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Bevacizumab no better than placebo for epistaxis in HHT
of nasal spray
Bevacizumab nasal spray is no more effective than a placebo for reducing epistaxis caused by hereditary hemorrhagic telangiectasia (HHT), according to a study published in JAMA.
Researchers compared 3 different doses of bevacizumab to a sodium chloride placebo and found no significant difference between the treatment groups in the frequency or duration of epistaxis, the need for transfusion, or hemoglobin/ferritin levels.
Sophie Dupuis-Girod, MD, PhD, of the Hopital Femme-Mere-Enfants in Bron, France, and her colleagues conducted this trial, enrolling 80 patients with HHT and a history of epistaxis.
The patients were randomized to receive placebo (0.9% sodium chloride, n=21) or 1 of 3 doses of bevacizumab nasal spray.
Patients in the bevacizumab groups received 25 mg (n=20), 50 mg (n=20), or 75 mg (n=19) in 3 doses, 14 days apart, for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, or 225 mg.
Epistaxis duration
The researchers measured the mean monthly epistaxis duration at 3 months and found no significant difference between the placebo group and the bevacizumab groups (P=0.57). Likewise, there were no significant differences between the bevacizumab groups.
However, most of the groups experienced improvements in epistaxis duration after treatment.
The mean monthly epistaxis duration (in minutes) before treatment (from day −90 to day −1) and after treatment (from day 29 to day 118), respectively, was:
- 262.8 and 200.4 in the placebo group
- 285.5 and 259.2 in the 25 mg group
- 229.0 and 244.0 in the 50 mg group
- 272.9 and 215.0 in the 75 mg group.
Epistaxis frequency
There was no significant difference between the bevacizumab groups and the placebo group when it came to the number of epistaxis episodes (P=0.55). However, patients in all of the groups saw a reduction in episodes after treatment.
The mean number of epistaxis episodes before treatment (from day −90 to day −1) and after (from day 29 to day 118), respectively, were:
- 31.37 and 24.27 in the placebo group
- 30.99 and 23.13 in the 25 mg bevacizumab group
- 25.06 and 20.01 in the 50 mg bevacizumab group
- 27.84 and 24.35 in the 75 mg bevacizumab group.
Other outcomes
There was no significant difference between the bevacizumab groups and the placebo group regarding the number of red blood cell transfusions at 3 months (P=0.35) and 6 months (P=0.39), mean hemoglobin levels (P=0.66), and mean ferritin levels (P=0.86).
There were no adverse events (AEs) thought to be treatment-related. There were 161 AEs overall and no significant differences between the groups—47 AEs in the 25 mg bevacizumab group, 33 in the 50 mg bevacizumab group, 38 in the 75 mg bevacizumab group, and 43 in the placebo group.
After an interim analysis, an independent data monitoring committee recommended terminating this study early due to treatment futility. So the study was stopped before entering phase 3.
of nasal spray
Bevacizumab nasal spray is no more effective than a placebo for reducing epistaxis caused by hereditary hemorrhagic telangiectasia (HHT), according to a study published in JAMA.
Researchers compared 3 different doses of bevacizumab to a sodium chloride placebo and found no significant difference between the treatment groups in the frequency or duration of epistaxis, the need for transfusion, or hemoglobin/ferritin levels.
Sophie Dupuis-Girod, MD, PhD, of the Hopital Femme-Mere-Enfants in Bron, France, and her colleagues conducted this trial, enrolling 80 patients with HHT and a history of epistaxis.
The patients were randomized to receive placebo (0.9% sodium chloride, n=21) or 1 of 3 doses of bevacizumab nasal spray.
Patients in the bevacizumab groups received 25 mg (n=20), 50 mg (n=20), or 75 mg (n=19) in 3 doses, 14 days apart, for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, or 225 mg.
Epistaxis duration
The researchers measured the mean monthly epistaxis duration at 3 months and found no significant difference between the placebo group and the bevacizumab groups (P=0.57). Likewise, there were no significant differences between the bevacizumab groups.
However, most of the groups experienced improvements in epistaxis duration after treatment.
