Patients with pulmonary embolism considered as low risk can be treated successfully as outpatients, according to a research letter by Dr. Margaret Fang and her associates.

Of nearly 5,000 patients included in the study, 494 were discharged from emergency departments. The proportion of PE patients discharged increased from 5.6% in 2004 to 11.1% in 2010. Just under 19% of those discharged visited the ED within 30 days, and 7.9% were hospitalized. Eleven patients were diagnosed with hemorrhage within 30 days, and there were two deaths within 90 days.

“Although still representing relatively few patients with PE, the proportion of discharges from ED settings nearly doubled during the 7-year study. Shifting appropriate patients to outpatient treatment may have benefits in terms of improved quality of life, enhanced physical and social functioning, and reduced costs of medical care,” the investigators said.

Find the full study in JAMA Internal Medicine (doi: 10.1001/jamainternmed.2015.0936).

Patients with pulmonary embolism considered as low risk can be treated successfully as outpatients, according to a research letter by Dr. Margaret Fang and her associates.

Of nearly 5,000 patients included in the study, 494 were discharged from emergency departments. The proportion of PE patients discharged increased from 5.6% in 2004 to 11.1% in 2010. Just under 19% of those discharged visited the ED within 30 days, and 7.9% were hospitalized. Eleven patients were diagnosed with hemorrhage within 30 days, and there were two deaths within 90 days.

“Although still representing relatively few patients with PE, the proportion of discharges from ED settings nearly doubled during the 7-year study. Shifting appropriate patients to outpatient treatment may have benefits in terms of improved quality of life, enhanced physical and social functioning, and reduced costs of medical care,” the investigators said.

Find the full study in JAMA Internal Medicine (doi: 10.1001/jamainternmed.2015.0936).

Patients with pulmonary embolism considered as low risk can be treated successfully as outpatients, according to a research letter by Dr. Margaret Fang and her associates.

Of nearly 5,000 patients included in the study, 494 were discharged from emergency departments. The proportion of PE patients discharged increased from 5.6% in 2004 to 11.1% in 2010. Just under 19% of those discharged visited the ED within 30 days, and 7.9% were hospitalized. Eleven patients were diagnosed with hemorrhage within 30 days, and there were two deaths within 90 days.

“Although still representing relatively few patients with PE, the proportion of discharges from ED settings nearly doubled during the 7-year study. Shifting appropriate patients to outpatient treatment may have benefits in terms of improved quality of life, enhanced physical and social functioning, and reduced costs of medical care,” the investigators said.

Find the full study in JAMA Internal Medicine (doi: 10.1001/jamainternmed.2015.0936).

Two changes in the pharmaceutical market in late 2010 dramatically reversed the alarming rise in fatal opioid overdoses that occurred during the preceding decade, according to a report published online April 20 in JAMA Internal Medicine.

Overdose deaths attributed to prescription opioids quadrupled in the U.S. between 1999 and 2010, in parallel with rapidly expanding sales of the drugs. Two changes in the pharmaceutical market were undertaken to address these unrelenting increases: replacing the standard formulation of OxyContin with an abuse-deterrent formulation (resistant to crushing and dissolving the tablets for ingestion, snorting, or injection) and withdrawing propoxyphene from sale, wrote Dr. Marc R. Larochelle of Harvard Pilgrim Health Care Institute and the department of population medicine, Harvard, both in Boston, and his associates.

To assess the impact of these 2 interventions, the investigators examined hospitalizations for prescription opioids as well as dispensing patterns using an insurance database covering adults in all 50 states. The data comprised 31,316,598 patients aged 18-64 who were enrolled in a commercial health plan between 2003 and 2012. There were 12,164 overdoses attributed to prescription opioids during the study period.

The “sudden, substantial, and sustained decreases” in the dispensing of prescription opioids at the end of 2010 was associated with parallel declines in fatal overdoses, which dropped by 19% in 2011 and by a further 20% in 2012. “Extrapolating our estimates at 2 years to the 124 million commercially insured U.S. residents aged 18-64 years, there would be 5,456 fewer prescription opioid overdoses . . . annually,” Dr. Larochelle and his associates said (JAMA Intern. Med. 2015 April 20 [doi:10.1001/jamainternmed.2015.0914]).

“This is the first study to demonstrate that a decrease in opioid supply is associated with a decrease in overall prescription opioid overdose,” they noted. “Our results have significant implications for policymakers and health care professionals grappling with the epidemic of opioid abuse and overdose.”

Two changes in the pharmaceutical market in late 2010 dramatically reversed the alarming rise in fatal opioid overdoses that occurred during the preceding decade, according to a report published online April 20 in JAMA Internal Medicine.

Overdose deaths attributed to prescription opioids quadrupled in the U.S. between 1999 and 2010, in parallel with rapidly expanding sales of the drugs. Two changes in the pharmaceutical market were undertaken to address these unrelenting increases: replacing the standard formulation of OxyContin with an abuse-deterrent formulation (resistant to crushing and dissolving the tablets for ingestion, snorting, or injection) and withdrawing propoxyphene from sale, wrote Dr. Marc R. Larochelle of Harvard Pilgrim Health Care Institute and the department of population medicine, Harvard, both in Boston, and his associates.

To assess the impact of these 2 interventions, the investigators examined hospitalizations for prescription opioids as well as dispensing patterns using an insurance database covering adults in all 50 states. The data comprised 31,316,598 patients aged 18-64 who were enrolled in a commercial health plan between 2003 and 2012. There were 12,164 overdoses attributed to prescription opioids during the study period.

The “sudden, substantial, and sustained decreases” in the dispensing of prescription opioids at the end of 2010 was associated with parallel declines in fatal overdoses, which dropped by 19% in 2011 and by a further 20% in 2012. “Extrapolating our estimates at 2 years to the 124 million commercially insured U.S. residents aged 18-64 years, there would be 5,456 fewer prescription opioid overdoses . . . annually,” Dr. Larochelle and his associates said (JAMA Intern. Med. 2015 April 20 [doi:10.1001/jamainternmed.2015.0914]).

“This is the first study to demonstrate that a decrease in opioid supply is associated with a decrease in overall prescription opioid overdose,” they noted. “Our results have significant implications for policymakers and health care professionals grappling with the epidemic of opioid abuse and overdose.”

Two changes in the pharmaceutical market in late 2010 dramatically reversed the alarming rise in fatal opioid overdoses that occurred during the preceding decade, according to a report published online April 20 in JAMA Internal Medicine.

