Audrey Odom, MD, PhD

Credit: Robert Boston

Researchers have uncovered a way in which the malaria parasite Plasmodium falciparum becomes resistant to an investigational drug called fosmidomycin.

The team reported this finding in Nature Communications.

The malaria parasite makes a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy.

Fosmidomycin can be used to block isoprenoid synthesis and kill the malaria parasite.

But over time, the drug often becomes less effective.

“In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study,” said Audrey R. Odom, MD, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?”

Using sequencing technology, she and her colleagues compared the genetics of malaria parasites that responded to the drug to the genetics of parasites that were resistant to it.

This revealed mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.

“The PfHAD1 protein is completely unstudied,” Dr Odom said. “It’s a member of a larger family of proteins, and there are almost no biological functions assigned to them.”

Dr Odom’s team showed that, in malaria parasites, the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing.

Since isoprenoids are necessary for life, it’s not clear why the organism would purposefully slow down isoprenoid production.

“We don’t know why the protein puts the brakes on under normal conditions; perhaps simply because it’s an energetically expensive pathway,” Dr Odom said. “But loss of PfHAD1 releases the brakes, increasing the pathway’s activity, so that even when the drug is there, it doesn’t kill the cells.”

Therefore, Dr Odom and her colleagues believe isoprenoid synthesis is an attractive drug target for malaria.

Audrey Odom, MD, PhD

Credit: Robert Boston

Researchers have uncovered a way in which the malaria parasite Plasmodium falciparum becomes resistant to an investigational drug called fosmidomycin.

The team reported this finding in Nature Communications.

The malaria parasite makes a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy.

Fosmidomycin can be used to block isoprenoid synthesis and kill the malaria parasite.

But over time, the drug often becomes less effective.

“In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study,” said Audrey R. Odom, MD, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?”

Using sequencing technology, she and her colleagues compared the genetics of malaria parasites that responded to the drug to the genetics of parasites that were resistant to it.

This revealed mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.

“The PfHAD1 protein is completely unstudied,” Dr Odom said. “It’s a member of a larger family of proteins, and there are almost no biological functions assigned to them.”

Dr Odom’s team showed that, in malaria parasites, the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing.

Since isoprenoids are necessary for life, it’s not clear why the organism would purposefully slow down isoprenoid production.

“We don’t know why the protein puts the brakes on under normal conditions; perhaps simply because it’s an energetically expensive pathway,” Dr Odom said. “But loss of PfHAD1 releases the brakes, increasing the pathway’s activity, so that even when the drug is there, it doesn’t kill the cells.”

Therefore, Dr Odom and her colleagues believe isoprenoid synthesis is an attractive drug target for malaria.

Audrey Odom, MD, PhD

Credit: Robert Boston

Researchers have uncovered a way in which the malaria parasite Plasmodium falciparum becomes resistant to an investigational drug called fosmidomycin.

The team reported this finding in Nature Communications.

The malaria parasite makes a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy.

Fosmidomycin can be used to block isoprenoid synthesis and kill the malaria parasite.

But over time, the drug often becomes less effective.

“In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study,” said Audrey R. Odom, MD, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?”

Using sequencing technology, she and her colleagues compared the genetics of malaria parasites that responded to the drug to the genetics of parasites that were resistant to it.

This revealed mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.

“The PfHAD1 protein is completely unstudied,” Dr Odom said. “It’s a member of a larger family of proteins, and there are almost no biological functions assigned to them.”

Dr Odom’s team showed that, in malaria parasites, the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing.

Since isoprenoids are necessary for life, it’s not clear why the organism would purposefully slow down isoprenoid production.

“We don’t know why the protein puts the brakes on under normal conditions; perhaps simply because it’s an energetically expensive pathway,” Dr Odom said. “But loss of PfHAD1 releases the brakes, increasing the pathway’s activity, so that even when the drug is there, it doesn’t kill the cells.”

Therefore, Dr Odom and her colleagues believe isoprenoid synthesis is an attractive drug target for malaria.

Patient receiving chemotherapy

Credit: Rhoda Baer

A biosimilar of the erythropoiesis-stimulating agent epoetin alfa can elicit responses in patients with chemotherapy-induced anemia, according to a study published in BMC Cancer.

The agent, epoetin zeta (Retacrit), produced a hemoglobin (Hb) response in more than 80% of patients at 3- and 6-month time points.

Response rates were similar in patients with hematologic malignancies and those with solid tumors.

And the rate of clinically significant adverse events was low. This included thromboembolic events, bleeding, infection, local intolerability, and increased blood pressure.

Mauricette Michallet, MD, PhD, of Centre Hospitalier Lyon in France, and her colleagues conducted this study, known as ORHEO. It was sponsored by Hospira, the makers of epoetin zeta.

The researchers evaluated 2310 adult patients with chemotherapy-induced anemia (Hb<11 g/dL). Patients had solid tumors (n=1838), lymphomas (n=301), or multiple myeloma (n=171).

Patients were taking a number of treatments aside from epoetin zeta and chemotherapy. This included intravenous iron (10%), oral iron (16%), antithrombotic agents (12%), folates (7%), vitamin B (4%), and other vitamins (2%). An additional 17% of patients were reported as being on “other treatments.”

In all, 99.9% of patients received epoetin zeta. The primary endpoint was the rate of response.

Response was defined as an increase in Hb levels to at least 10 g/dL since enrollment, an increase in Hb levels of at least 1 g/dL since enrollment, or reaching target Hb levels set at the start of study, without any blood transfusions in the 3 weeks prior to measurement. In patients with baseline Hb levels of at least 10 g/dL, only those who reached their Hb target or had an increase greater than 1 g/dL were considered responders.

Eighty-two percent of patients achieved a response at 3 months, and 87% had a response at 6 months. The overall mean change in Hb level was 1.52 ± 1.61 at 3 months and 1.72 ± 1.61 g/dL at 6 months. The rate of transfusion was 9% at 3 months and 6% at 6 months.

Between enrollment and month 6, 1202 patients discontinued epoetin zeta. Forty percent stopped because Hb levels were met, 27% stopped because they were stopping or changing chemotherapy, 15% stopped for both of the aforementioned reasons, 11% stopped because epoetin zeta was ineffective, and 2% stopped due to adverse events.

Seventeen percent of patients experienced an adverse event, including thromboembolic events (4%), infection (5%), bleeding (2%), local intolerability (0.2%), increased blood pressure (2%), and “other” events (9%).

Epoetin zeta was approved in Europe in 2007. For epoetin biosimilars to gain approval in the European Union, companies must agree to conduct post-marketing studies.

Patient receiving chemotherapy

Credit: Rhoda Baer

A biosimilar of the erythropoiesis-stimulating agent epoetin alfa can elicit responses in patients with chemotherapy-induced anemia, according to a study published in BMC Cancer.

The agent, epoetin zeta (Retacrit), produced a hemoglobin (Hb) response in more than 80% of patients at 3- and 6-month time points.

Response rates were similar in patients with hematologic malignancies and those with solid tumors.

And the rate of clinically significant adverse events was low. This included thromboembolic events, bleeding, infection, local intolerability, and increased blood pressure.

Mauricette Michallet, MD, PhD, of Centre Hospitalier Lyon in France, and her colleagues conducted this study, known as ORHEO. It was sponsored by Hospira, the makers of epoetin zeta.

The researchers evaluated 2310 adult patients with chemotherapy-induced anemia (Hb<11 g/dL). Patients had solid tumors (n=1838), lymphomas (n=301), or multiple myeloma (n=171).

Patients were taking a number of treatments aside from epoetin zeta and chemotherapy. This included intravenous iron (10%), oral iron (16%), antithrombotic agents (12%), folates (7%), vitamin B (4%), and other vitamins (2%). An additional 17% of patients were reported as being on “other treatments.”

In all, 99.9% of patients received epoetin zeta. The primary endpoint was the rate of response.

Response was defined as an increase in Hb levels to at least 10 g/dL since enrollment, an increase in Hb levels of at least 1 g/dL since enrollment, or reaching target Hb levels set at the start of study, without any blood transfusions in the 3 weeks prior to measurement. In patients with baseline Hb levels of at least 10 g/dL, only those who reached their Hb target or had an increase greater than 1 g/dL were considered responders.

Eighty-two percent of patients achieved a response at 3 months, and 87% had a response at 6 months. The overall mean change in Hb level was 1.52 ± 1.61 at 3 months and 1.72 ± 1.61 g/dL at 6 months. The rate of transfusion was 9% at 3 months and 6% at 6 months.

Between enrollment and month 6, 1202 patients discontinued epoetin zeta. Forty percent stopped because Hb levels were met, 27% stopped because they were stopping or changing chemotherapy, 15% stopped for both of the aforementioned reasons, 11% stopped because epoetin zeta was ineffective, and 2% stopped due to adverse events.

Seventeen percent of patients experienced an adverse event, including thromboembolic events (4%), infection (5%), bleeding (2%), local intolerability (0.2%), increased blood pressure (2%), and “other” events (9%).

Epoetin zeta was approved in Europe in 2007. For epoetin biosimilars to gain approval in the European Union, companies must agree to conduct post-marketing studies.

Patient receiving chemotherapy

Credit: Rhoda Baer

A biosimilar of the erythropoiesis-stimulating agent epoetin alfa can elicit responses in patients with chemotherapy-induced anemia, according to a study published in BMC Cancer.

The agent, epoetin zeta (Retacrit), produced a hemoglobin (Hb) response in more than 80% of patients at 3- and 6-month time points.