The mean monthly epistaxis duration (in minutes) before treatment (from day −90 to day −1) and after treatment (from day 29 to day 118), respectively, was:
- 262.8 and 200.4 in the placebo group
- 285.5 and 259.2 in the 25 mg group
- 229.0 and 244.0 in the 50 mg group
- 272.9 and 215.0 in the 75 mg group.
Epistaxis frequency
There was no significant difference between the bevacizumab groups and the placebo group when it came to the number of epistaxis episodes (P=0.55). However, patients in all of the groups saw a reduction in episodes after treatment.
The mean number of epistaxis episodes before treatment (from day −90 to day −1) and after (from day 29 to day 118), respectively, were:
- 31.37 and 24.27 in the placebo group
- 30.99 and 23.13 in the 25 mg bevacizumab group
- 25.06 and 20.01 in the 50 mg bevacizumab group
- 27.84 and 24.35 in the 75 mg bevacizumab group.
Other outcomes
There was no significant difference between the bevacizumab groups and the placebo group regarding the number of red blood cell transfusions at 3 months (P=0.35) and 6 months (P=0.39), mean hemoglobin levels (P=0.66), and mean ferritin levels (P=0.86).
There were no adverse events (AEs) thought to be treatment-related. There were 161 AEs overall and no significant differences between the groups—47 AEs in the 25 mg bevacizumab group, 33 in the 50 mg bevacizumab group, 38 in the 75 mg bevacizumab group, and 43 in the placebo group.
After an interim analysis, an independent data monitoring committee recommended terminating this study early due to treatment futility. So the study was stopped before entering phase 3.
of nasal spray
Bevacizumab nasal spray is no more effective than a placebo for reducing epistaxis caused by hereditary hemorrhagic telangiectasia (HHT), according to a study published in JAMA.
Researchers compared 3 different doses of bevacizumab to a sodium chloride placebo and found no significant difference between the treatment groups in the frequency or duration of epistaxis, the need for transfusion, or hemoglobin/ferritin levels.
Sophie Dupuis-Girod, MD, PhD, of the Hopital Femme-Mere-Enfants in Bron, France, and her colleagues conducted this trial, enrolling 80 patients with HHT and a history of epistaxis.
The patients were randomized to receive placebo (0.9% sodium chloride, n=21) or 1 of 3 doses of bevacizumab nasal spray.
Patients in the bevacizumab groups received 25 mg (n=20), 50 mg (n=20), or 75 mg (n=19) in 3 doses, 14 days apart, for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, or 225 mg.
Epistaxis duration
The researchers measured the mean monthly epistaxis duration at 3 months and found no significant difference between the placebo group and the bevacizumab groups (P=0.57). Likewise, there were no significant differences between the bevacizumab groups.
However, most of the groups experienced improvements in epistaxis duration after treatment.
The mean monthly epistaxis duration (in minutes) before treatment (from day −90 to day −1) and after treatment (from day 29 to day 118), respectively, was:
- 262.8 and 200.4 in the placebo group
- 285.5 and 259.2 in the 25 mg group
- 229.0 and 244.0 in the 50 mg group
- 272.9 and 215.0 in the 75 mg group.
Epistaxis frequency
There was no significant difference between the bevacizumab groups and the placebo group when it came to the number of epistaxis episodes (P=0.55). However, patients in all of the groups saw a reduction in episodes after treatment.
The mean number of epistaxis episodes before treatment (from day −90 to day −1) and after (from day 29 to day 118), respectively, were:
- 31.37 and 24.27 in the placebo group
- 30.99 and 23.13 in the 25 mg bevacizumab group
- 25.06 and 20.01 in the 50 mg bevacizumab group
- 27.84 and 24.35 in the 75 mg bevacizumab group.
Other outcomes
There was no significant difference between the bevacizumab groups and the placebo group regarding the number of red blood cell transfusions at 3 months (P=0.35) and 6 months (P=0.39), mean hemoglobin levels (P=0.66), and mean ferritin levels (P=0.86).
There were no adverse events (AEs) thought to be treatment-related. There were 161 AEs overall and no significant differences between the groups—47 AEs in the 25 mg bevacizumab group, 33 in the 50 mg bevacizumab group, 38 in the 75 mg bevacizumab group, and 43 in the placebo group.