Overdose deaths attributed to prescription opioids quadrupled in the U.S. between 1999 and 2010, in parallel with rapidly expanding sales of the drugs. Two changes in the pharmaceutical market were undertaken to address these unrelenting increases: replacing the standard formulation of OxyContin with an abuse-deterrent formulation (resistant to crushing and dissolving the tablets for ingestion, snorting, or injection) and withdrawing propoxyphene from sale, wrote Dr. Marc R. Larochelle of Harvard Pilgrim Health Care Institute and the department of population medicine, Harvard, both in Boston, and his associates.

To assess the impact of these 2 interventions, the investigators examined hospitalizations for prescription opioids as well as dispensing patterns using an insurance database covering adults in all 50 states. The data comprised 31,316,598 patients aged 18-64 who were enrolled in a commercial health plan between 2003 and 2012. There were 12,164 overdoses attributed to prescription opioids during the study period.

The “sudden, substantial, and sustained decreases” in the dispensing of prescription opioids at the end of 2010 was associated with parallel declines in fatal overdoses, which dropped by 19% in 2011 and by a further 20% in 2012. “Extrapolating our estimates at 2 years to the 124 million commercially insured U.S. residents aged 18-64 years, there would be 5,456 fewer prescription opioid overdoses . . . annually,” Dr. Larochelle and his associates said (JAMA Intern. Med. 2015 April 20 [doi:10.1001/jamainternmed.2015.0914]).

“This is the first study to demonstrate that a decrease in opioid supply is associated with a decrease in overall prescription opioid overdose,” they noted. “Our results have significant implications for policymakers and health care professionals grappling with the epidemic of opioid abuse and overdose.”

An EBV-infected cell (green)

among uninfected cells (blue)

Image courtesy of NIH/

Benjamin Chaigne-Delalande

PHILADELPHIA—Cytotoxic T lymphocytes designed to target Epstein-Barr virus (EBV-CTLs) can elicit durable responses in patients

with EBV–associated lymphoproliferative disorder (EBV-LPD), according to data presented at the AACRAnnual Meeting 2015.

Results from two trials showed that EBV-CTLs derived from a patient’s transplant donor could produce a response rate of 62%, and EBV-CTLs derived from third-party donors could produce a response rate of 61%.

Study investigators noted that, with the achievement of complete response (CR), remission proved durable. And, unlike with chemotherapy, partial responses (PRs) to EBV-CTLs were durable as well.

The team presented these results as abstract CT107.*

“The purpose of our clinical trials was to see if giving T cells from a normal-immune individual that were expanded in culture and stimulated to respond to multiple proteins from the Epstein-Barr virus could provide a safe and effective treatment,” said Richard J. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York.

“The good news from our two clinical trials is that EBV-CTLs generated from either the patient’s transplant donor or from the bank of normal donor T cells developed at Memorial Sloan Kettering put aggressive EBV-LPD that had failed to respond to rituximab into long-lasting remission in more than 60% of patients.”

In the first trial, 26 patients with EBV-LPD received EBV-CTLs generated from their transplant donor. Thirteen of these patients had previously received rituximab, and 16 had high-risk disease.

Thirteen patients in this trial received HLA-matched, EBV-CTLs from the Memorial Sloan Kettering Cancer Center bank of EBV-CTLs generated from third-party, healthy donors. All 13 patients had high-risk disease, and 12 had received prior rituximab.

Dr O’Reilly noted that good results were observed with EBV-CTLs from both sources in this trial. And because EBV-CTLs from the bank are available immediately, he and his team used only EBV-CTLs from the bank when treating the 18 patients enrolled in the second trial.

Among the 39 patients enrolled in the first trial, 23 had a CR, none had a PR, and 2 had stable disease.

For patients who received EBV-CTLs from their primary donor, the combined rate of CR and PR was 62% (16 CRs). For patients who received third-party EBV-CTLs, the combined rate of CR and PR was 54% (7 CRs).

Sixteen of the patients who achieved a CR are still doing well, Dr O’Reilly said. Eight of these patients are alive more than 5 years after receiving EBV-CTLs, and 1 is alive more than 10 years after treatment.

Among the 18 patients enrolled in the second trial, 9 had a CR, 3 had a PR, and 1 had stable disease. The combined rate of CR and PR was 67%.

All of the patients who achieved a CR in this trial continue to do well, and the investigators will be following them long-term, Dr O’Reilly said.

He also noted that toxicities with EBV-CTLs were minimal, and there were no treatment-related deaths. None of the patients developed cytokine release syndrome or graft-vs-host disease requiring systemic therapy.

“The EBV-CTLs work well for the majority of recipients,” Dr O’Reilly said. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about 7 to 14 days. We are rigorously pursuing the development of biomarkers or other tests to predict response earlier.”

Memorial Sloan Kettering Cancer Center has entered into an option agreement with Atara Biotherapeutics to further develop EBV-CTLs for clinical use. However, the data presented at AACR were accrued prior to that agreement.

Last month, the US Food and Drug Administration granted breakthrough therapy designation to EBV-CTLs generated from third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.

*Information in the abstract differs from that presented at the meeting. 

An EBV-infected cell (green)

among uninfected cells (blue)

Image courtesy of NIH/

Benjamin Chaigne-Delalande

PHILADELPHIA—Cytotoxic T lymphocytes designed to target Epstein-Barr virus (EBV-CTLs) can elicit durable responses in patients

with EBV–associated lymphoproliferative disorder (EBV-LPD), according to data presented at the AACRAnnual Meeting 2015.

Results from two trials showed that EBV-CTLs derived from a patient’s transplant donor could produce a response rate of 62%, and EBV-CTLs derived from third-party donors could produce a response rate of 61%.

Study investigators noted that, with the achievement of complete response (CR), remission proved durable. And, unlike with chemotherapy, partial responses (PRs) to EBV-CTLs were durable as well.

The team presented these results as abstract CT107.*

“The purpose of our clinical trials was to see if giving T cells from a normal-immune individual that were expanded in culture and stimulated to respond to multiple proteins from the Epstein-Barr virus could provide a safe and effective treatment,” said Richard J. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York.

“The good news from our two clinical trials is that EBV-CTLs generated from either the patient’s transplant donor or from the bank of normal donor T cells developed at Memorial Sloan Kettering put aggressive EBV-LPD that had failed to respond to rituximab into long-lasting remission in more than 60% of patients.”

In the first trial, 26 patients with EBV-LPD received EBV-CTLs generated from their transplant donor. Thirteen of these patients had previously received rituximab, and 16 had high-risk disease.

