketing EAGLES trial. The global multisite trial compared varenicline with bupropion, also approved for smoking cessation, as well as with nicotine replacement therapy and placebo.

Of the 19 voting advisory committee members, 10 voted in favor of eliminating the boxed warning, while 4 members voted for a modification of the existing boxed warning, and 5 voted to retain the warning. The vote represents a reversal for the committees. In 2014, the joint panels recommended retaining the black box warning on the drug. The FDA usually follows the recommendations of its advisory panels, but the recommendations are not binding.

The boxed warning, which advises prescribers of the potential for “serious neuropsychiatric events,” arose from individual postmarketing reports of agitation, hostility, depressed mood, and suicidal ideation and behavior. Though postmarketing observational studies had not shown a consistent signal for increased risk of neuropsychiatric events, a plausible psychopharmacologic mechanism existed for the reports, and a clinical trial examining neuropsychiatric safety was designed to settle the question.

The primary objectives of EAGLES were to assess the risk of “clinically significant” AEs for individuals using varenicline, bupropion, nicotine replacement, or placebo, and to determine whether a past history of psychiatric disorders increased the risk of neuropsychiatric AEs when either prescription medication was used for smoking cessation.

A total of 8,000 patients were randomized 1:1:1:1 to receive varenicline, bupropion, nicotine replacement via patch, or placebo. The double blind, triple dummy design meant that all patients took pills and applied a patch daily. Each study arm was evenly divided so that half of the participants had a prior psychiatric diagnosis of a mood, anxiety, psychotic, or personality disorder. Overall, 70.7% of the psychiatric cohort had a mood disorder, and just under half were receiving a psychotropic medication at baseline.

The other half of patients in each study arm had no current or past psychiatric diagnoses. Approximately 80% of participants completed the trial overall.

The FDA and Pfizer worked together to develop a composite neuropsychiatric safety endpoint that broadly included the postmarketing AEs that had been reported for varenicline. The composite was designed to increase sensitivity, but only “moderate” or “severe” events were included in the analysis to increase specificity by minimizing inclusion of symptoms that might be attributable to nicotine withdrawal.

Results were similar across treatment arms for the primary composite endpoint, with higher incidence of events for the psychiatric cohort regardless of treatment, according to Pfizer’s analysis of the data. Since the study was not designed with a specific hypothesis, the results were not expressed in terms of statistical significance, but rather in risk differences with accompanying confidence intervals (CIs). The confidence interval crossed zero for all study drugs (including nicotine), except when varenicline was compared with placebo in the nonpsychiatric cohort (risk difference, 1.28; 95% CI, –2.40 to –0.15).

Overall, Pfizer found that about 2% of smokers without mental illness experienced neuropsychiatric AEs, compared with 5%-7% in the psychiatric cohort, regardless of treatment arm.

The FDA also found a small decrease in AEs for varenicline when compared with placebo in those without mental illness, and a higher incidence of neuropsychiatric events for those patients with mental illness who took varenicline and bupropion than those on placebo. In the FDA’s analysis, 6.5% of those on varenicline and 6.7% of those on bupropion met the primary composite AE endpoint. However, the FDA found that severe neuropsychiatric events and scoring on the Columbia Suicide Severity Rating Scale (C-SSRS), though lower for participants without mental illness, were similar across treatment arms in both cohorts.

Reporting problems also complicated the panel’s task. As the FDA conceived it, said Celia Winchell, MD, each AE was to be accompanied by a narrative that captured not just test scores and coded clinician assessments, but also the verbatim patient report and any other relevant data, such as the police report of a traffic accident, or family members’ appraisals of the event. Instead, she said, many of the reports appeared to have been automatically generated and were lacking in detail. Compared with other studies she’s reviewed, “The quality of the narratives that were submitted were unusually uninformative,” said Dr. Winchell, clinical team leader in the FDA’s Division of Anesthesia, Analgesia, and Addiction Products (DAAAP).

Clinical trials were run at 139 sites in 16 countries, treating a total of 8,058 patients. Despite Pfizer’s extensive efforts to standardize adverse event categorization and reporting, the FDA and some panelists remained concerned that language difficulty and cultural variation in interpreting neuropsychiatric symptoms may have resulted in miscategorization or underreporting of such events. In addition, Pfizer’s own surveillance revealed data reporting problems at two overseas sites that resulted in those sites’ data being eliminated from analysis.

All of the trial data, together with a review of several observational studies, had to be weighed against the individual and public health risks of smoking. Individuals with serious mental illness are significantly more likely to smoke heavily and to relapse after quitting compared with the general population. Yet, those individuals are less likely to be prescribed medication to help stop smoking, Anne Eden Evins, MD, director of the Center for Addiction Medicine at Massachusetts General Hospital, Boston, said in her testimony on Pfizer’s behalf.

“The implication of EAGLES is that we can offer treatment to all smokers, including those with stable mental illness,” she said. “It is imperative we find ways to increase use of the most effective smoking cessation treatment for our patients who try time and again to quit smoking.”

Many committee members agreed, providing anecdotal evidence that the current boxed warning deters both prescribers and patients from considering varenicline for smoking cessation in patients with mental illness.

For David Pickar, MD, who voted to remove the warning, the decision was easy. “I have no ambivalence, whatsoever,” he said. “The risk-benefit ratio to me is as clear as anything I have seen. I have never, ever, ever seen a schizophrenia patient on this drug,” said Dr. Pickar, a psychiatrist affiliated with the Uniformed Services University of the Health Sciences, Bethesda, Md.

However, many panelists were disturbed by the variability seen between sites during the clinical trials and by the lack of depth in Pfizer’s adverse events reporting. Said Rajesh Narendran, MD, professor of radiology and psychiatry at the University of Pittsburgh: “I don’t think the trial was conducted with the same cleanliness and elegance” of a trial for a new drug application. “I wasn’t fully reassured, and I think that removing the black box does send the wrong message that this is now a safe drug,” he said.

Although the joint committees’ chair, Ruth Murphey Parker, MD, voted for modification of the boxed warning, she agreed. “I also felt that removal of the black box would be a signal for safety,” she said.

Others who voted for modification felt that prescribers should talk to their patients about risks and benefits. Said Christianne Roumie, MD, professor of internal medicine and pediatrics at Vanderbilt University, Nashville, Tenn., and a staff physician at Veterans Affairs Tennessee Valley Healthcare System, also in Nashville: “As a clinician, I always have the discussion. This should be a conversation and not ... carte blanche.”

[email protected]

On Twitter @karioakes

FROM AN FDA ADVISORY PANEL MEETING

The majority of attendees at a joint meeting of two Food and Drug Administration advisory committees voted Sept. 14 to eliminate the black box warning about neuropsychiatric risks for the smoking cessation drug varenicline.

Panelists weighed the need for greater adoption of effective smoking cessation interventions against the possibility that varenicline (Chantix) might increase the risk of such serious adverse events (AEs) as aggression and suicidal behavior. In assessing findings of a clinical trial designed to sort out neuropsychiatric risk, they also had to wade through differing interpretations of the clinical trial data presented by the drug’s sponsor and the FDA.