Response rates were similar in patients with hematologic malignancies and those with solid tumors.

And the rate of clinically significant adverse events was low. This included thromboembolic events, bleeding, infection, local intolerability, and increased blood pressure.

Mauricette Michallet, MD, PhD, of Centre Hospitalier Lyon in France, and her colleagues conducted this study, known as ORHEO. It was sponsored by Hospira, the makers of epoetin zeta.

The researchers evaluated 2310 adult patients with chemotherapy-induced anemia (Hb<11 g/dL). Patients had solid tumors (n=1838), lymphomas (n=301), or multiple myeloma (n=171).

Patients were taking a number of treatments aside from epoetin zeta and chemotherapy. This included intravenous iron (10%), oral iron (16%), antithrombotic agents (12%), folates (7%), vitamin B (4%), and other vitamins (2%). An additional 17% of patients were reported as being on “other treatments.”

In all, 99.9% of patients received epoetin zeta. The primary endpoint was the rate of response.

Response was defined as an increase in Hb levels to at least 10 g/dL since enrollment, an increase in Hb levels of at least 1 g/dL since enrollment, or reaching target Hb levels set at the start of study, without any blood transfusions in the 3 weeks prior to measurement. In patients with baseline Hb levels of at least 10 g/dL, only those who reached their Hb target or had an increase greater than 1 g/dL were considered responders.

Eighty-two percent of patients achieved a response at 3 months, and 87% had a response at 6 months. The overall mean change in Hb level was 1.52 ± 1.61 at 3 months and 1.72 ± 1.61 g/dL at 6 months. The rate of transfusion was 9% at 3 months and 6% at 6 months.

Between enrollment and month 6, 1202 patients discontinued epoetin zeta. Forty percent stopped because Hb levels were met, 27% stopped because they were stopping or changing chemotherapy, 15% stopped for both of the aforementioned reasons, 11% stopped because epoetin zeta was ineffective, and 2% stopped due to adverse events.

Seventeen percent of patients experienced an adverse event, including thromboembolic events (4%), infection (5%), bleeding (2%), local intolerability (0.2%), increased blood pressure (2%), and “other” events (9%).

Epoetin zeta was approved in Europe in 2007. For epoetin biosimilars to gain approval in the European Union, companies must agree to conduct post-marketing studies.

Clinical question

Does increased hospitalist workload affect efficiency and quality of care?

Bottom line

Increased hospitalist workload is associated with increased cost and length of stay (LOS). Quality metrics such as 30-day readmission rate, in-hospital mortality, and patient satisfaction were not affected by changes in workload. (LOE = 2b)

Reference

Elliott DJ, Young RS, Brice J, Aguiar R, Kolm P. Effect of hospitalist workload on the quality and efficiency of care. JAMA Intern Med 2014;174(5):786-793.

Study design

Cohort (retrospective)

Funding source

Other

Allocation

Uncertain

Setting

Inpatient (any location)

Synopsis

Using data abstracted from the central data warehouse of an academic community health system, these authors examined the association between hospitalist workload and the efficiency and quality of care provided. A private hospitalist group that provided 24-hour care to patients at 2 hospitals within the system was selected for the study. Patients included were those who either had an attending of record or had admission and discharge bills submitted by a physician in this hospitalist group. Physician daily workload was measured using the total number of relative value units (RVUs) generated and the physician’s census as determined by the number of billable encounters submitted. Efficiency was measured by LOS and cost. Quality was measured by in-hospital mortality, rapid response team activation, 30-day readmission rate, and patient satisfaction. Models were adjusted for patient characteristics, including demographics; severity of illness; visit characteristics, including admission day of the week; and hospital-level characteristics, including hospital occupancy. Approximately 20,000 hospitalizations were included in the study. Hospitalists had a mean of 15.5 patient encounters and 28.6 RVUs per day. Results for LOS were stratified by hospital occupancy. For less than 75% occupancy, LOS increased linearly from 5.5 days to 7.5 days as workload increased. For greater than 85% occupancy, the change in LOS was J-shaped with a significant increase around an RVU of 30 or a census of 17. Cost also increased with higher workloads. For every unit increase in RVU, cost increased by $111; for every unit increase in census, cost increased by $205 (after adjustment for LOS). There were no significant associations with change in workload and patient satisfaction, in-hospital mortality, rapid response team activation, or 30-day readmission rate.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does increased hospitalist workload affect efficiency and quality of care?

Bottom line

Increased hospitalist workload is associated with increased cost and length of stay (LOS). Quality metrics such as 30-day readmission rate, in-hospital mortality, and patient satisfaction were not affected by changes in workload. (LOE = 2b)

Reference

Elliott DJ, Young RS, Brice J, Aguiar R, Kolm P. Effect of hospitalist workload on the quality and efficiency of care. JAMA Intern Med 2014;174(5):786-793.

Study design

Cohort (retrospective)

Funding source

Other

Allocation

Uncertain

Setting

Inpatient (any location)

Synopsis

Using data abstracted from the central data warehouse of an academic community health system, these authors examined the association between hospitalist workload and the efficiency and quality of care provided. A private hospitalist group that provided 24-hour care to patients at 2 hospitals within the system was selected for the study. Patients included were those who either had an attending of record or had admission and discharge bills submitted by a physician in this hospitalist group. Physician daily workload was measured using the total number of relative value units (RVUs) generated and the physician’s census as determined by the number of billable encounters submitted. Efficiency was measured by LOS and cost. Quality was measured by in-hospital mortality, rapid response team activation, 30-day readmission rate, and patient satisfaction. Models were adjusted for patient characteristics, including demographics; severity of illness; visit characteristics, including admission day of the week; and hospital-level characteristics, including hospital occupancy. Approximately 20,000 hospitalizations were included in the study. Hospitalists had a mean of 15.5 patient encounters and 28.6 RVUs per day. Results for LOS were stratified by hospital occupancy. For less than 75% occupancy, LOS increased linearly from 5.5 days to 7.5 days as workload increased. For greater than 85% occupancy, the change in LOS was J-shaped with a significant increase around an RVU of 30 or a census of 17. Cost also increased with higher workloads. For every unit increase in RVU, cost increased by $111; for every unit increase in census, cost increased by $205 (after adjustment for LOS). There were no significant associations with change in workload and patient satisfaction, in-hospital mortality, rapid response team activation, or 30-day readmission rate.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does increased hospitalist workload affect efficiency and quality of care?

Bottom line

Increased hospitalist workload is associated with increased cost and length of stay (LOS). Quality metrics such as 30-day readmission rate, in-hospital mortality, and patient satisfaction were not affected by changes in workload. (LOE = 2b)

Reference

Elliott DJ, Young RS, Brice J, Aguiar R, Kolm P. Effect of hospitalist workload on the quality and efficiency of care. JAMA Intern Med 2014;174(5):786-793.

Study design

Cohort (retrospective)

Funding source

Other

Allocation

Uncertain

Setting

Inpatient (any location)

Synopsis

Using data abstracted from the central data warehouse of an academic community health system, these authors examined the association between hospitalist workload and the efficiency and quality of care provided. A private hospitalist group that provided 24-hour care to patients at 2 hospitals within the system was selected for the study. Patients included were those who either had an attending of record or had admission and discharge bills submitted by a physician in this hospitalist group. Physician daily workload was measured using the total number of relative value units (RVUs) generated and the physician’s census as determined by the number of billable encounters submitted. Efficiency was measured by LOS and cost. Quality was measured by in-hospital mortality, rapid response team activation, 30-day readmission rate, and patient satisfaction. Models were adjusted for patient characteristics, including demographics; severity of illness; visit characteristics, including admission day of the week; and hospital-level characteristics, including hospital occupancy. Approximately 20,000 hospitalizations were included in the study. Hospitalists had a mean of 15.5 patient encounters and 28.6 RVUs per day. Results for LOS were stratified by hospital occupancy. For less than 75% occupancy, LOS increased linearly from 5.5 days to 7.5 days as workload increased. For greater than 85% occupancy, the change in LOS was J-shaped with a significant increase around an RVU of 30 or a census of 17. Cost also increased with higher workloads. For every unit increase in RVU, cost increased by $111; for every unit increase in census, cost increased by $205 (after adjustment for LOS). There were no significant associations with change in workload and patient satisfaction, in-hospital mortality, rapid response team activation, or 30-day readmission rate.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

For patients with acute venous thromboembolism, is the use of anticoagulants plus nonsteroidal anti-inflammatory drugs or aspirin associated with an increased risk of bleeding?

Bottom line

For patients treated with anticoagulants for acute venous thromboembolism (VTE), the use of concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin is associated with an increased risk of bleeding. This can occur in patients treated with rivaroxaban, as well as in those treated with enoxaparin plus a vitamin K antagonist (VKA). (LOE = 2b)

Reference

Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med 2014;174(6):947-953.