Thirteen patients in this trial received HLA-matched, EBV-CTLs from the Memorial Sloan Kettering Cancer Center bank of EBV-CTLs generated from third-party, healthy donors. All 13 patients had high-risk disease, and 12 had received prior rituximab.

Dr O’Reilly noted that good results were observed with EBV-CTLs from both sources in this trial. And because EBV-CTLs from the bank are available immediately, he and his team used only EBV-CTLs from the bank when treating the 18 patients enrolled in the second trial.

Among the 39 patients enrolled in the first trial, 23 had a CR, none had a PR, and 2 had stable disease.

For patients who received EBV-CTLs from their primary donor, the combined rate of CR and PR was 62% (16 CRs). For patients who received third-party EBV-CTLs, the combined rate of CR and PR was 54% (7 CRs).

Sixteen of the patients who achieved a CR are still doing well, Dr O’Reilly said. Eight of these patients are alive more than 5 years after receiving EBV-CTLs, and 1 is alive more than 10 years after treatment.

Among the 18 patients enrolled in the second trial, 9 had a CR, 3 had a PR, and 1 had stable disease. The combined rate of CR and PR was 67%.

All of the patients who achieved a CR in this trial continue to do well, and the investigators will be following them long-term, Dr O’Reilly said.

He also noted that toxicities with EBV-CTLs were minimal, and there were no treatment-related deaths. None of the patients developed cytokine release syndrome or graft-vs-host disease requiring systemic therapy.

“The EBV-CTLs work well for the majority of recipients,” Dr O’Reilly said. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about 7 to 14 days. We are rigorously pursuing the development of biomarkers or other tests to predict response earlier.”

Memorial Sloan Kettering Cancer Center has entered into an option agreement with Atara Biotherapeutics to further develop EBV-CTLs for clinical use. However, the data presented at AACR were accrued prior to that agreement.

Last month, the US Food and Drug Administration granted breakthrough therapy designation to EBV-CTLs generated from third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.

*Information in the abstract differs from that presented at the meeting. 

An EBV-infected cell (green)

among uninfected cells (blue)

Image courtesy of NIH/

Benjamin Chaigne-Delalande

PHILADELPHIA—Cytotoxic T lymphocytes designed to target Epstein-Barr virus (EBV-CTLs) can elicit durable responses in patients

with EBV–associated lymphoproliferative disorder (EBV-LPD), according to data presented at the AACRAnnual Meeting 2015.

Results from two trials showed that EBV-CTLs derived from a patient’s transplant donor could produce a response rate of 62%, and EBV-CTLs derived from third-party donors could produce a response rate of 61%.

Study investigators noted that, with the achievement of complete response (CR), remission proved durable. And, unlike with chemotherapy, partial responses (PRs) to EBV-CTLs were durable as well.

The team presented these results as abstract CT107.*

“The purpose of our clinical trials was to see if giving T cells from a normal-immune individual that were expanded in culture and stimulated to respond to multiple proteins from the Epstein-Barr virus could provide a safe and effective treatment,” said Richard J. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York.

“The good news from our two clinical trials is that EBV-CTLs generated from either the patient’s transplant donor or from the bank of normal donor T cells developed at Memorial Sloan Kettering put aggressive EBV-LPD that had failed to respond to rituximab into long-lasting remission in more than 60% of patients.”

In the first trial, 26 patients with EBV-LPD received EBV-CTLs generated from their transplant donor. Thirteen of these patients had previously received rituximab, and 16 had high-risk disease.

Thirteen patients in this trial received HLA-matched, EBV-CTLs from the Memorial Sloan Kettering Cancer Center bank of EBV-CTLs generated from third-party, healthy donors. All 13 patients had high-risk disease, and 12 had received prior rituximab.

Dr O’Reilly noted that good results were observed with EBV-CTLs from both sources in this trial. And because EBV-CTLs from the bank are available immediately, he and his team used only EBV-CTLs from the bank when treating the 18 patients enrolled in the second trial.

Among the 39 patients enrolled in the first trial, 23 had a CR, none had a PR, and 2 had stable disease.

For patients who received EBV-CTLs from their primary donor, the combined rate of CR and PR was 62% (16 CRs). For patients who received third-party EBV-CTLs, the combined rate of CR and PR was 54% (7 CRs).

Sixteen of the patients who achieved a CR are still doing well, Dr O’Reilly said. Eight of these patients are alive more than 5 years after receiving EBV-CTLs, and 1 is alive more than 10 years after treatment.

Among the 18 patients enrolled in the second trial, 9 had a CR, 3 had a PR, and 1 had stable disease. The combined rate of CR and PR was 67%.

All of the patients who achieved a CR in this trial continue to do well, and the investigators will be following them long-term, Dr O’Reilly said.

He also noted that toxicities with EBV-CTLs were minimal, and there were no treatment-related deaths. None of the patients developed cytokine release syndrome or graft-vs-host disease requiring systemic therapy.

“The EBV-CTLs work well for the majority of recipients,” Dr O’Reilly said. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about 7 to 14 days. We are rigorously pursuing the development of biomarkers or other tests to predict response earlier.”

Memorial Sloan Kettering Cancer Center has entered into an option agreement with Atara Biotherapeutics to further develop EBV-CTLs for clinical use. However, the data presented at AACR were accrued prior to that agreement.

Last month, the US Food and Drug Administration granted breakthrough therapy designation to EBV-CTLs generated from third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.

*Information in the abstract differs from that presented at the meeting. 

Mark Cragg, PhD

Photo courtesy of the

University of Southampton

A newly developed monoclonal antibody (mAb) can reverse resistance to other mAbs in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), according to research published in Cancer Cell.

Investigators found that some cancer cells draw mAbs inside themselves, making them invisible to immune cells.

But a mAb called BI-1206 can prevent this process and enhance cancer killing by binding to a molecule called FcγRIIB.

In preclinical experiments, BI-1206 was able to overcome resistance to mAbs such as rituximab.

“With more monoclonal antibody treatments being developed, there is an urgent need to understand how tumors become resistant to them and develop ways to overcome it,” said study author Mark Cragg, PhD, of the University of Southampton in the UK.

“Not only does BI-1206 appear to be able to reverse resistance to a range of monoclonal antibodies, it is also effective at directly killing cancer cells itself.”

In the Cancer Cell paper, BI-1206 is referred to as 6G11. The investigators found that 6G11 can block rituximab internalization and has “potent antitumor activity” in vitro. 6G11 was also well-tolerated and did not prompt cytokine storm.