Members of the Psychopharmacologic Drugs Advisory and the Drug Safety and Risk Management committees heard Chantix’s sponsor, Pfizer, present results of the postmarketing EAGLES trial. The global multisite trial compared varenicline with bupropion, also approved for smoking cessation, as well as with nicotine replacement therapy and placebo.

Of the 19 voting advisory committee members, 10 voted in favor of eliminating the boxed warning, while 4 members voted for a modification of the existing boxed warning, and 5 voted to retain the warning. The vote represents a reversal for the committees. In 2014, the joint panels recommended retaining the black box warning on the drug. The FDA usually follows the recommendations of its advisory panels, but the recommendations are not binding.

The boxed warning, which advises prescribers of the potential for “serious neuropsychiatric events,” arose from individual postmarketing reports of agitation, hostility, depressed mood, and suicidal ideation and behavior. Though postmarketing observational studies had not shown a consistent signal for increased risk of neuropsychiatric events, a plausible psychopharmacologic mechanism existed for the reports, and a clinical trial examining neuropsychiatric safety was designed to settle the question.

The primary objectives of EAGLES were to assess the risk of “clinically significant” AEs for individuals using varenicline, bupropion, nicotine replacement, or placebo, and to determine whether a past history of psychiatric disorders increased the risk of neuropsychiatric AEs when either prescription medication was used for smoking cessation.

A total of 8,000 patients were randomized 1:1:1:1 to receive varenicline, bupropion, nicotine replacement via patch, or placebo. The double blind, triple dummy design meant that all patients took pills and applied a patch daily. Each study arm was evenly divided so that half of the participants had a prior psychiatric diagnosis of a mood, anxiety, psychotic, or personality disorder. Overall, 70.7% of the psychiatric cohort had a mood disorder, and just under half were receiving a psychotropic medication at baseline.

The other half of patients in each study arm had no current or past psychiatric diagnoses. Approximately 80% of participants completed the trial overall.

The FDA and Pfizer worked together to develop a composite neuropsychiatric safety endpoint that broadly included the postmarketing AEs that had been reported for varenicline. The composite was designed to increase sensitivity, but only “moderate” or “severe” events were included in the analysis to increase specificity by minimizing inclusion of symptoms that might be attributable to nicotine withdrawal.

Results were similar across treatment arms for the primary composite endpoint, with higher incidence of events for the psychiatric cohort regardless of treatment, according to Pfizer’s analysis of the data. Since the study was not designed with a specific hypothesis, the results were not expressed in terms of statistical significance, but rather in risk differences with accompanying confidence intervals (CIs). The confidence interval crossed zero for all study drugs (including nicotine), except when varenicline was compared with placebo in the nonpsychiatric cohort (risk difference, 1.28; 95% CI, –2.40 to –0.15).

Overall, Pfizer found that about 2% of smokers without mental illness experienced neuropsychiatric AEs, compared with 5%-7% in the psychiatric cohort, regardless of treatment arm.

The FDA also found a small decrease in AEs for varenicline when compared with placebo in those without mental illness, and a higher incidence of neuropsychiatric events for those patients with mental illness who took varenicline and bupropion than those on placebo. In the FDA’s analysis, 6.5% of those on varenicline and 6.7% of those on bupropion met the primary composite AE endpoint. However, the FDA found that severe neuropsychiatric events and scoring on the Columbia Suicide Severity Rating Scale (C-SSRS), though lower for participants without mental illness, were similar across treatment arms in both cohorts.

Reporting problems also complicated the panel’s task. As the FDA conceived it, said Celia Winchell, MD, each AE was to be accompanied by a narrative that captured not just test scores and coded clinician assessments, but also the verbatim patient report and any other relevant data, such as the police report of a traffic accident, or family members’ appraisals of the event. Instead, she said, many of the reports appeared to have been automatically generated and were lacking in detail. Compared with other studies she’s reviewed, “The quality of the narratives that were submitted were unusually uninformative,” said Dr. Winchell, clinical team leader in the FDA’s Division of Anesthesia, Analgesia, and Addiction Products (DAAAP).

Clinical trials were run at 139 sites in 16 countries, treating a total of 8,058 patients. Despite Pfizer’s extensive efforts to standardize adverse event categorization and reporting, the FDA and some panelists remained concerned that language difficulty and cultural variation in interpreting neuropsychiatric symptoms may have resulted in miscategorization or underreporting of such events. In addition, Pfizer’s own surveillance revealed data reporting problems at two overseas sites that resulted in those sites’ data being eliminated from analysis.

All of the trial data, together with a review of several observational studies, had to be weighed against the individual and public health risks of smoking. Individuals with serious mental illness are significantly more likely to smoke heavily and to relapse after quitting compared with the general population. Yet, those individuals are less likely to be prescribed medication to help stop smoking, Anne Eden Evins, MD, director of the Center for Addiction Medicine at Massachusetts General Hospital, Boston, said in her testimony on Pfizer’s behalf.

“The implication of EAGLES is that we can offer treatment to all smokers, including those with stable mental illness,” she said. “It is imperative we find ways to increase use of the most effective smoking cessation treatment for our patients who try time and again to quit smoking.”

Many committee members agreed, providing anecdotal evidence that the current boxed warning deters both prescribers and patients from considering varenicline for smoking cessation in patients with mental illness.

For David Pickar, MD, who voted to remove the warning, the decision was easy. “I have no ambivalence, whatsoever,” he said. “The risk-benefit ratio to me is as clear as anything I have seen. I have never, ever, ever seen a schizophrenia patient on this drug,” said Dr. Pickar, a psychiatrist affiliated with the Uniformed Services University of the Health Sciences, Bethesda, Md.

However, many panelists were disturbed by the variability seen between sites during the clinical trials and by the lack of depth in Pfizer’s adverse events reporting. Said Rajesh Narendran, MD, professor of radiology and psychiatry at the University of Pittsburgh: “I don’t think the trial was conducted with the same cleanliness and elegance” of a trial for a new drug application. “I wasn’t fully reassured, and I think that removing the black box does send the wrong message that this is now a safe drug,” he said.

Although the joint committees’ chair, Ruth Murphey Parker, MD, voted for modification of the boxed warning, she agreed. “I also felt that removal of the black box would be a signal for safety,” she said.

Others who voted for modification felt that prescribers should talk to their patients about risks and benefits. Said Christianne Roumie, MD, professor of internal medicine and pediatrics at Vanderbilt University, Nashville, Tenn., and a staff physician at Veterans Affairs Tennessee Valley Healthcare System, also in Nashville: “As a clinician, I always have the discussion. This should be a conversation and not ... carte blanche.”

[email protected]

On Twitter @karioakes

LONDON – Patients with chronic obstructive pulmonary disease (COPD) and persistent hypercapnia were half as likely to be readmitted to hospital 1 year after an acute hypercapnic exacerbation if they had received home mechanical ventilation (HMV) in addition to home oxygen therapy (HOT) than if they had not.