Study design

Cohort (prospective)

Funding source

Industry

Allocation

Uncertain

Setting

Outpatient (any)

Synopsis

The worldwide EINSTEIN DVT and EINSTEIN PE clinical trials compared rivaroxaban with enoxaparin plus a VKA for the treatment of acute VTE. These investigators used data from this cohort to examine the association between rivaroxaban or enoxaparin-VKA plus concomitant NSAID or aspirin use and the risk of clinically relevant and major bleeding. Clinically relevant bleeding was defined as nonmajor bleeding that resulted in either medical intervention, temporary cessation of study treatment, or patient discomfort. Major bleeding was that which resulted in death, occurred at a critical site, required tranfusion of at least 2 units of red blood cells, or was associated with a 2 g/dL drop in hemoglobin. The cohort comprised 8246 patients, with half receiving rivaroxaban and half receiving enoxaparin-VKA. The NSAID analysis was adjusted for sex, as there were more women in the NSAID group. The aspirin analysis was adjusted for age and creatinine clearance, as patients in the aspirin group tended to be older with worse kidney function than the nonaspirin group. The NSAID or aspirin exposure period included 7 days after stopping the medication to reflect an ongoing risk. Clinically relevant bleeding was more likely to occur in the NSAID group as compared with the non-NSAID group (37.5 bleeding events per 100 patient-years vs 16.6 per 100 patient-years; hazard ratio [HR] = 1.77; 95% CI, 1.46-2.14). Findings were similar for both the NSAID-rivaroxaban-treated patients and NSAID-enoxaparin-VKA-treated patients. In the aspirin group, clinically relevant bleeding was also increased as compared with the nonaspirin group (36.6 bleeding events per 100 patient-years vs 16.9 per 100 patient-years; HR = 1.70; 1.38-2.11). For both the NSAID and the aspirin groups, the bleeding events were spread evenly over the duration of the use, suggesting that longer duration of use does not increase the risk of bleeding. Major bleeding increased 2.4-fold in the NSAID group and 1.5-fold in the aspirin group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

For patients with acute venous thromboembolism, is the use of anticoagulants plus nonsteroidal anti-inflammatory drugs or aspirin associated with an increased risk of bleeding?

Bottom line

For patients treated with anticoagulants for acute venous thromboembolism (VTE), the use of concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin is associated with an increased risk of bleeding. This can occur in patients treated with rivaroxaban, as well as in those treated with enoxaparin plus a vitamin K antagonist (VKA). (LOE = 2b)

Reference

Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med 2014;174(6):947-953.

Study design

Cohort (prospective)

Funding source

Industry

Allocation

Uncertain

Setting

Outpatient (any)

Synopsis

The worldwide EINSTEIN DVT and EINSTEIN PE clinical trials compared rivaroxaban with enoxaparin plus a VKA for the treatment of acute VTE. These investigators used data from this cohort to examine the association between rivaroxaban or enoxaparin-VKA plus concomitant NSAID or aspirin use and the risk of clinically relevant and major bleeding. Clinically relevant bleeding was defined as nonmajor bleeding that resulted in either medical intervention, temporary cessation of study treatment, or patient discomfort. Major bleeding was that which resulted in death, occurred at a critical site, required tranfusion of at least 2 units of red blood cells, or was associated with a 2 g/dL drop in hemoglobin. The cohort comprised 8246 patients, with half receiving rivaroxaban and half receiving enoxaparin-VKA. The NSAID analysis was adjusted for sex, as there were more women in the NSAID group. The aspirin analysis was adjusted for age and creatinine clearance, as patients in the aspirin group tended to be older with worse kidney function than the nonaspirin group. The NSAID or aspirin exposure period included 7 days after stopping the medication to reflect an ongoing risk. Clinically relevant bleeding was more likely to occur in the NSAID group as compared with the non-NSAID group (37.5 bleeding events per 100 patient-years vs 16.6 per 100 patient-years; hazard ratio [HR] = 1.77; 95% CI, 1.46-2.14). Findings were similar for both the NSAID-rivaroxaban-treated patients and NSAID-enoxaparin-VKA-treated patients. In the aspirin group, clinically relevant bleeding was also increased as compared with the nonaspirin group (36.6 bleeding events per 100 patient-years vs 16.9 per 100 patient-years; HR = 1.70; 1.38-2.11). For both the NSAID and the aspirin groups, the bleeding events were spread evenly over the duration of the use, suggesting that longer duration of use does not increase the risk of bleeding. Major bleeding increased 2.4-fold in the NSAID group and 1.5-fold in the aspirin group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

For patients with acute venous thromboembolism, is the use of anticoagulants plus nonsteroidal anti-inflammatory drugs or aspirin associated with an increased risk of bleeding?

Bottom line

For patients treated with anticoagulants for acute venous thromboembolism (VTE), the use of concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin is associated with an increased risk of bleeding. This can occur in patients treated with rivaroxaban, as well as in those treated with enoxaparin plus a vitamin K antagonist (VKA). (LOE = 2b)

Reference

Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med 2014;174(6):947-953.

Study design

Cohort (prospective)

Funding source

Industry

Allocation

Uncertain

Setting

Outpatient (any)

Synopsis

The worldwide EINSTEIN DVT and EINSTEIN PE clinical trials compared rivaroxaban with enoxaparin plus a VKA for the treatment of acute VTE. These investigators used data from this cohort to examine the association between rivaroxaban or enoxaparin-VKA plus concomitant NSAID or aspirin use and the risk of clinically relevant and major bleeding. Clinically relevant bleeding was defined as nonmajor bleeding that resulted in either medical intervention, temporary cessation of study treatment, or patient discomfort. Major bleeding was that which resulted in death, occurred at a critical site, required tranfusion of at least 2 units of red blood cells, or was associated with a 2 g/dL drop in hemoglobin. The cohort comprised 8246 patients, with half receiving rivaroxaban and half receiving enoxaparin-VKA. The NSAID analysis was adjusted for sex, as there were more women in the NSAID group. The aspirin analysis was adjusted for age and creatinine clearance, as patients in the aspirin group tended to be older with worse kidney function than the nonaspirin group. The NSAID or aspirin exposure period included 7 days after stopping the medication to reflect an ongoing risk. Clinically relevant bleeding was more likely to occur in the NSAID group as compared with the non-NSAID group (37.5 bleeding events per 100 patient-years vs 16.6 per 100 patient-years; hazard ratio [HR] = 1.77; 95% CI, 1.46-2.14). Findings were similar for both the NSAID-rivaroxaban-treated patients and NSAID-enoxaparin-VKA-treated patients. In the aspirin group, clinically relevant bleeding was also increased as compared with the nonaspirin group (36.6 bleeding events per 100 patient-years vs 16.9 per 100 patient-years; HR = 1.70; 1.38-2.11). For both the NSAID and the aspirin groups, the bleeding events were spread evenly over the duration of the use, suggesting that longer duration of use does not increase the risk of bleeding. Major bleeding increased 2.4-fold in the NSAID group and 1.5-fold in the aspirin group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Which transitional care interventions are most effective in preventing readmissions in patients hospitalized with heart failure?

Bottom line

Moderate-to-high strength of evidence supports the use of home-visiting programs and outpatient multidisciplinary heart failure (MDS-HF) clinics to reduce readmission rates and mortality for hospitalized HF patients at 3 months to 6 months. Structured telephone support may also decrease mortality and HF-specific readmissions, but does not affect all-cause readmissions.(LOE = 1a)

Reference

Feltner C, Jones CD, Cene CW, et al. Transitional care interventions to prevent readmissions for persons with heart failure. Ann Intern Med 2014;160(11):774-784.

Study design

Meta-analysis (randomized controlled trials)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location) with outpatient follow-up

Synopsis

These authors searched multiple databases, including MEDLINE and the Cochrane Library, as well as reference lists of pertinent articles to find randomized controlled trials that compared transitional care interventions with either other interventions or usual care for patients hospitalized with HF with a focus on readmission rates and mortality. The interventions had to include at least one of the following components: patient/caregiver education, scheduled outpatient clinic visits, home visits, telemonitoring, structured telephone support, transition coaching, or increased provider continuity. Two authors independently reviewed the 47 selected studies for risk of bias. Studies with high or unclear risk of bias were not included in the meta-analysis. Results for readmission rates and mortality were stratified by intervention category and strength of evidence (SOE) grades were provided. For 30-day outcomes, a high-intensity home-visiting program consisting of 8 scheduled home visits starting at 24 hours after discharge decreased all-cause readmissions (number needed to treat [NNT] = 6) but the SOE was low. For 3-month to 6-month outcomes, data from 9 trials of home-visiting programs with varying intensities showed a reduction in all-cause readmissions (NNT= 9; SOE = high). Similarly, data from 2 trials of scheduled outpatient visits with MDS-HF clinics revealed lower readmission rates (NNT= 8; SOE = high). For HF-specific readmissions, 2 interventions, home-visiting programs and structured telephone support, decreased rates at 3 months to 6 months (home visits: NNT = 7; SOE = moderate; structured telephone support: NNT = 14; SOE = high). Finally, several interventions reduced mortality as compared to usual care at 3 to 6 months with moderate SOE, including home-visiting programs (NNT = 33), MDS-HF clinics (NNT = 18), and structured telephone support (NNT = 27). There were no significant benefits noted with scheduled visits to nurse-led clinics or primary care clinics or with educational interventions, although in most cases, there was insufficient evidence to determine whether these intervention were effective.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Which transitional care interventions are most effective in preventing readmissions in patients hospitalized with heart failure?

Bottom line

Moderate-to-high strength of evidence supports the use of home-visiting programs and outpatient multidisciplinary heart failure (MDS-HF) clinics to reduce readmission rates and mortality for hospitalized HF patients at 3 months to 6 months. Structured telephone support may also decrease mortality and HF-specific readmissions, but does not affect all-cause readmissions.(LOE = 1a)

Reference

Feltner C, Jones CD, Cene CW, et al. Transitional care interventions to prevent readmissions for persons with heart failure. Ann Intern Med 2014;160(11):774-784.