In a mouse model of CLL, 6G11 enhanced rituximab-mediated depletion of primary CLL cells and improved responses when compared to rituximab alone.

In mice engrafted with cells from patients with CLL that was refractory to rituximab, ofatumumab, and/or alemtuzumab, 6G11 alone depleted CLL cells but did not improve overall response rates compared to rituximab alone. However, 6G11 in combination with rituximab did improve overall response rates compared to rituximab alone.

In a mouse model of MCL, neither 6G11 nor rituximab alone improved long-term survival. However, 30% of mice treated with both drugs survived tumor-free out to 100 days.

Combining 6G11 with obinutuzumab significantly improved splenic tumor cell depletion in mice with CLL. And more than 90% of mice that received 6G11 and alemtuzumab had a complete response to the treatment.

The investigators said these data suggest 6G11 can overcome mAb resistance for multiple targets. They said the drug will be tested in patients with CLL and non-Hodgkin lymphoma in an early stage clinical trial.

Mark Cragg, PhD

Photo courtesy of the

University of Southampton

A newly developed monoclonal antibody (mAb) can reverse resistance to other mAbs in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), according to research published in Cancer Cell.

Investigators found that some cancer cells draw mAbs inside themselves, making them invisible to immune cells.

But a mAb called BI-1206 can prevent this process and enhance cancer killing by binding to a molecule called FcγRIIB.

In preclinical experiments, BI-1206 was able to overcome resistance to mAbs such as rituximab.

“With more monoclonal antibody treatments being developed, there is an urgent need to understand how tumors become resistant to them and develop ways to overcome it,” said study author Mark Cragg, PhD, of the University of Southampton in the UK.

“Not only does BI-1206 appear to be able to reverse resistance to a range of monoclonal antibodies, it is also effective at directly killing cancer cells itself.”

In the Cancer Cell paper, BI-1206 is referred to as 6G11. The investigators found that 6G11 can block rituximab internalization and has “potent antitumor activity” in vitro. 6G11 was also well-tolerated and did not prompt cytokine storm.

In a mouse model of CLL, 6G11 enhanced rituximab-mediated depletion of primary CLL cells and improved responses when compared to rituximab alone.

In mice engrafted with cells from patients with CLL that was refractory to rituximab, ofatumumab, and/or alemtuzumab, 6G11 alone depleted CLL cells but did not improve overall response rates compared to rituximab alone. However, 6G11 in combination with rituximab did improve overall response rates compared to rituximab alone.

In a mouse model of MCL, neither 6G11 nor rituximab alone improved long-term survival. However, 30% of mice treated with both drugs survived tumor-free out to 100 days.

Combining 6G11 with obinutuzumab significantly improved splenic tumor cell depletion in mice with CLL. And more than 90% of mice that received 6G11 and alemtuzumab had a complete response to the treatment.

The investigators said these data suggest 6G11 can overcome mAb resistance for multiple targets. They said the drug will be tested in patients with CLL and non-Hodgkin lymphoma in an early stage clinical trial.

Mark Cragg, PhD

Photo courtesy of the

University of Southampton

A newly developed monoclonal antibody (mAb) can reverse resistance to other mAbs in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), according to research published in Cancer Cell.

Investigators found that some cancer cells draw mAbs inside themselves, making them invisible to immune cells.

But a mAb called BI-1206 can prevent this process and enhance cancer killing by binding to a molecule called FcγRIIB.

In preclinical experiments, BI-1206 was able to overcome resistance to mAbs such as rituximab.

“With more monoclonal antibody treatments being developed, there is an urgent need to understand how tumors become resistant to them and develop ways to overcome it,” said study author Mark Cragg, PhD, of the University of Southampton in the UK.

“Not only does BI-1206 appear to be able to reverse resistance to a range of monoclonal antibodies, it is also effective at directly killing cancer cells itself.”

In the Cancer Cell paper, BI-1206 is referred to as 6G11. The investigators found that 6G11 can block rituximab internalization and has “potent antitumor activity” in vitro. 6G11 was also well-tolerated and did not prompt cytokine storm.

In a mouse model of CLL, 6G11 enhanced rituximab-mediated depletion of primary CLL cells and improved responses when compared to rituximab alone.

In mice engrafted with cells from patients with CLL that was refractory to rituximab, ofatumumab, and/or alemtuzumab, 6G11 alone depleted CLL cells but did not improve overall response rates compared to rituximab alone. However, 6G11 in combination with rituximab did improve overall response rates compared to rituximab alone.

In a mouse model of MCL, neither 6G11 nor rituximab alone improved long-term survival. However, 30% of mice treated with both drugs survived tumor-free out to 100 days.

Combining 6G11 with obinutuzumab significantly improved splenic tumor cell depletion in mice with CLL. And more than 90% of mice that received 6G11 and alemtuzumab had a complete response to the treatment.

The investigators said these data suggest 6G11 can overcome mAb resistance for multiple targets. They said the drug will be tested in patients with CLL and non-Hodgkin lymphoma in an early stage clinical trial.

For children as young as 2 years old, interventions such as behavioral therapy, flavored throat spray, a specialized pill cup, simple verbal instructions, and head-posture training were successful in improving pill swallowing abilities for more than half of the study population, according to the results of a data review published in Pediatrics.

Amee Patel, M.P.H., and her associates at the University of North Carolina at Chapel Hill, examined data from 211 articles identified in a PubMed search published between December 1986 and December 2013. Four cohort studies and one case series met the criteria for inclusion. Each of the studies concluded that pill acceptance rates were improved shortly after their intervention, with three studies reporting pill acceptance continuing for 3-6 months after the intervention.

“A major reason for the success of all the interventions is that every study recognized and specifically addressed problems with pill swallowing. As a result, there was a conscious effort to help children with their difficulties in swallowing pills,” the investigators wrote.

Read the entire article here: Pediatrics 2015 (doi: 10.1542/peds.2014-2114).

For children as young as 2 years old, interventions such as behavioral therapy, flavored throat spray, a specialized pill cup, simple verbal instructions, and head-posture training were successful in improving pill swallowing abilities for more than half of the study population, according to the results of a data review published in Pediatrics.

Amee Patel, M.P.H., and her associates at the University of North Carolina at Chapel Hill, examined data from 211 articles identified in a PubMed search published between December 1986 and December 2013. Four cohort studies and one case series met the criteria for inclusion. Each of the studies concluded that pill acceptance rates were improved shortly after their intervention, with three studies reporting pill acceptance continuing for 3-6 months after the intervention.