The median admission-free survival time in the HOT-HMV U.K. trial was 4.3 months when HMV was used in addition to HOT, versus 1.4 months for HOT alone (unadjusted hazard ratio = 0.54, P = .007).

©designer491/Thinkstock

“I think what’s really important is that we now have a treatment that we know that if we direct toward [patients with persistent hypercapnia after acute hypercapnic exacerbation] that we effect a significant change in their outcomes,” said study investigator Patrick Murphy, MBBS, PhD, a consultant physician and honorary senior lecturer at the Lane Fox Respiratory Unit at Guy’s and St Thomas’ NHS Foundation Trust (London).

Speaking at the annual congress of the European Respiratory Society, he added: “We need to titrate the home ventilation to control nocturnal hypoventilation, and although I’ve not presented the data as time is short, there is no deleterious effect on quality of life.”

Nicholas Hart, MBBS, PhD, co–study investigator and clinical and academic director of Lane Fox Respiratory Unit, said in a statement issued by Philips Respironics that the results “have the ability to change the way that COPD patients are treated worldwide.”

“We’re looking forward to continuing the trial over the next 5 years to monitor survival rates, which we hope will rise, and readmission rates, which will hopefully fall,” he added.

The HOT-HMV UK Trial was conducted in 15 centers and involved patients with severe COPD who had persistent hypercapnia 2-4 weeks after experiencing an acute, life-threatening hypercapnic exacerbation requiring hospitalization. Persistent hypercapnia was defined as a pH of 7.3 or more and a PaCO2 of 7 kPa or higher. Patients had to have a 20-year or more pack year history of smoking, a forced expiratory volume in 1 second (FEV₁) of 50% or less, and FEV₁ to forced vital capacity (FVC) ratio of below 60%.

Dr. Murphy observed that the trial design assumed that the rate of hospital readmission at 1 year could be reduced from 55% to 25% with the use of noninvasive ventilation (NIV). The hypothesis was that HMV plus long-term HOT would increase admission-free survival compared with HOT alone.

More than 2,000 patients were initially screened for inclusion in the trial, with 116 randomized. Of the excluded patients, 1,609 did not meet inclusion criteria, 296 declined to participate, and 8 patients were not included for other reasons.

The average age of patients participating in the study was 67 years. The patients had a median body mass index of 21.6 kg/m² and most (61%) were female. Prior long-term oxygen therapy had been used by most (80%), and 61% had three or more COPD-related hospital admissions in the last year.

Putting the primary endpoint data into perspective, Dr. Murphy said that six patients with persistent hypercapnia after treatment for an acute exacerbation needed to be treated with HMV to prevent one readmission in the following 12-month period.

Improved nocturnal hypercapnia and sleep-disordered breathing led to improved daytime hypercapnia, he observed. The change in daytime hypercapnia after 6 weeks and 3 months showed a clear statistical benefit for the combined HMV/HOT approach over HOT alone, although this lost statistical significance after 6 and 12 months’ follow-up. “That’s in part explained by the fact that the patient numbers were reduced, but also by the fact that, as part of the trial protocol, once [HOT only] patients had reached the primary outcome we allowed them to move onto HMV.”

The study was supported by Guy’s and St. Thomas’ Charity, Philips Respironics, ResMed, and the ResMed Foundation. Dr. Murphy has received hospitality for conferences and lecturing from Philips Respironics, lecturing from Fisher & Paykel Healthcare, and hospitality for conferences from ResMed.

LONDON – Patients with chronic obstructive pulmonary disease (COPD) and persistent hypercapnia were half as likely to be readmitted to hospital 1 year after an acute hypercapnic exacerbation if they had received home mechanical ventilation (HMV) in addition to home oxygen therapy (HOT) than if they had not.

The median admission-free survival time in the HOT-HMV U.K. trial was 4.3 months when HMV was used in addition to HOT, versus 1.4 months for HOT alone (unadjusted hazard ratio = 0.54, P = .007).

©designer491/Thinkstock

“I think what’s really important is that we now have a treatment that we know that if we direct toward [patients with persistent hypercapnia after acute hypercapnic exacerbation] that we effect a significant change in their outcomes,” said study investigator Patrick Murphy, MBBS, PhD, a consultant physician and honorary senior lecturer at the Lane Fox Respiratory Unit at Guy’s and St Thomas’ NHS Foundation Trust (London).

Speaking at the annual congress of the European Respiratory Society, he added: “We need to titrate the home ventilation to control nocturnal hypoventilation, and although I’ve not presented the data as time is short, there is no deleterious effect on quality of life.”

Nicholas Hart, MBBS, PhD, co–study investigator and clinical and academic director of Lane Fox Respiratory Unit, said in a statement issued by Philips Respironics that the results “have the ability to change the way that COPD patients are treated worldwide.”

“We’re looking forward to continuing the trial over the next 5 years to monitor survival rates, which we hope will rise, and readmission rates, which will hopefully fall,” he added.

The HOT-HMV UK Trial was conducted in 15 centers and involved patients with severe COPD who had persistent hypercapnia 2-4 weeks after experiencing an acute, life-threatening hypercapnic exacerbation requiring hospitalization. Persistent hypercapnia was defined as a pH of 7.3 or more and a PaCO2 of 7 kPa or higher. Patients had to have a 20-year or more pack year history of smoking, a forced expiratory volume in 1 second (FEV₁) of 50% or less, and FEV₁ to forced vital capacity (FVC) ratio of below 60%.

Dr. Murphy observed that the trial design assumed that the rate of hospital readmission at 1 year could be reduced from 55% to 25% with the use of noninvasive ventilation (NIV). The hypothesis was that HMV plus long-term HOT would increase admission-free survival compared with HOT alone.

More than 2,000 patients were initially screened for inclusion in the trial, with 116 randomized. Of the excluded patients, 1,609 did not meet inclusion criteria, 296 declined to participate, and 8 patients were not included for other reasons.

The average age of patients participating in the study was 67 years. The patients had a median body mass index of 21.6 kg/m² and most (61%) were female. Prior long-term oxygen therapy had been used by most (80%), and 61% had three or more COPD-related hospital admissions in the last year.

Putting the primary endpoint data into perspective, Dr. Murphy said that six patients with persistent hypercapnia after treatment for an acute exacerbation needed to be treated with HMV to prevent one readmission in the following 12-month period.

Improved nocturnal hypercapnia and sleep-disordered breathing led to improved daytime hypercapnia, he observed. The change in daytime hypercapnia after 6 weeks and 3 months showed a clear statistical benefit for the combined HMV/HOT approach over HOT alone, although this lost statistical significance after 6 and 12 months’ follow-up. “That’s in part explained by the fact that the patient numbers were reduced, but also by the fact that, as part of the trial protocol, once [HOT only] patients had reached the primary outcome we allowed them to move onto HMV.”

The study was supported by Guy’s and St. Thomas’ Charity, Philips Respironics, ResMed, and the ResMed Foundation. Dr. Murphy has received hospitality for conferences and lecturing from Philips Respironics, lecturing from Fisher & Paykel Healthcare, and hospitality for conferences from ResMed.