Study design

Meta-analysis (randomized controlled trials)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location) with outpatient follow-up

Synopsis

These authors searched multiple databases, including MEDLINE and the Cochrane Library, as well as reference lists of pertinent articles to find randomized controlled trials that compared transitional care interventions with either other interventions or usual care for patients hospitalized with HF with a focus on readmission rates and mortality. The interventions had to include at least one of the following components: patient/caregiver education, scheduled outpatient clinic visits, home visits, telemonitoring, structured telephone support, transition coaching, or increased provider continuity. Two authors independently reviewed the 47 selected studies for risk of bias. Studies with high or unclear risk of bias were not included in the meta-analysis. Results for readmission rates and mortality were stratified by intervention category and strength of evidence (SOE) grades were provided. For 30-day outcomes, a high-intensity home-visiting program consisting of 8 scheduled home visits starting at 24 hours after discharge decreased all-cause readmissions (number needed to treat [NNT] = 6) but the SOE was low. For 3-month to 6-month outcomes, data from 9 trials of home-visiting programs with varying intensities showed a reduction in all-cause readmissions (NNT= 9; SOE = high). Similarly, data from 2 trials of scheduled outpatient visits with MDS-HF clinics revealed lower readmission rates (NNT= 8; SOE = high). For HF-specific readmissions, 2 interventions, home-visiting programs and structured telephone support, decreased rates at 3 months to 6 months (home visits: NNT = 7; SOE = moderate; structured telephone support: NNT = 14; SOE = high). Finally, several interventions reduced mortality as compared to usual care at 3 to 6 months with moderate SOE, including home-visiting programs (NNT = 33), MDS-HF clinics (NNT = 18), and structured telephone support (NNT = 27). There were no significant benefits noted with scheduled visits to nurse-led clinics or primary care clinics or with educational interventions, although in most cases, there was insufficient evidence to determine whether these intervention were effective.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Which transitional care interventions are most effective in preventing readmissions in patients hospitalized with heart failure?

Bottom line

Moderate-to-high strength of evidence supports the use of home-visiting programs and outpatient multidisciplinary heart failure (MDS-HF) clinics to reduce readmission rates and mortality for hospitalized HF patients at 3 months to 6 months. Structured telephone support may also decrease mortality and HF-specific readmissions, but does not affect all-cause readmissions.(LOE = 1a)

Reference

Feltner C, Jones CD, Cene CW, et al. Transitional care interventions to prevent readmissions for persons with heart failure. Ann Intern Med 2014;160(11):774-784.

Study design

Meta-analysis (randomized controlled trials)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location) with outpatient follow-up

Synopsis

These authors searched multiple databases, including MEDLINE and the Cochrane Library, as well as reference lists of pertinent articles to find randomized controlled trials that compared transitional care interventions with either other interventions or usual care for patients hospitalized with HF with a focus on readmission rates and mortality. The interventions had to include at least one of the following components: patient/caregiver education, scheduled outpatient clinic visits, home visits, telemonitoring, structured telephone support, transition coaching, or increased provider continuity. Two authors independently reviewed the 47 selected studies for risk of bias. Studies with high or unclear risk of bias were not included in the meta-analysis. Results for readmission rates and mortality were stratified by intervention category and strength of evidence (SOE) grades were provided. For 30-day outcomes, a high-intensity home-visiting program consisting of 8 scheduled home visits starting at 24 hours after discharge decreased all-cause readmissions (number needed to treat [NNT] = 6) but the SOE was low. For 3-month to 6-month outcomes, data from 9 trials of home-visiting programs with varying intensities showed a reduction in all-cause readmissions (NNT= 9; SOE = high). Similarly, data from 2 trials of scheduled outpatient visits with MDS-HF clinics revealed lower readmission rates (NNT= 8; SOE = high). For HF-specific readmissions, 2 interventions, home-visiting programs and structured telephone support, decreased rates at 3 months to 6 months (home visits: NNT = 7; SOE = moderate; structured telephone support: NNT = 14; SOE = high). Finally, several interventions reduced mortality as compared to usual care at 3 to 6 months with moderate SOE, including home-visiting programs (NNT = 33), MDS-HF clinics (NNT = 18), and structured telephone support (NNT = 27). There were no significant benefits noted with scheduled visits to nurse-led clinics or primary care clinics or with educational interventions, although in most cases, there was insufficient evidence to determine whether these intervention were effective.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Prescription medications

Credit: CDC

A series of papers published in The BMJ have raised concerns about the anticoagulant dabigatran (Pradaxa).

The papers claim the company developing dabigatran has underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.

The company, Boehringer Ingelheim (BI), has denied these allegations.

“During the course of litigation involving Pradaxa, specifically hand-picked fragments of our robust internal discussions were made available to the media by external parties, which resulted in a gross distortion of the facts about Pradaxa and Boehringer Ingelheim,” said John Smith, a regional medical director at BI.

“As a result, some media reports have wrongfully suggested that BI purposefully suppressed data and have questioned the company’s ethics in efforts to alert regulators, healthcare professionals, and patients of the risks associated with Pradaxa.  Some reports have even accused BI of improper trial conduct. All of these allegations are absolutely false . . . .”

Concerns about the RE-LY trial

One of the papers published in The BMJ, “Concerns over data in key dabigatran trial,” said the design and oversight of the RE-LY trial were poor.

The trial compared dabigatran at 110 mg or 150 mg twice daily to dose-adjusted warfarin in patients with atrial fibrillation. Results suggested dabigatran was noninferior, and in some cases superior, to warfarin.

The BMJ article said the open-label design of this trial allowed for bias. And events—such as bleeding and myocardial infarctions—have been misreported.

The article also suggested that reviews by BI have failed to uncover all of the inaccuracies in the trial data, and all of the information has not been released—either to regulators or the public.

BI refuted these claims, saying regulators found RE-LY’s design “robust and valid.” And although reviews have uncovered inaccuracies, the results have not affected the trial’s conclusions.

In fact, the US Food and Drug Administration (FDA) “reaffirmed the positive efficacy-safety profile of Pradaxa” when it reviewed data from more than 134,000 patients.

BI also said it has provided the FDA and the European Medicines Agency (EMA) with the complete data set, and both regulators have affirmed the conclusions of the trial.

Allegations of withheld data

Another article in The BMJ, “Dabigatran: how the drug company withheld important analyses,” suggested BI withheld information indicating that monitoring and dose adjustment could improve the safety of dabigatran.

The article said the company did not provide regulators with data showing a 5.5-fold variation in plasma levels among dabigatran-treated patients. And the company withheld data garnered from analyses calculating how many major bleeds could be prevented by dose adjustment.

The analyses suggested that monitoring and dose adjustment could reduce major bleeds by 30% to 40% compared with well-controlled warfarin. And the adjustment would have little or no effect on the risk of ischemic stroke.

BI conceded that, in 2012, company scientists performed exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve the efficacy and safety profile of dabigatran.

However, the initial hypothesis “could not be supported when applied to the actual clinical data from the RE-LY population.” So the company did not supply the data to the FDA or EMA.

Furthermore, “the totality of scientific evidence does not support dosing decisions for Pradaxa based solely on blood levels.” Instead, the company said that patient characteristics such as age, kidney function, and certain medications are the critical factors that contribute to the risk of bleeding.

The role of regulators, physicians, and patients

A third article in The BMJ, “Dabigatran, bleeding, and the regulators,” investigated the role the FDA and the EMA have played in all this.

The author said the EMA has made information, tests, and varying strengths of dabigatran available to promote safer use of the drug.

The FDA, on the other hand, has focused on efficacy rather than reducing the risk of bleeding. The agency approved only the 150-mg dose of the drug and has not approved a plasma-level diagnostic test.

The BMJ also published an editorial titled “The trouble with dabigatran.” It suggested that doctors and patients should “tread carefully” due to emerging risks associated with the drug.

Prescription medications

Credit: CDC

A series of papers published in The BMJ have raised concerns about the anticoagulant dabigatran (Pradaxa).

The papers claim the company developing dabigatran has underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.

The company, Boehringer Ingelheim (BI), has denied these allegations.

“During the course of litigation involving Pradaxa, specifically hand-picked fragments of our robust internal discussions were made available to the media by external parties, which resulted in a gross distortion of the facts about Pradaxa and Boehringer Ingelheim,” said John Smith, a regional medical director at BI.

“As a result, some media reports have wrongfully suggested that BI purposefully suppressed data and have questioned the company’s ethics in efforts to alert regulators, healthcare professionals, and patients of the risks associated with Pradaxa.  Some reports have even accused BI of improper trial conduct. All of these allegations are absolutely false . . . .”

Concerns about the RE-LY trial

One of the papers published in The BMJ, “Concerns over data in key dabigatran trial,” said the design and oversight of the RE-LY trial were poor.

The trial compared dabigatran at 110 mg or 150 mg twice daily to dose-adjusted warfarin in patients with atrial fibrillation. Results suggested dabigatran was noninferior, and in some cases superior, to warfarin.

The BMJ article said the open-label design of this trial allowed for bias. And events—such as bleeding and myocardial infarctions—have been misreported.

The article also suggested that reviews by BI have failed to uncover all of the inaccuracies in the trial data, and all of the information has not been released—either to regulators or the public.

BI refuted these claims, saying regulators found RE-LY’s design “robust and valid.” And although reviews have uncovered inaccuracies, the results have not affected the trial’s conclusions.