“A major reason for the success of all the interventions is that every study recognized and specifically addressed problems with pill swallowing. As a result, there was a conscious effort to help children with their difficulties in swallowing pills,” the investigators wrote.

Read the entire article here: Pediatrics 2015 (doi: 10.1542/peds.2014-2114).

For children as young as 2 years old, interventions such as behavioral therapy, flavored throat spray, a specialized pill cup, simple verbal instructions, and head-posture training were successful in improving pill swallowing abilities for more than half of the study population, according to the results of a data review published in Pediatrics.

Amee Patel, M.P.H., and her associates at the University of North Carolina at Chapel Hill, examined data from 211 articles identified in a PubMed search published between December 1986 and December 2013. Four cohort studies and one case series met the criteria for inclusion. Each of the studies concluded that pill acceptance rates were improved shortly after their intervention, with three studies reporting pill acceptance continuing for 3-6 months after the intervention.

“A major reason for the success of all the interventions is that every study recognized and specifically addressed problems with pill swallowing. As a result, there was a conscious effort to help children with their difficulties in swallowing pills,” the investigators wrote.

Read the entire article here: Pediatrics 2015 (doi: 10.1542/peds.2014-2114).

Deficiency of the endogenous anticoagulant proteins antithrombin, protein C, and protein S are significantly associated with an increased risk of a first episode of venous thromboembolism, according to a study published in Thrombosis Research.

To determine the impact of inherited deficiency of natural anticoagulants on VTE risk, the authors performed a systematic review and meta-analysis of 21 studies comprising a total of 3,452 cases and 11,562 controls. The investigation showed a significantly increased risk of first VTE in antithrombin deficient subjects compared to controls (OR 16.26), as well as an in protein C (OR 7.51) and protein S deficient patients (OR 5.37). For VTE recurrence, they found a significant association with antithrombin (OR 3.61) and protein C deficiencies (OR 2.94), but not with protein S deficiency.

“The strength of association between the deficiency of these natural anticoagulants and the risk of a first episode of VTE . . . may justify the research of these uncommon anticoagulant deficiencies, in particular in patients with unprovoked events,” wrote Dr. Matteo Nicola Dario Di Minno of Federico II University in Naples, Italy and his associates.

Read the full article in Thrombosis Research here: (DOI: http://dx.doi.org/10.1016/j.thromres.2015.03.010)

Deficiency of the endogenous anticoagulant proteins antithrombin, protein C, and protein S are significantly associated with an increased risk of a first episode of venous thromboembolism, according to a study published in Thrombosis Research.

To determine the impact of inherited deficiency of natural anticoagulants on VTE risk, the authors performed a systematic review and meta-analysis of 21 studies comprising a total of 3,452 cases and 11,562 controls. The investigation showed a significantly increased risk of first VTE in antithrombin deficient subjects compared to controls (OR 16.26), as well as an in protein C (OR 7.51) and protein S deficient patients (OR 5.37). For VTE recurrence, they found a significant association with antithrombin (OR 3.61) and protein C deficiencies (OR 2.94), but not with protein S deficiency.

“The strength of association between the deficiency of these natural anticoagulants and the risk of a first episode of VTE . . . may justify the research of these uncommon anticoagulant deficiencies, in particular in patients with unprovoked events,” wrote Dr. Matteo Nicola Dario Di Minno of Federico II University in Naples, Italy and his associates.

Read the full article in Thrombosis Research here: (DOI: http://dx.doi.org/10.1016/j.thromres.2015.03.010)

Deficiency of the endogenous anticoagulant proteins antithrombin, protein C, and protein S are significantly associated with an increased risk of a first episode of venous thromboembolism, according to a study published in Thrombosis Research.

To determine the impact of inherited deficiency of natural anticoagulants on VTE risk, the authors performed a systematic review and meta-analysis of 21 studies comprising a total of 3,452 cases and 11,562 controls. The investigation showed a significantly increased risk of first VTE in antithrombin deficient subjects compared to controls (OR 16.26), as well as an in protein C (OR 7.51) and protein S deficient patients (OR 5.37). For VTE recurrence, they found a significant association with antithrombin (OR 3.61) and protein C deficiencies (OR 2.94), but not with protein S deficiency.

“The strength of association between the deficiency of these natural anticoagulants and the risk of a first episode of VTE . . . may justify the research of these uncommon anticoagulant deficiencies, in particular in patients with unprovoked events,” wrote Dr. Matteo Nicola Dario Di Minno of Federico II University in Naples, Italy and his associates.

Read the full article in Thrombosis Research here: (DOI: http://dx.doi.org/10.1016/j.thromres.2015.03.010)

Fondaparinux was just as safe as unfractionated heparin for venous thromboembolism prophylaxis in ischemic stroke, report Dr. C.T. Hackett and co-authors of the department of neurology and Allegheny General Hospital Comprehensive Stroke Center at the University of South Carolina.

In an analysis of 644 acute ischemic stroke patients receiving either fondaparinux or unfractionated heparin (UFH) for venous thromboembolism (VTE) prophylaxis, major hemorrhages occurred in just 1.2% of patients in the fondaparinux group, compared with 3.7% in the UFH group. This difference was not statistically significant (P = .08). Additionally, there was no significant difference in total hemorrhage (P = .15), intracranial hemorrhage (P = .48), major extracranial hemorrhage, (P = .18) or symptomatic VTE (P = 1.00) between the two groups.

The findings “provide supportive safety data for a prospective trial of extended VTE prophylaxis with fondaparinux in acute ischemic stroke,” the authors wrote.

Read the full article in Thrombosis Research: http://dx.doi.org/10.1016/j.thromres.2014.11.041.

Fondaparinux was just as safe as unfractionated heparin for venous thromboembolism prophylaxis in ischemic stroke, report Dr. C.T. Hackett and co-authors of the department of neurology and Allegheny General Hospital Comprehensive Stroke Center at the University of South Carolina.

In an analysis of 644 acute ischemic stroke patients receiving either fondaparinux or unfractionated heparin (UFH) for venous thromboembolism (VTE) prophylaxis, major hemorrhages occurred in just 1.2% of patients in the fondaparinux group, compared with 3.7% in the UFH group. This difference was not statistically significant (P = .08). Additionally, there was no significant difference in total hemorrhage (P = .15), intracranial hemorrhage (P = .48), major extracranial hemorrhage, (P = .18) or symptomatic VTE (P = 1.00) between the two groups.

The findings “provide supportive safety data for a prospective trial of extended VTE prophylaxis with fondaparinux in acute ischemic stroke,” the authors wrote.