LONDON – Patients with chronic obstructive pulmonary disease (COPD) and persistent hypercapnia were half as likely to be readmitted to hospital 1 year after an acute hypercapnic exacerbation if they had received home mechanical ventilation (HMV) in addition to home oxygen therapy (HOT) than if they had not.

The median admission-free survival time in the HOT-HMV U.K. trial was 4.3 months when HMV was used in addition to HOT, versus 1.4 months for HOT alone (unadjusted hazard ratio = 0.54, P = .007).

©designer491/Thinkstock

“I think what’s really important is that we now have a treatment that we know that if we direct toward [patients with persistent hypercapnia after acute hypercapnic exacerbation] that we effect a significant change in their outcomes,” said study investigator Patrick Murphy, MBBS, PhD, a consultant physician and honorary senior lecturer at the Lane Fox Respiratory Unit at Guy’s and St Thomas’ NHS Foundation Trust (London).

Speaking at the annual congress of the European Respiratory Society, he added: “We need to titrate the home ventilation to control nocturnal hypoventilation, and although I’ve not presented the data as time is short, there is no deleterious effect on quality of life.”

Nicholas Hart, MBBS, PhD, co–study investigator and clinical and academic director of Lane Fox Respiratory Unit, said in a statement issued by Philips Respironics that the results “have the ability to change the way that COPD patients are treated worldwide.”

“We’re looking forward to continuing the trial over the next 5 years to monitor survival rates, which we hope will rise, and readmission rates, which will hopefully fall,” he added.

The HOT-HMV UK Trial was conducted in 15 centers and involved patients with severe COPD who had persistent hypercapnia 2-4 weeks after experiencing an acute, life-threatening hypercapnic exacerbation requiring hospitalization. Persistent hypercapnia was defined as a pH of 7.3 or more and a PaCO2 of 7 kPa or higher. Patients had to have a 20-year or more pack year history of smoking, a forced expiratory volume in 1 second (FEV₁) of 50% or less, and FEV₁ to forced vital capacity (FVC) ratio of below 60%.

Dr. Murphy observed that the trial design assumed that the rate of hospital readmission at 1 year could be reduced from 55% to 25% with the use of noninvasive ventilation (NIV). The hypothesis was that HMV plus long-term HOT would increase admission-free survival compared with HOT alone.

More than 2,000 patients were initially screened for inclusion in the trial, with 116 randomized. Of the excluded patients, 1,609 did not meet inclusion criteria, 296 declined to participate, and 8 patients were not included for other reasons.

The average age of patients participating in the study was 67 years. The patients had a median body mass index of 21.6 kg/m² and most (61%) were female. Prior long-term oxygen therapy had been used by most (80%), and 61% had three or more COPD-related hospital admissions in the last year.

Putting the primary endpoint data into perspective, Dr. Murphy said that six patients with persistent hypercapnia after treatment for an acute exacerbation needed to be treated with HMV to prevent one readmission in the following 12-month period.

Improved nocturnal hypercapnia and sleep-disordered breathing led to improved daytime hypercapnia, he observed. The change in daytime hypercapnia after 6 weeks and 3 months showed a clear statistical benefit for the combined HMV/HOT approach over HOT alone, although this lost statistical significance after 6 and 12 months’ follow-up. “That’s in part explained by the fact that the patient numbers were reduced, but also by the fact that, as part of the trial protocol, once [HOT only] patients had reached the primary outcome we allowed them to move onto HMV.”

The study was supported by Guy’s and St. Thomas’ Charity, Philips Respironics, ResMed, and the ResMed Foundation. Dr. Murphy has received hospitality for conferences and lecturing from Philips Respironics, lecturing from Fisher & Paykel Healthcare, and hospitality for conferences from ResMed.

LONDON – Phase III evidence confirms the multiple benefits of using a triple, fixed-dose combination (FDC) therapy over standard options in patients with severe chronic obstructive pulmonary disease (COPD), according to a presentation on two trials at the annual congress of the European Respiratory Society.

In the TRINITY trial, the combination of the inhaled corticosteroid (ICS) beclometasone diproprionate (BDP), the long-acting beta-agonist (LABA) formoterol fumarate (FF), and the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GB) delivered via a single pressurized metered-dose inhaler (pMDI), was more effective at reducing exacerbations than was tiotropium bromide (Spiriva, Boehringer Ingelheim) monotherapy.

Results of the TRILOGY trial, which were simultaneously published in The Lancet (doi: 10.1016/S0140-6736(16)31354-X) at the time of their presentation at the ERS meeting, showed that the novel single-inhaler, triple fixed-dose combination could induce greater improvements in lung function when compared to a double fixed-dose combination of BDP and FF (Foster, Chiesi Farmaceutici SpA).

Sara Freeman/Frontline Medical News

“LAMA monotherapy or ICS/LABA are standard options for treating patients with advanced COPD,” Jørgen Vestbo, MD, president of ERS and professor of respiratory medicine at the University of Manchester (England), said in an interview.

Dr. Vestbo, who was an investigator in both the TRINITY and TRILOGY trials, added that the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines also mention that these drugs can be combined in patients who continue to experience COPD exacerbations. “But the evidence behind that is fairly weak,” he observed.

Although many patients are already being treated with triple therapy, this is via two inhalers, and “there have not been that many really good, long-term outcome studies” that have proven this approach to be the best way to manage those at risk for continued exacerbations of COPD, he said.

Drug companies are now starting to combine these three drugs into one inhaler, however, and this means that registration studies need to be done to get the products licensed, and so “there is an interest in coming up with the evidence,” Dr. Vestbo said.

“What is good about these two studies is that they are both 1-year studies and they are of sufficient size to give quite good estimates … These are studies that we should have done 5 years ago,” he said. Although the ideal is to have patients on as little therapy as possible, the results of TRINITY and TRILOGY now provide much needed evidence that it will work better than either LAMA or ICS/LABA.

The piece of evidence that is still missing is what the benefit, if any, is over a LAMA/LABA combination, a fact noted during discussion following the presentations of these data at the ERS meeting and in an editorial by Peter Calverley, MD, of the University of Liverpool (England) that accompanied the published TRILOGY findings (Lancet. 2016;388:937-8). There also is a question over whether twice daily is really better than once daily dosing, or vice versa.

“Until these next studies become available, we can be comforted by the knowledge that three therapies can be combined in a single inhaler which offers more effective therapy than at least one of the recommended treatment regimens for patients with severe COPD,” Dr. Calverley observed in reference to TRILOGY only.

Dr. Vestbo noted that at the time the TRILOGY and TRINITY studies were designed, there wasn’t the evidence from other studies such as the FLAME study (N Engl J Med. 2016. doi: 10.1056/NEJMoa1516385), showing the benefit of the LABA/LAMA combination over ICS/LABA. The TRILOGY and TRINITY studies “give that degree of evidence that was needed,” he said.

“I am not sure that the guidelines [for treating severe COPD] will change much, but at least they can say with better certainty that you can use the triple,” he added.

TRINITY – can triple better LAMA monotherapy?