After an interim analysis, an independent data monitoring committee recommended terminating this study early due to treatment futility. So the study was stopped before entering phase 3.
Improvements needed in SCD care, report says
Photo courtesy of St. Jude
Children’s Hospital
A new report suggests the current state of care for sickle cell disease (SCD) is inadequate, and improvements are needed.
The State of Sickle Cell Disease: 2016 Report outlines 4 main areas for improvement—SCD patients’ access to care, the training and education of healthcare professionals treating patients with SCD, research and clinical trials pertaining to SCD, and global health issues related to the disease.
The American Society of Hematology (ASH) published the report, with the endorsement of organizations in the SCD community.
The report includes statistics that highlight the need for improvements as well as future goals and recommended actions.
Access to care
The report states that more than 75% of adults with SCD who have frequent pain crises do not receive the recommended treatment, hydroxyurea.
One potential solution, according to the report, is to ensure that existing standard-of-care guidelines are being used. Another solution is to develop coordinated healthcare delivery models that ensure SCD patients can access quality care regardless of their age, location, and socioeconomic status.
“Not only are individuals with SCD burdened by the pain and disability that comes with a chronic condition, but they also have very few accessible treatment options due to our fragmented healthcare system,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
Training and education
The report cites a national survey in which only 20.4% of family physicians said they felt comfortable treating SCD. And 69.4% of family physicians said clinical decision support tools would be useful for helping to guide their treatment decisions for SCD patients.
Therefore, the report recommends devising an “actionable plan” to educate healthcare providers about best practices in caring for SCD patients, developing clinical support tools, and encouraging medical trainees to pursue careers in SCD care, among other solutions.
“There are many unique challenges that people with SCD face,” said ASH Vice President Alexis Thompson, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.
“For example, the transition from pediatric to adult care can be especially difficult, and many people struggle to find healthcare providers with comprehensive knowledge and expertise to provide proper care, especially in rural communities.”
Research and clinical trials
The report notes that hydroxyurea is the only drug approved by the US Food and Drug Administration to treat SCD. Therefore, research is needed to develop novel therapies, new drug delivery modes, and new agents that can be used in combination with hydroxyurea.
The report also highlights other areas where research is needed and recommends developing clinical trial networks to increase enrollment in trials.
Global issues
According to the report, roughly 1000 children in Africa are born with SCD every day, and more than half will die before they reach the age of 5. In addition, more than 90% of children with SCD who live in resource-poor countries do not survive to adulthood.
Therefore, the report recommends expanding newborn screening and early intervention programs, increasing SCD awareness and education, and improving access to quality care in developing regions.
Sickle Cell Disease Coalition
To address the aforementioned challenges, ASH and more than 20 other organizations launched the Sickle Cell Disease Coalition. The coalition is focused on promoting research, clinical care, education, training, and advocacy.
The aim of the coalition is to provide a platform to encourage stakeholders to work together to implement projects and activities that will ultimately help the SCD community and improve patient outcomes.
The coalition consists of leading patient advocacy groups, people with SCD and their families, researchers, clinicians, policymakers, industry stakeholders, and foundations with an interest in SCD.
Photo courtesy of St. Jude
Children’s Hospital
A new report suggests the current state of care for sickle cell disease (SCD) is inadequate, and improvements are needed.
The State of Sickle Cell Disease: 2016 Report outlines 4 main areas for improvement—SCD patients’ access to care, the training and education of healthcare professionals treating patients with SCD, research and clinical trials pertaining to SCD, and global health issues related to the disease.
The American Society of Hematology (ASH) published the report, with the endorsement of organizations in the SCD community.
The report includes statistics that highlight the need for improvements as well as future goals and recommended actions.
Access to care
The report states that more than 75% of adults with SCD who have frequent pain crises do not receive the recommended treatment, hydroxyurea.
One potential solution, according to the report, is to ensure that existing standard-of-care guidelines are being used. Another solution is to develop coordinated healthcare delivery models that ensure SCD patients can access quality care regardless of their age, location, and socioeconomic status.