In fact, the US Food and Drug Administration (FDA) “reaffirmed the positive efficacy-safety profile of Pradaxa” when it reviewed data from more than 134,000 patients.

BI also said it has provided the FDA and the European Medicines Agency (EMA) with the complete data set, and both regulators have affirmed the conclusions of the trial.

Allegations of withheld data

Another article in The BMJ, “Dabigatran: how the drug company withheld important analyses,” suggested BI withheld information indicating that monitoring and dose adjustment could improve the safety of dabigatran.

The article said the company did not provide regulators with data showing a 5.5-fold variation in plasma levels among dabigatran-treated patients. And the company withheld data garnered from analyses calculating how many major bleeds could be prevented by dose adjustment.

The analyses suggested that monitoring and dose adjustment could reduce major bleeds by 30% to 40% compared with well-controlled warfarin. And the adjustment would have little or no effect on the risk of ischemic stroke.

BI conceded that, in 2012, company scientists performed exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve the efficacy and safety profile of dabigatran.

However, the initial hypothesis “could not be supported when applied to the actual clinical data from the RE-LY population.” So the company did not supply the data to the FDA or EMA.

Furthermore, “the totality of scientific evidence does not support dosing decisions for Pradaxa based solely on blood levels.” Instead, the company said that patient characteristics such as age, kidney function, and certain medications are the critical factors that contribute to the risk of bleeding.

The role of regulators, physicians, and patients

A third article in The BMJ, “Dabigatran, bleeding, and the regulators,” investigated the role the FDA and the EMA have played in all this.

The author said the EMA has made information, tests, and varying strengths of dabigatran available to promote safer use of the drug.

The FDA, on the other hand, has focused on efficacy rather than reducing the risk of bleeding. The agency approved only the 150-mg dose of the drug and has not approved a plasma-level diagnostic test.

The BMJ also published an editorial titled “The trouble with dabigatran.” It suggested that doctors and patients should “tread carefully” due to emerging risks associated with the drug.

Prescription medications

Credit: CDC

A series of papers published in The BMJ have raised concerns about the anticoagulant dabigatran (Pradaxa).

The papers claim the company developing dabigatran has underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.

The company, Boehringer Ingelheim (BI), has denied these allegations.

“During the course of litigation involving Pradaxa, specifically hand-picked fragments of our robust internal discussions were made available to the media by external parties, which resulted in a gross distortion of the facts about Pradaxa and Boehringer Ingelheim,” said John Smith, a regional medical director at BI.

“As a result, some media reports have wrongfully suggested that BI purposefully suppressed data and have questioned the company’s ethics in efforts to alert regulators, healthcare professionals, and patients of the risks associated with Pradaxa.  Some reports have even accused BI of improper trial conduct. All of these allegations are absolutely false . . . .”

Concerns about the RE-LY trial

One of the papers published in The BMJ, “Concerns over data in key dabigatran trial,” said the design and oversight of the RE-LY trial were poor.

The trial compared dabigatran at 110 mg or 150 mg twice daily to dose-adjusted warfarin in patients with atrial fibrillation. Results suggested dabigatran was noninferior, and in some cases superior, to warfarin.

The BMJ article said the open-label design of this trial allowed for bias. And events—such as bleeding and myocardial infarctions—have been misreported.

The article also suggested that reviews by BI have failed to uncover all of the inaccuracies in the trial data, and all of the information has not been released—either to regulators or the public.

BI refuted these claims, saying regulators found RE-LY’s design “robust and valid.” And although reviews have uncovered inaccuracies, the results have not affected the trial’s conclusions.

In fact, the US Food and Drug Administration (FDA) “reaffirmed the positive efficacy-safety profile of Pradaxa” when it reviewed data from more than 134,000 patients.

BI also said it has provided the FDA and the European Medicines Agency (EMA) with the complete data set, and both regulators have affirmed the conclusions of the trial.

Allegations of withheld data

Another article in The BMJ, “Dabigatran: how the drug company withheld important analyses,” suggested BI withheld information indicating that monitoring and dose adjustment could improve the safety of dabigatran.

The article said the company did not provide regulators with data showing a 5.5-fold variation in plasma levels among dabigatran-treated patients. And the company withheld data garnered from analyses calculating how many major bleeds could be prevented by dose adjustment.

The analyses suggested that monitoring and dose adjustment could reduce major bleeds by 30% to 40% compared with well-controlled warfarin. And the adjustment would have little or no effect on the risk of ischemic stroke.

BI conceded that, in 2012, company scientists performed exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve the efficacy and safety profile of dabigatran.

However, the initial hypothesis “could not be supported when applied to the actual clinical data from the RE-LY population.” So the company did not supply the data to the FDA or EMA.

Furthermore, “the totality of scientific evidence does not support dosing decisions for Pradaxa based solely on blood levels.” Instead, the company said that patient characteristics such as age, kidney function, and certain medications are the critical factors that contribute to the risk of bleeding.

The role of regulators, physicians, and patients

A third article in The BMJ, “Dabigatran, bleeding, and the regulators,” investigated the role the FDA and the EMA have played in all this.

The author said the EMA has made information, tests, and varying strengths of dabigatran available to promote safer use of the drug.

The FDA, on the other hand, has focused on efficacy rather than reducing the risk of bleeding. The agency approved only the 150-mg dose of the drug and has not approved a plasma-level diagnostic test.

The BMJ also published an editorial titled “The trouble with dabigatran.” It suggested that doctors and patients should “tread carefully” due to emerging risks associated with the drug.

Sellafield nuclear power station

Young people living near nuclear facilities in the UK since the 1990s are not at an increased risk of developing cancer, according to research published in the British Journal of Cancer.

Researchers studied cancer rates between 1963 and 2006 among individuals under age 25 who were living near Sellafield—a nuclear reprocessing site in Cumbria, England—or Dounreay, the site of 2 nuclear facilities in the highlands of Scotland—when diagnosed.

The team found no difference in cancer incidence from 1991 to 2006 between people living near the nuclear power plants and the general population.

However, the study confirmed an increased risk of cancers, particularly leukemia, already reported for earlier time periods.

“For many years, there have been concerns over the potential raised cancer risk among people—particularly children—who live near nuclear installations,” said study author Kathryn Bunch, of the University of Oxford in the UK.

“This study found that children, teenagers, and young adults living close to Sellafield and Dounreay are no longer at an increased risk of developing cancer. Furthermore, there is no evidence of any increased risk of cancer later in life for those who were born near these power plants.”

Sellafield analysis

The researchers performed a cross-sectional analysis using census data to derive age-specific estimates of cancer incidence for 3 areas:

1. Seascale, the village closest to Sellafield
2. The county districts of Allerdale and Copeland, which are relatively close to Sellafield; Seascale is located in Copeland, but this group excludes the Seascale ward
3. The remainder of Cumbria.

Ages 0 to 14

There was a significantly increased risk of leukemia in the Seascale ward for patients aged 0 to 14 years from 1963 to 1983—standardized incidence ratio (SIR) of 9.85 (P<0.01)—and from 1963 to 2006—SIR of 6.85 (P<0.01).

There was also a significantly increased risk of all malignancies in the Seascale ward from 1963 to 1983—SIR of 4.12 (P<0.05)—and from 1963 to 2006—SIR of 3.58 (P<0.01).

There was no increased risk of leukemia or other malignancies in the Copeland and Allerdale county districts for any time period. However, there was an increased risk of leukemia from 1984 to 1990 for individuals living in the remainder of Cumbria—SIR 1.56 (P<0.05).

Ages 15 to 24

There was no increased risk in leukemia cases among 15-to-24-year-olds in the Seascale ward for any time period. However, there was an increased risk for other tumors—SIR 10.61 (P<0.05)—and all malignancies combined—SIR 9.25 (P<0.05)—from 1984 to 1990.

There was no increased risk of leukemia or other malignancies in Copeland and Allerdale county districts for any time period.

In the remainder of Cumbria, there was a decreased risk of leukemia and all malignancies combined from 1963 to 2006—SIRs of 0.58 and 0.85, respectively (P<0.05 for both).

Dounreay analysis

The researchers analyzed 2 geographical areas surrounding the Dounreay nuclear facilities. The area closest to Dounreay consists of the civil parishes of Thurso and Reay. The second area consists of the remaining civil parishes of Caithness, which is a much larger area but has a relatively sparse population.

For individuals aged 0 to 14, there was no increased incidence of leukemia or other malignancies for any time period or either geographic area.

In Thurso and Reay, there was an increased risk of leukemia among individuals aged 15 to 24, from 1984 to 1990—SIR of 9.22 (P<0.05).

In the remaining civil parishes of Caithness, the older age group had a decreased risk of all malignancies from 1963 to 2006—SIR of 0.55 (P<0.05).

The researchers said these results suggest that children, adolescents, and young adults living near Sellafield and Dounreay in recent years do not have an increased risk of leukemia or other cancers.

However, the analyses did indicate an increased incidence of leukemia and other cancers for earlier time periods.

“There has been a lot of concern that nuclear power stations could increase the risk of cancer, particularly leukemia,” said Julie Sharp, PhD, of Cancer Research UK, which funded this research.

“This study is reassuring for anyone who happens to be living near a power plant, as it shows no increased risk among children, teenagers, or young adults in recent years.”

Sellafield nuclear power station

Young people living near nuclear facilities in the UK since the 1990s are not at an increased risk of developing cancer, according to research published in the British Journal of Cancer.