The TRINITY study looked at whether patients with GOLD 3-4 COPD would be better off treated with LAMA monotherapy (tiotropium 18 mcg, one puff per day), the triple fixed-dose combination of BDP (100 mcg), FF (6 mcg), and GB (12.5 mcg) given via the novel pressurized metered-dose inhaler (two puffs twice daily), or a “free” triple combination of BDP (100 mcg) and FF (6 mcg) given via one pressurized metered-dose inhaler (two puffs daily) plus the same dose of the once-daily LAMA.

In all, 2,690 patients were randomized to these three treatments arms. The mean age of patients was 63 years and the majority (74%-77%) were men, with an average FEV₁ predicted of 36% and one COPD exacerbation in the past year. Just under half of the study population were current smokers. Most (75%) had received prior treatment with an ICS/LABA combination, with about 11% receiving LAMA, and the rest either ICS/LAMA (3%), or LABA/LAMA (12%)

The annualized exacerbation rate (the primary endpoint) was 0.457 in the 1,077 patients who were treated with the triple fixed-dose combination versus 0.571 in the 1,074 patients who received tiotropium alone. The rate ratio was 0.8 indicating a 20% reduction in exacerbations was achieved (P = .003).

The annualized exacerbation rate in the 532 patients given the “free” triple combination (BDP/FF plus tiotropium) was 0.452, with a rate ratio of 0.790 (P =.010) versus those who received the LAMA as monotherapy.

There was no significant difference between the two triple combination strategies.

Presenting these data, Dr. Vestbo noted that the benefit was seen in preventing both severe and moderate COPD exacerbations. Significantly improved lung function, as measured by the change in FEV₁ from baseline to week 52, was also observed to a greater degree with the triple therapy approaches than with the LAMA monotherapy.

“All three treatments were well tolerated and there were no particular safety concerns in this study,” he said.

TRILOGY – are three drugs better than two?

In contrast to the TRINITY study, the TRILOGY study looked at whether patients with severe COPD would be better off taking an ICS/LABA or the new triple fixed-dose combination pressurized metered-dose inhaler.

Just over 1,200 patients were recruited into the study, which had two co–primary endpoints: change from baseline to week 26 in predose morning FEV₁ and 2-hour postdose FEV₁, and the change in transition dyspnea index focal score at week 26.

Results showed that the triple fixed-dose combination improved predose FEV₁ by 0.081 L and 2-hour postdose FEV₁ by 0.117 L compared with the ICS/LABA combination (P less than .001 for both comparisons). Mean transition dyspnea index scores were 1.71 and 1.50, with a nonsignificant difference of 0.21.

“To be honest, I don’t think we had expected that [the triple combination] would mean much for patients, but we were hoping there would be a significant increase in lung function and a reduction of symptoms,” Dr. Vestbo said about the TRILOGY study. “What we saw was there was [symptomatic improvement] but it was not quite as impressive as we thought, but we reduced exacerbations.”

There was a significant, 23% reduction in the annualized exacerbation rate via the triple combination versus the ICS/LABA combination (0.41 vs 0.53, adjusted rate ratio 0.77, P = .005).

The triple approach was well tolerated, with no increase in adverse events versus the dual combination. The results support the idea that instead of giving patients an ICS/LABA at the start, better disease control can be achieved with a triple fixed-dose combination, Dr. Vestbo suggested.

Writing in The Lancet, Dr. Calverley noted: “The inability to meet one part of a co–primary endpoint clouds the interpretation of the other findings in the study, a familiar problem in COPD trials.” He added that there was a significant difference in the overall St George’s Respiratory Questionnaire scores favoring the triple over double therapy.

Chiesi Farmaceutici SpA funded the studies. Dr. Vestbo was an investigator for both TRINITY and TRILOGY and has received honoraria for advising and presenting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis. Dr. Calverley has consulted for Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca.

LONDON – Phase III evidence confirms the multiple benefits of using a triple, fixed-dose combination (FDC) therapy over standard options in patients with severe chronic obstructive pulmonary disease (COPD), according to a presentation on two trials at the annual congress of the European Respiratory Society.

In the TRINITY trial, the combination of the inhaled corticosteroid (ICS) beclometasone diproprionate (BDP), the long-acting beta-agonist (LABA) formoterol fumarate (FF), and the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GB) delivered via a single pressurized metered-dose inhaler (pMDI), was more effective at reducing exacerbations than was tiotropium bromide (Spiriva, Boehringer Ingelheim) monotherapy.

Results of the TRILOGY trial, which were simultaneously published in The Lancet (doi: 10.1016/S0140-6736(16)31354-X) at the time of their presentation at the ERS meeting, showed that the novel single-inhaler, triple fixed-dose combination could induce greater improvements in lung function when compared to a double fixed-dose combination of BDP and FF (Foster, Chiesi Farmaceutici SpA).

Sara Freeman/Frontline Medical News

“LAMA monotherapy or ICS/LABA are standard options for treating patients with advanced COPD,” Jørgen Vestbo, MD, president of ERS and professor of respiratory medicine at the University of Manchester (England), said in an interview.

Dr. Vestbo, who was an investigator in both the TRINITY and TRILOGY trials, added that the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines also mention that these drugs can be combined in patients who continue to experience COPD exacerbations. “But the evidence behind that is fairly weak,” he observed.

Although many patients are already being treated with triple therapy, this is via two inhalers, and “there have not been that many really good, long-term outcome studies” that have proven this approach to be the best way to manage those at risk for continued exacerbations of COPD, he said.

Drug companies are now starting to combine these three drugs into one inhaler, however, and this means that registration studies need to be done to get the products licensed, and so “there is an interest in coming up with the evidence,” Dr. Vestbo said.

“What is good about these two studies is that they are both 1-year studies and they are of sufficient size to give quite good estimates … These are studies that we should have done 5 years ago,” he said. Although the ideal is to have patients on as little therapy as possible, the results of TRINITY and TRILOGY now provide much needed evidence that it will work better than either LAMA or ICS/LABA.

The piece of evidence that is still missing is what the benefit, if any, is over a LAMA/LABA combination, a fact noted during discussion following the presentations of these data at the ERS meeting and in an editorial by Peter Calverley, MD, of the University of Liverpool (England) that accompanied the published TRILOGY findings (Lancet. 2016;388:937-8). There also is a question over whether twice daily is really better than once daily dosing, or vice versa.

“Until these next studies become available, we can be comforted by the knowledge that three therapies can be combined in a single inhaler which offers more effective therapy than at least one of the recommended treatment regimens for patients with severe COPD,” Dr. Calverley observed in reference to TRILOGY only.

Dr. Vestbo noted that at the time the TRILOGY and TRINITY studies were designed, there wasn’t the evidence from other studies such as the FLAME study (N Engl J Med. 2016. doi: 10.1056/NEJMoa1516385), showing the benefit of the LABA/LAMA combination over ICS/LABA. The TRILOGY and TRINITY studies “give that degree of evidence that was needed,” he said.

“I am not sure that the guidelines [for treating severe COPD] will change much, but at least they can say with better certainty that you can use the triple,” he added.

TRINITY – can triple better LAMA monotherapy?