Read the full article in Thrombosis Research: http://dx.doi.org/10.1016/j.thromres.2014.11.041.

Fondaparinux was just as safe as unfractionated heparin for venous thromboembolism prophylaxis in ischemic stroke, report Dr. C.T. Hackett and co-authors of the department of neurology and Allegheny General Hospital Comprehensive Stroke Center at the University of South Carolina.

In an analysis of 644 acute ischemic stroke patients receiving either fondaparinux or unfractionated heparin (UFH) for venous thromboembolism (VTE) prophylaxis, major hemorrhages occurred in just 1.2% of patients in the fondaparinux group, compared with 3.7% in the UFH group. This difference was not statistically significant (P = .08). Additionally, there was no significant difference in total hemorrhage (P = .15), intracranial hemorrhage (P = .48), major extracranial hemorrhage, (P = .18) or symptomatic VTE (P = 1.00) between the two groups.

The findings “provide supportive safety data for a prospective trial of extended VTE prophylaxis with fondaparinux in acute ischemic stroke,” the authors wrote.

Read the full article in Thrombosis Research: http://dx.doi.org/10.1016/j.thromres.2014.11.041.

Workers in mining, construction, and the accommodations and food services industries report the highest rates of alcohol and substance abuse across a wide range of industries, according to the latest analysis of data from the National Survey on Drug Use and Health.

The survey, published April 16 in The CBHSQ Report, showed that the prevalence of heavy alcohol use in the previous month ranged from a high of 17.5% in the mining industry to 4.4% among workers in health care and social assistance. A total of 19.1% of accommodations and food services workers reported illicit drug use in the past month, compared with 4.3% in public administration.

A comparison of data from 2003-2007 and 2008-2012 also revealed that illicit drug use has increased in the accommodations and food services industries, and in educational services, but decreased in construction workers (The CBHSQ Report 2015, April 16).

“An extension of this research could examine whether the changes in use rates correspond to either changes in climate in the industries (e.g., attitudes towards substance use, distribution of prevention messages) or shifts in the demographic compositions of the industries across these time periods,” wrote Dr. Donna M. Bush and Dr. Rachel N. Lipari from the Substance Abuse and Mental Health Services Administration.

The annual National Survey on Drug Use and Health is sponsored by the Substance Abuse and Mental Health Services Administration. No conflicts of interest were declared.

Workers in mining, construction, and the accommodations and food services industries report the highest rates of alcohol and substance abuse across a wide range of industries, according to the latest analysis of data from the National Survey on Drug Use and Health.

The survey, published April 16 in The CBHSQ Report, showed that the prevalence of heavy alcohol use in the previous month ranged from a high of 17.5% in the mining industry to 4.4% among workers in health care and social assistance. A total of 19.1% of accommodations and food services workers reported illicit drug use in the past month, compared with 4.3% in public administration.

A comparison of data from 2003-2007 and 2008-2012 also revealed that illicit drug use has increased in the accommodations and food services industries, and in educational services, but decreased in construction workers (The CBHSQ Report 2015, April 16).

“An extension of this research could examine whether the changes in use rates correspond to either changes in climate in the industries (e.g., attitudes towards substance use, distribution of prevention messages) or shifts in the demographic compositions of the industries across these time periods,” wrote Dr. Donna M. Bush and Dr. Rachel N. Lipari from the Substance Abuse and Mental Health Services Administration.

The annual National Survey on Drug Use and Health is sponsored by the Substance Abuse and Mental Health Services Administration. No conflicts of interest were declared.

Workers in mining, construction, and the accommodations and food services industries report the highest rates of alcohol and substance abuse across a wide range of industries, according to the latest analysis of data from the National Survey on Drug Use and Health.

The survey, published April 16 in The CBHSQ Report, showed that the prevalence of heavy alcohol use in the previous month ranged from a high of 17.5% in the mining industry to 4.4% among workers in health care and social assistance. A total of 19.1% of accommodations and food services workers reported illicit drug use in the past month, compared with 4.3% in public administration.

A comparison of data from 2003-2007 and 2008-2012 also revealed that illicit drug use has increased in the accommodations and food services industries, and in educational services, but decreased in construction workers (The CBHSQ Report 2015, April 16).

“An extension of this research could examine whether the changes in use rates correspond to either changes in climate in the industries (e.g., attitudes towards substance use, distribution of prevention messages) or shifts in the demographic compositions of the industries across these time periods,” wrote Dr. Donna M. Bush and Dr. Rachel N. Lipari from the Substance Abuse and Mental Health Services Administration.

The annual National Survey on Drug Use and Health is sponsored by the Substance Abuse and Mental Health Services Administration. No conflicts of interest were declared.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

New research provides genetic evidence that malaria parasites in Africa are developing resistance to antimalarial drugs.

Researchers found that Plasmodium falciparum parasites with a mutation in the gene ap2mu were less sensitive to both artemisinin and quinine.

A study published in 2013 suggested a link between a mutation in ap2mu and low levels of malaria parasites remaining in the blood of Kenyan children after treatment with artemisinin.

However, further research was needed to confirm that these genetic characteristics represented an early step toward resistance.

In the new study, published in Antimicrobial Agents and Chemotherapy, researchers genetically altered the malaria parasite to mutate ap2mu in the same way that had been observed in Kenya.

The team found the altered parasite was significantly less susceptible to treatment, requiring 32% more drug to be killed by artemisinin. The genetically altered parasite was also 42.4% less susceptible to quinine.

Earlier this year, a different research group discovered mutations in the gene kelch13, which were linked to reduced susceptibility to artemisinin combination treatment in South East Asia.

Historically, resistance to antimalarial medicines has emerged in South East Asia and then spread to Africa. But these new findings suggest a different route to drug resistance may be developing independently in Africa.

“Our findings could be a sign of much worse things to come for malaria in Africa,” said study author Colin Sutherland, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“The malaria parasite is constantly evolving to evade our control efforts. We’ve already moved away from using quinine to treat cases as the malaria parasite has become more resistant to it, but if further drug resistance were to develop against our most valuable malaria drug, artemisinin, we would be facing a grave situation.”

“We now know that the gene ap2mu is an important factor in determining how well our drugs kill malaria parasites. We will be conducting laboratory and field studies to more accurately measure the impact of mutations in the ap2mu gene. We hope our findings will help [us] understand resistance of malaria to drugs and potentially be an important tool for monitoring malaria treatment in the future.”

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

New research provides genetic evidence that malaria parasites in Africa are developing resistance to antimalarial drugs.