Researchers studied cancer rates between 1963 and 2006 among individuals under age 25 who were living near Sellafield—a nuclear reprocessing site in Cumbria, England—or Dounreay, the site of 2 nuclear facilities in the highlands of Scotland—when diagnosed.

The team found no difference in cancer incidence from 1991 to 2006 between people living near the nuclear power plants and the general population.

However, the study confirmed an increased risk of cancers, particularly leukemia, already reported for earlier time periods.

“For many years, there have been concerns over the potential raised cancer risk among people—particularly children—who live near nuclear installations,” said study author Kathryn Bunch, of the University of Oxford in the UK.

“This study found that children, teenagers, and young adults living close to Sellafield and Dounreay are no longer at an increased risk of developing cancer. Furthermore, there is no evidence of any increased risk of cancer later in life for those who were born near these power plants.”

Sellafield analysis

The researchers performed a cross-sectional analysis using census data to derive age-specific estimates of cancer incidence for 3 areas:

1. Seascale, the village closest to Sellafield
2. The county districts of Allerdale and Copeland, which are relatively close to Sellafield; Seascale is located in Copeland, but this group excludes the Seascale ward
3. The remainder of Cumbria.

Ages 0 to 14

There was a significantly increased risk of leukemia in the Seascale ward for patients aged 0 to 14 years from 1963 to 1983—standardized incidence ratio (SIR) of 9.85 (P<0.01)—and from 1963 to 2006—SIR of 6.85 (P<0.01).

There was also a significantly increased risk of all malignancies in the Seascale ward from 1963 to 1983—SIR of 4.12 (P<0.05)—and from 1963 to 2006—SIR of 3.58 (P<0.01).

There was no increased risk of leukemia or other malignancies in the Copeland and Allerdale county districts for any time period. However, there was an increased risk of leukemia from 1984 to 1990 for individuals living in the remainder of Cumbria—SIR 1.56 (P<0.05).

Ages 15 to 24

There was no increased risk in leukemia cases among 15-to-24-year-olds in the Seascale ward for any time period. However, there was an increased risk for other tumors—SIR 10.61 (P<0.05)—and all malignancies combined—SIR 9.25 (P<0.05)—from 1984 to 1990.

There was no increased risk of leukemia or other malignancies in Copeland and Allerdale county districts for any time period.

In the remainder of Cumbria, there was a decreased risk of leukemia and all malignancies combined from 1963 to 2006—SIRs of 0.58 and 0.85, respectively (P<0.05 for both).

Dounreay analysis

The researchers analyzed 2 geographical areas surrounding the Dounreay nuclear facilities. The area closest to Dounreay consists of the civil parishes of Thurso and Reay. The second area consists of the remaining civil parishes of Caithness, which is a much larger area but has a relatively sparse population.

For individuals aged 0 to 14, there was no increased incidence of leukemia or other malignancies for any time period or either geographic area.

In Thurso and Reay, there was an increased risk of leukemia among individuals aged 15 to 24, from 1984 to 1990—SIR of 9.22 (P<0.05).

In the remaining civil parishes of Caithness, the older age group had a decreased risk of all malignancies from 1963 to 2006—SIR of 0.55 (P<0.05).

The researchers said these results suggest that children, adolescents, and young adults living near Sellafield and Dounreay in recent years do not have an increased risk of leukemia or other cancers.

However, the analyses did indicate an increased incidence of leukemia and other cancers for earlier time periods.

“There has been a lot of concern that nuclear power stations could increase the risk of cancer, particularly leukemia,” said Julie Sharp, PhD, of Cancer Research UK, which funded this research.

“This study is reassuring for anyone who happens to be living near a power plant, as it shows no increased risk among children, teenagers, or young adults in recent years.”

Sellafield nuclear power station

Young people living near nuclear facilities in the UK since the 1990s are not at an increased risk of developing cancer, according to research published in the British Journal of Cancer.

Researchers studied cancer rates between 1963 and 2006 among individuals under age 25 who were living near Sellafield—a nuclear reprocessing site in Cumbria, England—or Dounreay, the site of 2 nuclear facilities in the highlands of Scotland—when diagnosed.

The team found no difference in cancer incidence from 1991 to 2006 between people living near the nuclear power plants and the general population.

However, the study confirmed an increased risk of cancers, particularly leukemia, already reported for earlier time periods.

“For many years, there have been concerns over the potential raised cancer risk among people—particularly children—who live near nuclear installations,” said study author Kathryn Bunch, of the University of Oxford in the UK.

“This study found that children, teenagers, and young adults living close to Sellafield and Dounreay are no longer at an increased risk of developing cancer. Furthermore, there is no evidence of any increased risk of cancer later in life for those who were born near these power plants.”

Sellafield analysis

The researchers performed a cross-sectional analysis using census data to derive age-specific estimates of cancer incidence for 3 areas:

1. Seascale, the village closest to Sellafield
2. The county districts of Allerdale and Copeland, which are relatively close to Sellafield; Seascale is located in Copeland, but this group excludes the Seascale ward
3. The remainder of Cumbria.

Ages 0 to 14

There was a significantly increased risk of leukemia in the Seascale ward for patients aged 0 to 14 years from 1963 to 1983—standardized incidence ratio (SIR) of 9.85 (P<0.01)—and from 1963 to 2006—SIR of 6.85 (P<0.01).

There was also a significantly increased risk of all malignancies in the Seascale ward from 1963 to 1983—SIR of 4.12 (P<0.05)—and from 1963 to 2006—SIR of 3.58 (P<0.01).

There was no increased risk of leukemia or other malignancies in the Copeland and Allerdale county districts for any time period. However, there was an increased risk of leukemia from 1984 to 1990 for individuals living in the remainder of Cumbria—SIR 1.56 (P<0.05).

Ages 15 to 24

There was no increased risk in leukemia cases among 15-to-24-year-olds in the Seascale ward for any time period. However, there was an increased risk for other tumors—SIR 10.61 (P<0.05)—and all malignancies combined—SIR 9.25 (P<0.05)—from 1984 to 1990.

There was no increased risk of leukemia or other malignancies in Copeland and Allerdale county districts for any time period.

In the remainder of Cumbria, there was a decreased risk of leukemia and all malignancies combined from 1963 to 2006—SIRs of 0.58 and 0.85, respectively (P<0.05 for both).

Dounreay analysis

The researchers analyzed 2 geographical areas surrounding the Dounreay nuclear facilities. The area closest to Dounreay consists of the civil parishes of Thurso and Reay. The second area consists of the remaining civil parishes of Caithness, which is a much larger area but has a relatively sparse population.

For individuals aged 0 to 14, there was no increased incidence of leukemia or other malignancies for any time period or either geographic area.

In Thurso and Reay, there was an increased risk of leukemia among individuals aged 15 to 24, from 1984 to 1990—SIR of 9.22 (P<0.05).

In the remaining civil parishes of Caithness, the older age group had a decreased risk of all malignancies from 1963 to 2006—SIR of 0.55 (P<0.05).

The researchers said these results suggest that children, adolescents, and young adults living near Sellafield and Dounreay in recent years do not have an increased risk of leukemia or other cancers.

However, the analyses did indicate an increased incidence of leukemia and other cancers for earlier time periods.

“There has been a lot of concern that nuclear power stations could increase the risk of cancer, particularly leukemia,” said Julie Sharp, PhD, of Cancer Research UK, which funded this research.

“This study is reassuring for anyone who happens to be living near a power plant, as it shows no increased risk among children, teenagers, or young adults in recent years.”

Coronary artery

Credit: Mass. General Hospital

The UK’s National Institute for Health and Care Excellence (NICE) has decided to expand its recommendation for the antiplatelet agent prasugrel (Efient).

NICE’s new guidance recommends prasugrel in combination with aspirin to prevent thrombosis in patients with unstable angina, ST segment elevation myocardial infarction (STEMI), or non-ST segment elevation myocardial infarction (NSTEMI) who are undergoing percutaneous coronary intervention (PCI).

The previous guidance recommended prasugrel in combination with aspirin for patients with acute coronary syndromes undergoing PCI only when immediate primary PCI for STEMI was necessary, stent thrombosis occurred during clopidogrel treatment, or the patient had diabetes.

“[A NICE committee] assessed the clinical and cost effectiveness of prasugrel, noting that, since the original guidance was published in 2009, NICE has also published guidance on the use of ticagrelor for the same indication, and the price of another drug, clopidogrel, has reduced as generic versions have become available,” said Carole Longson, Director of the Centre for Health Technology Evaluation at NICE.

“Taking these factors into consideration, we are now recommending prasugrel as an option for more people with acute coronary syndromes than our previous guidance. The committee also heard from clinical experts that the faster action of prasugrel compared to clopidogrel could be an advantage for STEMI patients who need immediate percutaneous coronary intervention. The guidance also recommends prasugrel as an option for people with NSTEMI and unstable angina, with or without diabetes.”

The price of prasugrel is £47.56 per 28-tab pack (excluding value-added tax). The cost of treatment for 12 months is £628.48 (excluding value-added tax). Costs may vary in different settings because of negotiated procurement discounts.

The incremental cost-effectiveness ratios for all 4 of the patient subgroups reviewed (STEMI with diabetes, STEMI without diabetes, unstable angina or NSTEMI with diabetes, unstable angina and NSTEMI without diabetes) were lower than £20,000 per quality-adjusted life-year gained.

For patients with unstable angina or NSTEMI and diabetes, prasugrel proved more effective and less costly than clopidogrel.