The TRINITY study looked at whether patients with GOLD 3-4 COPD would be better off treated with LAMA monotherapy (tiotropium 18 mcg, one puff per day), the triple fixed-dose combination of BDP (100 mcg), FF (6 mcg), and GB (12.5 mcg) given via the novel pressurized metered-dose inhaler (two puffs twice daily), or a “free” triple combination of BDP (100 mcg) and FF (6 mcg) given via one pressurized metered-dose inhaler (two puffs daily) plus the same dose of the once-daily LAMA.

In all, 2,690 patients were randomized to these three treatments arms. The mean age of patients was 63 years and the majority (74%-77%) were men, with an average FEV₁ predicted of 36% and one COPD exacerbation in the past year. Just under half of the study population were current smokers. Most (75%) had received prior treatment with an ICS/LABA combination, with about 11% receiving LAMA, and the rest either ICS/LAMA (3%), or LABA/LAMA (12%)

The annualized exacerbation rate (the primary endpoint) was 0.457 in the 1,077 patients who were treated with the triple fixed-dose combination versus 0.571 in the 1,074 patients who received tiotropium alone. The rate ratio was 0.8 indicating a 20% reduction in exacerbations was achieved (P = .003).

The annualized exacerbation rate in the 532 patients given the “free” triple combination (BDP/FF plus tiotropium) was 0.452, with a rate ratio of 0.790 (P =.010) versus those who received the LAMA as monotherapy.

There was no significant difference between the two triple combination strategies.

Presenting these data, Dr. Vestbo noted that the benefit was seen in preventing both severe and moderate COPD exacerbations. Significantly improved lung function, as measured by the change in FEV₁ from baseline to week 52, was also observed to a greater degree with the triple therapy approaches than with the LAMA monotherapy.

“All three treatments were well tolerated and there were no particular safety concerns in this study,” he said.

TRILOGY – are three drugs better than two?

In contrast to the TRINITY study, the TRILOGY study looked at whether patients with severe COPD would be better off taking an ICS/LABA or the new triple fixed-dose combination pressurized metered-dose inhaler.

Just over 1,200 patients were recruited into the study, which had two co–primary endpoints: change from baseline to week 26 in predose morning FEV₁ and 2-hour postdose FEV₁, and the change in transition dyspnea index focal score at week 26.

Results showed that the triple fixed-dose combination improved predose FEV₁ by 0.081 L and 2-hour postdose FEV₁ by 0.117 L compared with the ICS/LABA combination (P less than .001 for both comparisons). Mean transition dyspnea index scores were 1.71 and 1.50, with a nonsignificant difference of 0.21.

“To be honest, I don’t think we had expected that [the triple combination] would mean much for patients, but we were hoping there would be a significant increase in lung function and a reduction of symptoms,” Dr. Vestbo said about the TRILOGY study. “What we saw was there was [symptomatic improvement] but it was not quite as impressive as we thought, but we reduced exacerbations.”

There was a significant, 23% reduction in the annualized exacerbation rate via the triple combination versus the ICS/LABA combination (0.41 vs 0.53, adjusted rate ratio 0.77, P = .005).

The triple approach was well tolerated, with no increase in adverse events versus the dual combination. The results support the idea that instead of giving patients an ICS/LABA at the start, better disease control can be achieved with a triple fixed-dose combination, Dr. Vestbo suggested.

Writing in The Lancet, Dr. Calverley noted: “The inability to meet one part of a co–primary endpoint clouds the interpretation of the other findings in the study, a familiar problem in COPD trials.” He added that there was a significant difference in the overall St George’s Respiratory Questionnaire scores favoring the triple over double therapy.

Chiesi Farmaceutici SpA funded the studies. Dr. Vestbo was an investigator for both TRINITY and TRILOGY and has received honoraria for advising and presenting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis. Dr. Calverley has consulted for Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca.

LONDON – Phase III evidence confirms the multiple benefits of using a triple, fixed-dose combination (FDC) therapy over standard options in patients with severe chronic obstructive pulmonary disease (COPD), according to a presentation on two trials at the annual congress of the European Respiratory Society.

In the TRINITY trial, the combination of the inhaled corticosteroid (ICS) beclometasone diproprionate (BDP), the long-acting beta-agonist (LABA) formoterol fumarate (FF), and the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GB) delivered via a single pressurized metered-dose inhaler (pMDI), was more effective at reducing exacerbations than was tiotropium bromide (Spiriva, Boehringer Ingelheim) monotherapy.

Results of the TRILOGY trial, which were simultaneously published in The Lancet (doi: 10.1016/S0140-6736(16)31354-X) at the time of their presentation at the ERS meeting, showed that the novel single-inhaler, triple fixed-dose combination could induce greater improvements in lung function when compared to a double fixed-dose combination of BDP and FF (Foster, Chiesi Farmaceutici SpA).

Sara Freeman/Frontline Medical News

“LAMA monotherapy or ICS/LABA are standard options for treating patients with advanced COPD,” Jørgen Vestbo, MD, president of ERS and professor of respiratory medicine at the University of Manchester (England), said in an interview.

Dr. Vestbo, who was an investigator in both the TRINITY and TRILOGY trials, added that the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines also mention that these drugs can be combined in patients who continue to experience COPD exacerbations. “But the evidence behind that is fairly weak,” he observed.

Although many patients are already being treated with triple therapy, this is via two inhalers, and “there have not been that many really good, long-term outcome studies” that have proven this approach to be the best way to manage those at risk for continued exacerbations of COPD, he said.

Drug companies are now starting to combine these three drugs into one inhaler, however, and this means that registration studies need to be done to get the products licensed, and so “there is an interest in coming up with the evidence,” Dr. Vestbo said.

“What is good about these two studies is that they are both 1-year studies and they are of sufficient size to give quite good estimates … These are studies that we should have done 5 years ago,” he said. Although the ideal is to have patients on as little therapy as possible, the results of TRINITY and TRILOGY now provide much needed evidence that it will work better than either LAMA or ICS/LABA.

The piece of evidence that is still missing is what the benefit, if any, is over a LAMA/LABA combination, a fact noted during discussion following the presentations of these data at the ERS meeting and in an editorial by Peter Calverley, MD, of the University of Liverpool (England) that accompanied the published TRILOGY findings (Lancet. 2016;388:937-8). There also is a question over whether twice daily is really better than once daily dosing, or vice versa.

“Until these next studies become available, we can be comforted by the knowledge that three therapies can be combined in a single inhaler which offers more effective therapy than at least one of the recommended treatment regimens for patients with severe COPD,” Dr. Calverley observed in reference to TRILOGY only.

Dr. Vestbo noted that at the time the TRILOGY and TRINITY studies were designed, there wasn’t the evidence from other studies such as the FLAME study (N Engl J Med. 2016. doi: 10.1056/NEJMoa1516385), showing the benefit of the LABA/LAMA combination over ICS/LABA. The TRILOGY and TRINITY studies “give that degree of evidence that was needed,” he said.

“I am not sure that the guidelines [for treating severe COPD] will change much, but at least they can say with better certainty that you can use the triple,” he added.