Researchers found that Plasmodium falciparum parasites with a mutation in the gene ap2mu were less sensitive to both artemisinin and quinine.

A study published in 2013 suggested a link between a mutation in ap2mu and low levels of malaria parasites remaining in the blood of Kenyan children after treatment with artemisinin.

However, further research was needed to confirm that these genetic characteristics represented an early step toward resistance.

In the new study, published in Antimicrobial Agents and Chemotherapy, researchers genetically altered the malaria parasite to mutate ap2mu in the same way that had been observed in Kenya.

The team found the altered parasite was significantly less susceptible to treatment, requiring 32% more drug to be killed by artemisinin. The genetically altered parasite was also 42.4% less susceptible to quinine.

Earlier this year, a different research group discovered mutations in the gene kelch13, which were linked to reduced susceptibility to artemisinin combination treatment in South East Asia.

Historically, resistance to antimalarial medicines has emerged in South East Asia and then spread to Africa. But these new findings suggest a different route to drug resistance may be developing independently in Africa.

“Our findings could be a sign of much worse things to come for malaria in Africa,” said study author Colin Sutherland, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“The malaria parasite is constantly evolving to evade our control efforts. We’ve already moved away from using quinine to treat cases as the malaria parasite has become more resistant to it, but if further drug resistance were to develop against our most valuable malaria drug, artemisinin, we would be facing a grave situation.”

“We now know that the gene ap2mu is an important factor in determining how well our drugs kill malaria parasites. We will be conducting laboratory and field studies to more accurately measure the impact of mutations in the ap2mu gene. We hope our findings will help [us] understand resistance of malaria to drugs and potentially be an important tool for monitoring malaria treatment in the future.”

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

New research provides genetic evidence that malaria parasites in Africa are developing resistance to antimalarial drugs.

Researchers found that Plasmodium falciparum parasites with a mutation in the gene ap2mu were less sensitive to both artemisinin and quinine.

A study published in 2013 suggested a link between a mutation in ap2mu and low levels of malaria parasites remaining in the blood of Kenyan children after treatment with artemisinin.

However, further research was needed to confirm that these genetic characteristics represented an early step toward resistance.

In the new study, published in Antimicrobial Agents and Chemotherapy, researchers genetically altered the malaria parasite to mutate ap2mu in the same way that had been observed in Kenya.

The team found the altered parasite was significantly less susceptible to treatment, requiring 32% more drug to be killed by artemisinin. The genetically altered parasite was also 42.4% less susceptible to quinine.

Earlier this year, a different research group discovered mutations in the gene kelch13, which were linked to reduced susceptibility to artemisinin combination treatment in South East Asia.

Historically, resistance to antimalarial medicines has emerged in South East Asia and then spread to Africa. But these new findings suggest a different route to drug resistance may be developing independently in Africa.

“Our findings could be a sign of much worse things to come for malaria in Africa,” said study author Colin Sutherland, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“The malaria parasite is constantly evolving to evade our control efforts. We’ve already moved away from using quinine to treat cases as the malaria parasite has become more resistant to it, but if further drug resistance were to develop against our most valuable malaria drug, artemisinin, we would be facing a grave situation.”

“We now know that the gene ap2mu is an important factor in determining how well our drugs kill malaria parasites. We will be conducting laboratory and field studies to more accurately measure the impact of mutations in the ap2mu gene. We hope our findings will help [us] understand resistance of malaria to drugs and potentially be an important tool for monitoring malaria treatment in the future.”

SAN DIEGO – The novel oral anticoagulants clearly outperformed warfarin for stroke prevention and safety endpoints in patients with atrial fibrillation and comorbid heart failure in a meta-analysis of four recent landmark Phase 3 clinical trials.

Collectively the four novel oral anticoagulants (NOACs) approved for stroke prophylaxis in nonvalvular atrial fibrillation (AF) reduced the risk of stroke and systemic embolism by 14%, compared with patients randomized to warfarin. Moreover, the NOACs decreased the risks of major bleeding and intracranial bleeding by 23% and 45%, respectively, Dr. Gianluigi Savarese reported at the annual meeting of the American College of Cardiology.

Bruce Jancin/Frontline Medical News

“NOACs represent a valuable therapeutic option in patients with nonvalvular atrial fibrillation and heart failure,” concluded Dr. Savarese of Federico II University, Naples.

There has never been a randomized trial comparing a NOAC to warfarin specifically in patients with these dual diagnoses. In the absence of such a definitive study, the next best thing is a meta-analysis of the pivotal Phase 3 trials in which warfarin was compared to dabigatran (Pradaxa, the RE-LY study), apixaban (Eliquis, ARISTOTLE), rivaroxaban (Xarelto, ROCKET AF), and edoxaban (Savaysa, ENGAGE AF-TIMI 48).

The meta-analysis focused on a subset population of 26,384 randomized patients with AF and heart failure. It’s important to know how the NOACs stack up against warfarin in this population because symptomatic heart failure is common: indeed, it’s present in 30% of patients with AF. Patients with AF and comorbid heart failure are generally older, frailer, have more comorbidities, and are at higher risk of both stroke and bleeding, compared with AF patients without heart failure. Since heart failure is a recognized risk factor for reduced time in the therapeutic international normalized ratio (INR) range for patients on warfarin, it’s likely that warfarin-treated dual diagnosis patients would be exposed to further increased risks of stroke and bleeding, according to Dr. Savarese.

In the meta-analysis, in addition to the NOAC-treated patients’ significantly reduced risks of stroke, major bleeding, and intracranial bleeding, they showed a 12% decrease in total bleeding and an 8% reduction in cardiovascular death, compared with warfarin-treated controls, although neither of those latter two favorable trends achieved statistical significance.

The four NOACs didn’t differ significantly on any of the prespecified outcomes in the meta-analysis.

One audience member noted that while the relative risk reductions for stroke and major bleeding seen with the NOACs in the meta-analysis were large and impressive, the absolute risk reductions were actually quite small. For example, warfarin-treated controls in RE-LY, the first of the major trials, had a stroke/systemic embolism rate of 1.69%/year and a major bleeding rate of 3.4%/year (N. Engl. J. Med. 2009;361:1139-51), while controls in ENGAGE AF-TIMI 48 had annualized stroke and major bleeding rates of 1.5% and 3.4%, respectively (N. Engl. J. Med. 2013;369:2093-2104).

Dr. Savarese replied that he and his coinvestigators consider those absolute risk reductions to be clinically meaningful, especially in light of the enormous and rapidly growing number of patients with both AF and heart failure.