Coronary artery

Credit: Mass. General Hospital

The UK’s National Institute for Health and Care Excellence (NICE) has decided to expand its recommendation for the antiplatelet agent prasugrel (Efient).

NICE’s new guidance recommends prasugrel in combination with aspirin to prevent thrombosis in patients with unstable angina, ST segment elevation myocardial infarction (STEMI), or non-ST segment elevation myocardial infarction (NSTEMI) who are undergoing percutaneous coronary intervention (PCI).

The previous guidance recommended prasugrel in combination with aspirin for patients with acute coronary syndromes undergoing PCI only when immediate primary PCI for STEMI was necessary, stent thrombosis occurred during clopidogrel treatment, or the patient had diabetes.

“[A NICE committee] assessed the clinical and cost effectiveness of prasugrel, noting that, since the original guidance was published in 2009, NICE has also published guidance on the use of ticagrelor for the same indication, and the price of another drug, clopidogrel, has reduced as generic versions have become available,” said Carole Longson, Director of the Centre for Health Technology Evaluation at NICE.

“Taking these factors into consideration, we are now recommending prasugrel as an option for more people with acute coronary syndromes than our previous guidance. The committee also heard from clinical experts that the faster action of prasugrel compared to clopidogrel could be an advantage for STEMI patients who need immediate percutaneous coronary intervention. The guidance also recommends prasugrel as an option for people with NSTEMI and unstable angina, with or without diabetes.”

The price of prasugrel is £47.56 per 28-tab pack (excluding value-added tax). The cost of treatment for 12 months is £628.48 (excluding value-added tax). Costs may vary in different settings because of negotiated procurement discounts.

The incremental cost-effectiveness ratios for all 4 of the patient subgroups reviewed (STEMI with diabetes, STEMI without diabetes, unstable angina or NSTEMI with diabetes, unstable angina and NSTEMI without diabetes) were lower than £20,000 per quality-adjusted life-year gained.

For patients with unstable angina or NSTEMI and diabetes, prasugrel proved more effective and less costly than clopidogrel.

Coronary artery

Credit: Mass. General Hospital

The UK’s National Institute for Health and Care Excellence (NICE) has decided to expand its recommendation for the antiplatelet agent prasugrel (Efient).

NICE’s new guidance recommends prasugrel in combination with aspirin to prevent thrombosis in patients with unstable angina, ST segment elevation myocardial infarction (STEMI), or non-ST segment elevation myocardial infarction (NSTEMI) who are undergoing percutaneous coronary intervention (PCI).

The previous guidance recommended prasugrel in combination with aspirin for patients with acute coronary syndromes undergoing PCI only when immediate primary PCI for STEMI was necessary, stent thrombosis occurred during clopidogrel treatment, or the patient had diabetes.

“[A NICE committee] assessed the clinical and cost effectiveness of prasugrel, noting that, since the original guidance was published in 2009, NICE has also published guidance on the use of ticagrelor for the same indication, and the price of another drug, clopidogrel, has reduced as generic versions have become available,” said Carole Longson, Director of the Centre for Health Technology Evaluation at NICE.

“Taking these factors into consideration, we are now recommending prasugrel as an option for more people with acute coronary syndromes than our previous guidance. The committee also heard from clinical experts that the faster action of prasugrel compared to clopidogrel could be an advantage for STEMI patients who need immediate percutaneous coronary intervention. The guidance also recommends prasugrel as an option for people with NSTEMI and unstable angina, with or without diabetes.”

The price of prasugrel is £47.56 per 28-tab pack (excluding value-added tax). The cost of treatment for 12 months is £628.48 (excluding value-added tax). Costs may vary in different settings because of negotiated procurement discounts.

The incremental cost-effectiveness ratios for all 4 of the patient subgroups reviewed (STEMI with diabetes, STEMI without diabetes, unstable angina or NSTEMI with diabetes, unstable angina and NSTEMI without diabetes) were lower than £20,000 per quality-adjusted life-year gained.

For patients with unstable angina or NSTEMI and diabetes, prasugrel proved more effective and less costly than clopidogrel.

The US Food and Drug Administration (FDA) has approved the PI3K delta inhibitor idelalisib (Zydelig) for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL).

The drug was granted traditional approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.

Idelalisib has also received accelerated approval to treat patients with relapsed FL or SLL who have received at least 2 prior systemic therapies.

The FDA’s accelerated approval program allows for approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.

This program provides earlier patient access to a drug while the developer—in this case, Gilead Sciences—conducts trials confirming the drug’s benefit.

Idelalisib in CLL: Results of a phase 3 study

The approval of idelalisib in CLL is based on results of a phase 3 trial (Study 116), which was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment group, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Idelalisib in FL and SLL: Results of a phase 2 study

Idelalisib’s accelerated approval in FL and SLL is supported by data from a single-arm, phase 2 trial (Study 101-09).

The drug was given as a single agent to patients who were refractory to rituximab and alkylating-agent-containing chemotherapy. Seventy-two patients had FL, and 26 had SLL.

The overall response rate was 54% in FL and 58% in SLL. Eight percent of FL responses were complete, and all responses in SLL patients were partial.

The median duration of response was 11.9 months in SLL patients (range, 0-14.7 months) but was not reached in FL patients (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib: Dosing, boxed warning and REMS

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

The drug is available as 150 mg and 100 mg tablets, administered orally twice-daily, but 150 mg is the recommended starting dose.

Idelalisib has a boxed warning on its label communicating the risks of fatal and serious toxicities, which include hepatic toxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation.

The drug is being approved with a risk evaluation and mitigation strategy (REMS) comprised of a communication plan to ensure healthcare providers are fully informed about these risks. For more information on this program, visit www.ZydeligREMS.com.

The US Food and Drug Administration (FDA) has approved the PI3K delta inhibitor idelalisib (Zydelig) for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL).

The drug was granted traditional approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.

Idelalisib has also received accelerated approval to treat patients with relapsed FL or SLL who have received at least 2 prior systemic therapies.

The FDA’s accelerated approval program allows for approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.

This program provides earlier patient access to a drug while the developer—in this case, Gilead Sciences—conducts trials confirming the drug’s benefit.

Idelalisib in CLL: Results of a phase 3 study

The approval of idelalisib in CLL is based on results of a phase 3 trial (Study 116), which was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment group, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Idelalisib in FL and SLL: Results of a phase 2 study

Idelalisib’s accelerated approval in FL and SLL is supported by data from a single-arm, phase 2 trial (Study 101-09).

The drug was given as a single agent to patients who were refractory to rituximab and alkylating-agent-containing chemotherapy. Seventy-two patients had FL, and 26 had SLL.

The overall response rate was 54% in FL and 58% in SLL. Eight percent of FL responses were complete, and all responses in SLL patients were partial.

The median duration of response was 11.9 months in SLL patients (range, 0-14.7 months) but was not reached in FL patients (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib: Dosing, boxed warning and REMS

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

The drug is available as 150 mg and 100 mg tablets, administered orally twice-daily, but 150 mg is the recommended starting dose.

Idelalisib has a boxed warning on its label communicating the risks of fatal and serious toxicities, which include hepatic toxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation.

The drug is being approved with a risk evaluation and mitigation strategy (REMS) comprised of a communication plan to ensure healthcare providers are fully informed about these risks. For more information on this program, visit www.ZydeligREMS.com.

The US Food and Drug Administration (FDA) has approved the PI3K delta inhibitor idelalisib (Zydelig) for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL).

The drug was granted traditional approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.

Idelalisib has also received accelerated approval to treat patients with relapsed FL or SLL who have received at least 2 prior systemic therapies.

The FDA’s accelerated approval program allows for approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.

This program provides earlier patient access to a drug while the developer—in this case, Gilead Sciences—conducts trials confirming the drug’s benefit.

Idelalisib in CLL: Results of a phase 3 study

The approval of idelalisib in CLL is based on results of a phase 3 trial (Study 116), which was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment group, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Idelalisib in FL and SLL: Results of a phase 2 study

Idelalisib’s accelerated approval in FL and SLL is supported by data from a single-arm, phase 2 trial (Study 101-09).

The drug was given as a single agent to patients who were refractory to rituximab and alkylating-agent-containing chemotherapy. Seventy-two patients had FL, and 26 had SLL.

The overall response rate was 54% in FL and 58% in SLL. Eight percent of FL responses were complete, and all responses in SLL patients were partial.

The median duration of response was 11.9 months in SLL patients (range, 0-14.7 months) but was not reached in FL patients (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib: Dosing, boxed warning and REMS

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

The drug is available as 150 mg and 100 mg tablets, administered orally twice-daily, but 150 mg is the recommended starting dose.

Idelalisib has a boxed warning on its label communicating the risks of fatal and serious toxicities, which include hepatic toxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation.

The drug is being approved with a risk evaluation and mitigation strategy (REMS) comprised of a communication plan to ensure healthcare providers are fully informed about these risks. For more information on this program, visit www.ZydeligREMS.com.

NEW YORK – A consensus group has developed evidence-based treatment recommendations for patients with psoriatic arthritis and nail involvement and raised the possibility of issuing them independent of recommendations for the skin, according to a report on the deliberations.

"The suggestion has been made to separate out skin from nail because the assessment is quite different to the point where you can potentially have patients with severe nail disease but limited skin disease," reported Dr. April W. Armstrong, director of the psoriasis program at the University of Colorado, Denver.