TRINITY – can triple better LAMA monotherapy?

The TRINITY study looked at whether patients with GOLD 3-4 COPD would be better off treated with LAMA monotherapy (tiotropium 18 mcg, one puff per day), the triple fixed-dose combination of BDP (100 mcg), FF (6 mcg), and GB (12.5 mcg) given via the novel pressurized metered-dose inhaler (two puffs twice daily), or a “free” triple combination of BDP (100 mcg) and FF (6 mcg) given via one pressurized metered-dose inhaler (two puffs daily) plus the same dose of the once-daily LAMA.

In all, 2,690 patients were randomized to these three treatments arms. The mean age of patients was 63 years and the majority (74%-77%) were men, with an average FEV₁ predicted of 36% and one COPD exacerbation in the past year. Just under half of the study population were current smokers. Most (75%) had received prior treatment with an ICS/LABA combination, with about 11% receiving LAMA, and the rest either ICS/LAMA (3%), or LABA/LAMA (12%)

The annualized exacerbation rate (the primary endpoint) was 0.457 in the 1,077 patients who were treated with the triple fixed-dose combination versus 0.571 in the 1,074 patients who received tiotropium alone. The rate ratio was 0.8 indicating a 20% reduction in exacerbations was achieved (P = .003).

The annualized exacerbation rate in the 532 patients given the “free” triple combination (BDP/FF plus tiotropium) was 0.452, with a rate ratio of 0.790 (P =.010) versus those who received the LAMA as monotherapy.

There was no significant difference between the two triple combination strategies.

Presenting these data, Dr. Vestbo noted that the benefit was seen in preventing both severe and moderate COPD exacerbations. Significantly improved lung function, as measured by the change in FEV₁ from baseline to week 52, was also observed to a greater degree with the triple therapy approaches than with the LAMA monotherapy.

“All three treatments were well tolerated and there were no particular safety concerns in this study,” he said.

TRILOGY – are three drugs better than two?

In contrast to the TRINITY study, the TRILOGY study looked at whether patients with severe COPD would be better off taking an ICS/LABA or the new triple fixed-dose combination pressurized metered-dose inhaler.

Just over 1,200 patients were recruited into the study, which had two co–primary endpoints: change from baseline to week 26 in predose morning FEV₁ and 2-hour postdose FEV₁, and the change in transition dyspnea index focal score at week 26.

Results showed that the triple fixed-dose combination improved predose FEV₁ by 0.081 L and 2-hour postdose FEV₁ by 0.117 L compared with the ICS/LABA combination (P less than .001 for both comparisons). Mean transition dyspnea index scores were 1.71 and 1.50, with a nonsignificant difference of 0.21.

“To be honest, I don’t think we had expected that [the triple combination] would mean much for patients, but we were hoping there would be a significant increase in lung function and a reduction of symptoms,” Dr. Vestbo said about the TRILOGY study. “What we saw was there was [symptomatic improvement] but it was not quite as impressive as we thought, but we reduced exacerbations.”

There was a significant, 23% reduction in the annualized exacerbation rate via the triple combination versus the ICS/LABA combination (0.41 vs 0.53, adjusted rate ratio 0.77, P = .005).

The triple approach was well tolerated, with no increase in adverse events versus the dual combination. The results support the idea that instead of giving patients an ICS/LABA at the start, better disease control can be achieved with a triple fixed-dose combination, Dr. Vestbo suggested.

Writing in The Lancet, Dr. Calverley noted: “The inability to meet one part of a co–primary endpoint clouds the interpretation of the other findings in the study, a familiar problem in COPD trials.” He added that there was a significant difference in the overall St George’s Respiratory Questionnaire scores favoring the triple over double therapy.

Chiesi Farmaceutici SpA funded the studies. Dr. Vestbo was an investigator for both TRINITY and TRILOGY and has received honoraria for advising and presenting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis. Dr. Calverley has consulted for Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca.

BOSTON – Field cancerization poses unique treatment challenges, but useful approaches to managing patients with such extreme dermatoheliosis are emerging, according to Anokhi Jambusaria-Pahlajani, MD.

In patients with extensive sun damage to the head and neck, she said she performs initial curettage of any hyperkeratotic actinic keratoses, followed by topical 0.5% 5-fluorouracil applied twice daily on postcurettage days 1 through 5. On day 6, she performs aminolevulinic acid photodynamic therapy (PDT) with 1 hour of incubation.

“Basically, on day zero they come into my office, and I look for anything that’s hyperkeratotic, and I numb it up and curette it. The goal of that is to get rid of the scale so that when I do the topical 5-fluorouracil or I do the photodynamic therapy, the medicine is actually getting to where we want it to go,” Dr. Jambusaria-Pahlajani, a dermatologist in Round Rock, Tex., said at the American Academy of Dermatology summer meeting.

She discussed one such patient – a lung transplant recipient – in whom this approach worked particularly well. At 6 months’ follow-up, the patient had had a significant response, and during a follow-up of at least 2 years, he did not develop a single actinic keratosis.

Early results with this combination approach were so encouraging that she and her colleagues published a case series of four solid organ transplant recipients. “All four patients tolerated the approach well, demonstrated excellent response to treatment with complete or near complete resolution of actinic keratosis and squamous cell carcinoma in situ lesions,” she said. At 1-6 months following treatment, “basically patients were clear,” she added (Dermatol Surg. 2016 Jan;42:S66-72).

Dr. Jambusaria-Pahlajani also said she has seen “great results” in most of the 30-40 other patients she has treated using this approach. “I’ve followed up patients for years, and they really haven’t had a problem like what they had prior to getting this treatment,” she said.

She noted that, anecdotally, many patients who had been treated with multiple courses of topical 5-fluorouracil monotherapy or photodynamic therapy actually preferred the combination approach. They felt that they were out of commission for a shorter period of time, and most of the patients “tended to be kind of red and inflamed for about 7-10 days total from start to finish, which was a lot better than with, for example, 5-fluorouracil,” she said.

One patient – another lung transplant recipient – initially responded to combination therapy, but returned in 3 months with numerous recurrent lesions. Based on findings from a 2010 study, a cyclic approach to PDT was tried in this patient. In that study of 12 solid organ transplant recipients, cyclic PDT reduced the incidence of squamous cell carcinoma (Dermatol Surg. 2010 May;36[5]:652-8).

The study subjects had a high burden of squamous cell carcinoma in situ. The cyclic PDT they received included blue light PDT with 1 hour of incubation every 4-8 weeks for 2 years. The median number of new invasive and in situ squamous cell carcinomas declined from about 20 to 4 in the first year (a 79% reduction vs. 1 month prior to first treatment) and to 1 at 2 years (a 95% reduction).

“This patient happened to be a transplant patient as well, but I think you could also use [this approach] in nontransplant patients,” Dr. Jambusaria-Pahlajani said. His response was “pretty significant,” and after 18 months of treatment he was doing well.