He reported having no financial conflicts regarding this meta-analysis, which was carried out free of commercial support.

[email protected]

SAN DIEGO – The novel oral anticoagulants clearly outperformed warfarin for stroke prevention and safety endpoints in patients with atrial fibrillation and comorbid heart failure in a meta-analysis of four recent landmark Phase 3 clinical trials.

Collectively the four novel oral anticoagulants (NOACs) approved for stroke prophylaxis in nonvalvular atrial fibrillation (AF) reduced the risk of stroke and systemic embolism by 14%, compared with patients randomized to warfarin. Moreover, the NOACs decreased the risks of major bleeding and intracranial bleeding by 23% and 45%, respectively, Dr. Gianluigi Savarese reported at the annual meeting of the American College of Cardiology.

Bruce Jancin/Frontline Medical News

“NOACs represent a valuable therapeutic option in patients with nonvalvular atrial fibrillation and heart failure,” concluded Dr. Savarese of Federico II University, Naples.

There has never been a randomized trial comparing a NOAC to warfarin specifically in patients with these dual diagnoses. In the absence of such a definitive study, the next best thing is a meta-analysis of the pivotal Phase 3 trials in which warfarin was compared to dabigatran (Pradaxa, the RE-LY study), apixaban (Eliquis, ARISTOTLE), rivaroxaban (Xarelto, ROCKET AF), and edoxaban (Savaysa, ENGAGE AF-TIMI 48).

The meta-analysis focused on a subset population of 26,384 randomized patients with AF and heart failure. It’s important to know how the NOACs stack up against warfarin in this population because symptomatic heart failure is common: indeed, it’s present in 30% of patients with AF. Patients with AF and comorbid heart failure are generally older, frailer, have more comorbidities, and are at higher risk of both stroke and bleeding, compared with AF patients without heart failure. Since heart failure is a recognized risk factor for reduced time in the therapeutic international normalized ratio (INR) range for patients on warfarin, it’s likely that warfarin-treated dual diagnosis patients would be exposed to further increased risks of stroke and bleeding, according to Dr. Savarese.

In the meta-analysis, in addition to the NOAC-treated patients’ significantly reduced risks of stroke, major bleeding, and intracranial bleeding, they showed a 12% decrease in total bleeding and an 8% reduction in cardiovascular death, compared with warfarin-treated controls, although neither of those latter two favorable trends achieved statistical significance.

The four NOACs didn’t differ significantly on any of the prespecified outcomes in the meta-analysis.

One audience member noted that while the relative risk reductions for stroke and major bleeding seen with the NOACs in the meta-analysis were large and impressive, the absolute risk reductions were actually quite small. For example, warfarin-treated controls in RE-LY, the first of the major trials, had a stroke/systemic embolism rate of 1.69%/year and a major bleeding rate of 3.4%/year (N. Engl. J. Med. 2009;361:1139-51), while controls in ENGAGE AF-TIMI 48 had annualized stroke and major bleeding rates of 1.5% and 3.4%, respectively (N. Engl. J. Med. 2013;369:2093-2104).

Dr. Savarese replied that he and his coinvestigators consider those absolute risk reductions to be clinically meaningful, especially in light of the enormous and rapidly growing number of patients with both AF and heart failure.

He reported having no financial conflicts regarding this meta-analysis, which was carried out free of commercial support.

[email protected]

SAN DIEGO – The novel oral anticoagulants clearly outperformed warfarin for stroke prevention and safety endpoints in patients with atrial fibrillation and comorbid heart failure in a meta-analysis of four recent landmark Phase 3 clinical trials.

Collectively the four novel oral anticoagulants (NOACs) approved for stroke prophylaxis in nonvalvular atrial fibrillation (AF) reduced the risk of stroke and systemic embolism by 14%, compared with patients randomized to warfarin. Moreover, the NOACs decreased the risks of major bleeding and intracranial bleeding by 23% and 45%, respectively, Dr. Gianluigi Savarese reported at the annual meeting of the American College of Cardiology.

Bruce Jancin/Frontline Medical News

“NOACs represent a valuable therapeutic option in patients with nonvalvular atrial fibrillation and heart failure,” concluded Dr. Savarese of Federico II University, Naples.

There has never been a randomized trial comparing a NOAC to warfarin specifically in patients with these dual diagnoses. In the absence of such a definitive study, the next best thing is a meta-analysis of the pivotal Phase 3 trials in which warfarin was compared to dabigatran (Pradaxa, the RE-LY study), apixaban (Eliquis, ARISTOTLE), rivaroxaban (Xarelto, ROCKET AF), and edoxaban (Savaysa, ENGAGE AF-TIMI 48).

The meta-analysis focused on a subset population of 26,384 randomized patients with AF and heart failure. It’s important to know how the NOACs stack up against warfarin in this population because symptomatic heart failure is common: indeed, it’s present in 30% of patients with AF. Patients with AF and comorbid heart failure are generally older, frailer, have more comorbidities, and are at higher risk of both stroke and bleeding, compared with AF patients without heart failure. Since heart failure is a recognized risk factor for reduced time in the therapeutic international normalized ratio (INR) range for patients on warfarin, it’s likely that warfarin-treated dual diagnosis patients would be exposed to further increased risks of stroke and bleeding, according to Dr. Savarese.

In the meta-analysis, in addition to the NOAC-treated patients’ significantly reduced risks of stroke, major bleeding, and intracranial bleeding, they showed a 12% decrease in total bleeding and an 8% reduction in cardiovascular death, compared with warfarin-treated controls, although neither of those latter two favorable trends achieved statistical significance.

The four NOACs didn’t differ significantly on any of the prespecified outcomes in the meta-analysis.

One audience member noted that while the relative risk reductions for stroke and major bleeding seen with the NOACs in the meta-analysis were large and impressive, the absolute risk reductions were actually quite small. For example, warfarin-treated controls in RE-LY, the first of the major trials, had a stroke/systemic embolism rate of 1.69%/year and a major bleeding rate of 3.4%/year (N. Engl. J. Med. 2009;361:1139-51), while controls in ENGAGE AF-TIMI 48 had annualized stroke and major bleeding rates of 1.5% and 3.4%, respectively (N. Engl. J. Med. 2013;369:2093-2104).

Dr. Savarese replied that he and his coinvestigators consider those absolute risk reductions to be clinically meaningful, especially in light of the enormous and rapidly growing number of patients with both AF and heart failure.

He reported having no financial conflicts regarding this meta-analysis, which was carried out free of commercial support.

[email protected]