The proposal was made in the course of presenting the preliminary evidence-based recommendations on managing psoriatic arthritis (PsA) nail involvement to the full membership of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. GRAPPA is in the process of preparing a new set of PsA treatment recommendations.

The decision to address nails separately from skin was not a unanimous recommendation within the committee, and no conclusion was reached, but Dr. Armstrong brought the issue forward "to be clear about our ambiguity" regarding this specific aspect of how to best outline treatment options useful to clinicians.

Other recommendations, based on evidence, are more assured of making the final version, because they are evidence based. When presented at GRAPPA, which convened its most recent annual meeting jointly with the Spondyloarthritis Research & Treatment Network, each recommendation was graded for the quality of the evidence and strength of the consensus.

For example, the committee found little controlled evidence to support a significant benefit from topical therapies, including those commonly used, such as steroids and vitamin D analogs. Although the consensus committee concluded that the risk of adverse events is low and the costs are low to moderate, the efficacy is only modest. The strength for recommending topical therapies overall was characterized as "weak."

For procedural therapies, such as pulsed-dye laser or intralesional injections, no placebo-controlled trials could be identified by the committee, and the expert opinion of its members was that the efficacy is relatively low in general even if benefit is achieved in some individuals. The cost was characterized as low to moderate. The committee concluded that only a "weak" recommendation should be conferred to these types of interventions for nail involvement.

The proposed recommendation for oral therapies, such a methotrexate, cyclosporine, leflunomide, and acitretin, was considered "stronger than that for topical therapies" when nail involvement is moderate, but the committee also found supportive evidence of benefit to be of "low quality." Again, although recognizing that some PsA patients may benefit, the recommendation for oral therapies overall for nail involvement was characterized as weak.

For biologics, including both tumor necrosis factor (TNF) inhibitors and the interleukin 12/23 inhibitor ustekinumab, the consensus committee reported that there are good quality data showing efficacy in nails, including some studies showing superiority of TNF inhibitors to methotrexate and cyclosporine. For patients with moderate to severe nail involvement warranting the potential risks of these therapies, the preliminary recommendation for these agents was "strong" even if the costs of these therapies were characterized as "high to crazy."

One unresolved issue, however, is which strategy to recommend for placing nail involvement into "mild," "moderate," or "severe" categories. Objective scores, such as Nail Psoriasis Severity Index (NAPSI), were considered by the consensus committee to be helpful but insufficient.

"Perhaps in addition to objective scoring of nail disease, we should also take into account [the impact] on quality of life as well as function," Dr. Armstrong said.

The final GRAPPA treatment recommendations for nail involvement, as well as other aspects of PsA management, will be made after a discussion of the consensus group proposals over the next several months, followed by voting among the GRAPPA membership. As GRAPPA is an international organization, it is intended that final recommendations will be broadly applicable.

Dr. Armstrong reported financial relationships with AbbVie, Amgen, Janssen Biotech, Merck, Novartis, and Pfizer.

NEW YORK – A consensus group has developed evidence-based treatment recommendations for patients with psoriatic arthritis and nail involvement and raised the possibility of issuing them independent of recommendations for the skin, according to a report on the deliberations.

"The suggestion has been made to separate out skin from nail because the assessment is quite different to the point where you can potentially have patients with severe nail disease but limited skin disease," reported Dr. April W. Armstrong, director of the psoriasis program at the University of Colorado, Denver.

The proposal was made in the course of presenting the preliminary evidence-based recommendations on managing psoriatic arthritis (PsA) nail involvement to the full membership of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. GRAPPA is in the process of preparing a new set of PsA treatment recommendations.

The decision to address nails separately from skin was not a unanimous recommendation within the committee, and no conclusion was reached, but Dr. Armstrong brought the issue forward "to be clear about our ambiguity" regarding this specific aspect of how to best outline treatment options useful to clinicians.

Other recommendations, based on evidence, are more assured of making the final version, because they are evidence based. When presented at GRAPPA, which convened its most recent annual meeting jointly with the Spondyloarthritis Research & Treatment Network, each recommendation was graded for the quality of the evidence and strength of the consensus.

For example, the committee found little controlled evidence to support a significant benefit from topical therapies, including those commonly used, such as steroids and vitamin D analogs. Although the consensus committee concluded that the risk of adverse events is low and the costs are low to moderate, the efficacy is only modest. The strength for recommending topical therapies overall was characterized as "weak."

For procedural therapies, such as pulsed-dye laser or intralesional injections, no placebo-controlled trials could be identified by the committee, and the expert opinion of its members was that the efficacy is relatively low in general even if benefit is achieved in some individuals. The cost was characterized as low to moderate. The committee concluded that only a "weak" recommendation should be conferred to these types of interventions for nail involvement.

The proposed recommendation for oral therapies, such a methotrexate, cyclosporine, leflunomide, and acitretin, was considered "stronger than that for topical therapies" when nail involvement is moderate, but the committee also found supportive evidence of benefit to be of "low quality." Again, although recognizing that some PsA patients may benefit, the recommendation for oral therapies overall for nail involvement was characterized as weak.

For biologics, including both tumor necrosis factor (TNF) inhibitors and the interleukin 12/23 inhibitor ustekinumab, the consensus committee reported that there are good quality data showing efficacy in nails, including some studies showing superiority of TNF inhibitors to methotrexate and cyclosporine. For patients with moderate to severe nail involvement warranting the potential risks of these therapies, the preliminary recommendation for these agents was "strong" even if the costs of these therapies were characterized as "high to crazy."

One unresolved issue, however, is which strategy to recommend for placing nail involvement into "mild," "moderate," or "severe" categories. Objective scores, such as Nail Psoriasis Severity Index (NAPSI), were considered by the consensus committee to be helpful but insufficient.

"Perhaps in addition to objective scoring of nail disease, we should also take into account [the impact] on quality of life as well as function," Dr. Armstrong said.

The final GRAPPA treatment recommendations for nail involvement, as well as other aspects of PsA management, will be made after a discussion of the consensus group proposals over the next several months, followed by voting among the GRAPPA membership. As GRAPPA is an international organization, it is intended that final recommendations will be broadly applicable.

Dr. Armstrong reported financial relationships with AbbVie, Amgen, Janssen Biotech, Merck, Novartis, and Pfizer.

NEW YORK – A consensus group has developed evidence-based treatment recommendations for patients with psoriatic arthritis and nail involvement and raised the possibility of issuing them independent of recommendations for the skin, according to a report on the deliberations.

"The suggestion has been made to separate out skin from nail because the assessment is quite different to the point where you can potentially have patients with severe nail disease but limited skin disease," reported Dr. April W. Armstrong, director of the psoriasis program at the University of Colorado, Denver.

The proposal was made in the course of presenting the preliminary evidence-based recommendations on managing psoriatic arthritis (PsA) nail involvement to the full membership of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. GRAPPA is in the process of preparing a new set of PsA treatment recommendations.

The decision to address nails separately from skin was not a unanimous recommendation within the committee, and no conclusion was reached, but Dr. Armstrong brought the issue forward "to be clear about our ambiguity" regarding this specific aspect of how to best outline treatment options useful to clinicians.

Other recommendations, based on evidence, are more assured of making the final version, because they are evidence based. When presented at GRAPPA, which convened its most recent annual meeting jointly with the Spondyloarthritis Research & Treatment Network, each recommendation was graded for the quality of the evidence and strength of the consensus.

For example, the committee found little controlled evidence to support a significant benefit from topical therapies, including those commonly used, such as steroids and vitamin D analogs. Although the consensus committee concluded that the risk of adverse events is low and the costs are low to moderate, the efficacy is only modest. The strength for recommending topical therapies overall was characterized as "weak."

For procedural therapies, such as pulsed-dye laser or intralesional injections, no placebo-controlled trials could be identified by the committee, and the expert opinion of its members was that the efficacy is relatively low in general even if benefit is achieved in some individuals. The cost was characterized as low to moderate. The committee concluded that only a "weak" recommendation should be conferred to these types of interventions for nail involvement.

The proposed recommendation for oral therapies, such a methotrexate, cyclosporine, leflunomide, and acitretin, was considered "stronger than that for topical therapies" when nail involvement is moderate, but the committee also found supportive evidence of benefit to be of "low quality." Again, although recognizing that some PsA patients may benefit, the recommendation for oral therapies overall for nail involvement was characterized as weak.

For biologics, including both tumor necrosis factor (TNF) inhibitors and the interleukin 12/23 inhibitor ustekinumab, the consensus committee reported that there are good quality data showing efficacy in nails, including some studies showing superiority of TNF inhibitors to methotrexate and cyclosporine. For patients with moderate to severe nail involvement warranting the potential risks of these therapies, the preliminary recommendation for these agents was "strong" even if the costs of these therapies were characterized as "high to crazy."

One unresolved issue, however, is which strategy to recommend for placing nail involvement into "mild," "moderate," or "severe" categories. Objective scores, such as Nail Psoriasis Severity Index (NAPSI), were considered by the consensus committee to be helpful but insufficient.

"Perhaps in addition to objective scoring of nail disease, we should also take into account [the impact] on quality of life as well as function," Dr. Armstrong said.

The final GRAPPA treatment recommendations for nail involvement, as well as other aspects of PsA management, will be made after a discussion of the consensus group proposals over the next several months, followed by voting among the GRAPPA membership. As GRAPPA is an international organization, it is intended that final recommendations will be broadly applicable.

Dr. Armstrong reported financial relationships with AbbVie, Amgen, Janssen Biotech, Merck, Novartis, and Pfizer.