“The main thing that you have to remember, though, is that these patients have to be willing to come in every 4-8 weeks to get the PDT,” which, she added, “is not for every patient.” It’s also not for every provider. Aside from staff or resource access limitations, these treatments can be very time consuming and costly, she noted. “Treating these patients can be a challenge, but it can be rewarding, as well,” she commented.

She reported having no relevant financial disclosures.

BOSTON – Field cancerization poses unique treatment challenges, but useful approaches to managing patients with such extreme dermatoheliosis are emerging, according to Anokhi Jambusaria-Pahlajani, MD.

In patients with extensive sun damage to the head and neck, she said she performs initial curettage of any hyperkeratotic actinic keratoses, followed by topical 0.5% 5-fluorouracil applied twice daily on postcurettage days 1 through 5. On day 6, she performs aminolevulinic acid photodynamic therapy (PDT) with 1 hour of incubation.

“Basically, on day zero they come into my office, and I look for anything that’s hyperkeratotic, and I numb it up and curette it. The goal of that is to get rid of the scale so that when I do the topical 5-fluorouracil or I do the photodynamic therapy, the medicine is actually getting to where we want it to go,” Dr. Jambusaria-Pahlajani, a dermatologist in Round Rock, Tex., said at the American Academy of Dermatology summer meeting.

She discussed one such patient – a lung transplant recipient – in whom this approach worked particularly well. At 6 months’ follow-up, the patient had had a significant response, and during a follow-up of at least 2 years, he did not develop a single actinic keratosis.

Early results with this combination approach were so encouraging that she and her colleagues published a case series of four solid organ transplant recipients. “All four patients tolerated the approach well, demonstrated excellent response to treatment with complete or near complete resolution of actinic keratosis and squamous cell carcinoma in situ lesions,” she said. At 1-6 months following treatment, “basically patients were clear,” she added (Dermatol Surg. 2016 Jan;42:S66-72).

Dr. Jambusaria-Pahlajani also said she has seen “great results” in most of the 30-40 other patients she has treated using this approach. “I’ve followed up patients for years, and they really haven’t had a problem like what they had prior to getting this treatment,” she said.

She noted that, anecdotally, many patients who had been treated with multiple courses of topical 5-fluorouracil monotherapy or photodynamic therapy actually preferred the combination approach. They felt that they were out of commission for a shorter period of time, and most of the patients “tended to be kind of red and inflamed for about 7-10 days total from start to finish, which was a lot better than with, for example, 5-fluorouracil,” she said.

One patient – another lung transplant recipient – initially responded to combination therapy, but returned in 3 months with numerous recurrent lesions. Based on findings from a 2010 study, a cyclic approach to PDT was tried in this patient. In that study of 12 solid organ transplant recipients, cyclic PDT reduced the incidence of squamous cell carcinoma (Dermatol Surg. 2010 May;36[5]:652-8).

The study subjects had a high burden of squamous cell carcinoma in situ. The cyclic PDT they received included blue light PDT with 1 hour of incubation every 4-8 weeks for 2 years. The median number of new invasive and in situ squamous cell carcinomas declined from about 20 to 4 in the first year (a 79% reduction vs. 1 month prior to first treatment) and to 1 at 2 years (a 95% reduction).

“This patient happened to be a transplant patient as well, but I think you could also use [this approach] in nontransplant patients,” Dr. Jambusaria-Pahlajani said. His response was “pretty significant,” and after 18 months of treatment he was doing well.

“The main thing that you have to remember, though, is that these patients have to be willing to come in every 4-8 weeks to get the PDT,” which, she added, “is not for every patient.” It’s also not for every provider. Aside from staff or resource access limitations, these treatments can be very time consuming and costly, she noted. “Treating these patients can be a challenge, but it can be rewarding, as well,” she commented.

She reported having no relevant financial disclosures.

BOSTON – Field cancerization poses unique treatment challenges, but useful approaches to managing patients with such extreme dermatoheliosis are emerging, according to Anokhi Jambusaria-Pahlajani, MD.

In patients with extensive sun damage to the head and neck, she said she performs initial curettage of any hyperkeratotic actinic keratoses, followed by topical 0.5% 5-fluorouracil applied twice daily on postcurettage days 1 through 5. On day 6, she performs aminolevulinic acid photodynamic therapy (PDT) with 1 hour of incubation.

“Basically, on day zero they come into my office, and I look for anything that’s hyperkeratotic, and I numb it up and curette it. The goal of that is to get rid of the scale so that when I do the topical 5-fluorouracil or I do the photodynamic therapy, the medicine is actually getting to where we want it to go,” Dr. Jambusaria-Pahlajani, a dermatologist in Round Rock, Tex., said at the American Academy of Dermatology summer meeting.

She discussed one such patient – a lung transplant recipient – in whom this approach worked particularly well. At 6 months’ follow-up, the patient had had a significant response, and during a follow-up of at least 2 years, he did not develop a single actinic keratosis.

Early results with this combination approach were so encouraging that she and her colleagues published a case series of four solid organ transplant recipients. “All four patients tolerated the approach well, demonstrated excellent response to treatment with complete or near complete resolution of actinic keratosis and squamous cell carcinoma in situ lesions,” she said. At 1-6 months following treatment, “basically patients were clear,” she added (Dermatol Surg. 2016 Jan;42:S66-72).

Dr. Jambusaria-Pahlajani also said she has seen “great results” in most of the 30-40 other patients she has treated using this approach. “I’ve followed up patients for years, and they really haven’t had a problem like what they had prior to getting this treatment,” she said.

She noted that, anecdotally, many patients who had been treated with multiple courses of topical 5-fluorouracil monotherapy or photodynamic therapy actually preferred the combination approach. They felt that they were out of commission for a shorter period of time, and most of the patients “tended to be kind of red and inflamed for about 7-10 days total from start to finish, which was a lot better than with, for example, 5-fluorouracil,” she said.

One patient – another lung transplant recipient – initially responded to combination therapy, but returned in 3 months with numerous recurrent lesions. Based on findings from a 2010 study, a cyclic approach to PDT was tried in this patient. In that study of 12 solid organ transplant recipients, cyclic PDT reduced the incidence of squamous cell carcinoma (Dermatol Surg. 2010 May;36[5]:652-8).

The study subjects had a high burden of squamous cell carcinoma in situ. The cyclic PDT they received included blue light PDT with 1 hour of incubation every 4-8 weeks for 2 years. The median number of new invasive and in situ squamous cell carcinomas declined from about 20 to 4 in the first year (a 79% reduction vs. 1 month prior to first treatment) and to 1 at 2 years (a 95% reduction).

“This patient happened to be a transplant patient as well, but I think you could also use [this approach] in nontransplant patients,” Dr. Jambusaria-Pahlajani said. His response was “pretty significant,” and after 18 months of treatment he was doing well.

“The main thing that you have to remember, though, is that these patients have to be willing to come in every 4-8 weeks to get the PDT,” which, she added, “is not for every patient.” It’s also not for every provider. Aside from staff or resource access limitations, these treatments can be very time consuming and costly, she noted. “Treating these patients can be a challenge, but it can be rewarding, as well,” she commented.

She reported having no relevant financial disclosures.