“Not only are individuals with SCD burdened by the pain and disability that comes with a chronic condition, but they also have very few accessible treatment options due to our fragmented healthcare system,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
Training and education
The report cites a national survey in which only 20.4% of family physicians said they felt comfortable treating SCD. And 69.4% of family physicians said clinical decision support tools would be useful for helping to guide their treatment decisions for SCD patients.
Therefore, the report recommends devising an “actionable plan” to educate healthcare providers about best practices in caring for SCD patients, developing clinical support tools, and encouraging medical trainees to pursue careers in SCD care, among other solutions.
“There are many unique challenges that people with SCD face,” said ASH Vice President Alexis Thompson, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.
“For example, the transition from pediatric to adult care can be especially difficult, and many people struggle to find healthcare providers with comprehensive knowledge and expertise to provide proper care, especially in rural communities.”
Research and clinical trials
The report notes that hydroxyurea is the only drug approved by the US Food and Drug Administration to treat SCD. Therefore, research is needed to develop novel therapies, new drug delivery modes, and new agents that can be used in combination with hydroxyurea.
The report also highlights other areas where research is needed and recommends developing clinical trial networks to increase enrollment in trials.
Global issues
According to the report, roughly 1000 children in Africa are born with SCD every day, and more than half will die before they reach the age of 5. In addition, more than 90% of children with SCD who live in resource-poor countries do not survive to adulthood.
Therefore, the report recommends expanding newborn screening and early intervention programs, increasing SCD awareness and education, and improving access to quality care in developing regions.
Sickle Cell Disease Coalition
To address the aforementioned challenges, ASH and more than 20 other organizations launched the Sickle Cell Disease Coalition. The coalition is focused on promoting research, clinical care, education, training, and advocacy.
The aim of the coalition is to provide a platform to encourage stakeholders to work together to implement projects and activities that will ultimately help the SCD community and improve patient outcomes.
The coalition consists of leading patient advocacy groups, people with SCD and their families, researchers, clinicians, policymakers, industry stakeholders, and foundations with an interest in SCD.
Photo courtesy of St. Jude
Children’s Hospital
A new report suggests the current state of care for sickle cell disease (SCD) is inadequate, and improvements are needed.
The State of Sickle Cell Disease: 2016 Report outlines 4 main areas for improvement—SCD patients’ access to care, the training and education of healthcare professionals treating patients with SCD, research and clinical trials pertaining to SCD, and global health issues related to the disease.
The American Society of Hematology (ASH) published the report, with the endorsement of organizations in the SCD community.
The report includes statistics that highlight the need for improvements as well as future goals and recommended actions.
Access to care
The report states that more than 75% of adults with SCD who have frequent pain crises do not receive the recommended treatment, hydroxyurea.
One potential solution, according to the report, is to ensure that existing standard-of-care guidelines are being used. Another solution is to develop coordinated healthcare delivery models that ensure SCD patients can access quality care regardless of their age, location, and socioeconomic status.
“Not only are individuals with SCD burdened by the pain and disability that comes with a chronic condition, but they also have very few accessible treatment options due to our fragmented healthcare system,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
Training and education
The report cites a national survey in which only 20.4% of family physicians said they felt comfortable treating SCD. And 69.4% of family physicians said clinical decision support tools would be useful for helping to guide their treatment decisions for SCD patients.
Therefore, the report recommends devising an “actionable plan” to educate healthcare providers about best practices in caring for SCD patients, developing clinical support tools, and encouraging medical trainees to pursue careers in SCD care, among other solutions.
“There are many unique challenges that people with SCD face,” said ASH Vice President Alexis Thompson, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.
“For example, the transition from pediatric to adult care can be especially difficult, and many people struggle to find healthcare providers with comprehensive knowledge and expertise to provide proper care, especially in rural communities.”
Research and clinical trials
The report notes that hydroxyurea is the only drug approved by the US Food and Drug Administration to treat SCD. Therefore, research is needed to develop novel therapies, new drug delivery modes, and new agents that can be used in combination with hydroxyurea.
The report also highlights other areas where research is needed and recommends developing clinical trial networks to increase enrollment in trials.
Global issues
According to the report, roughly 1000 children in Africa are born with SCD every day, and more than half will die before they reach the age of 5. In addition, more than 90% of children with SCD who live in resource-poor countries do not survive to adulthood.
Therefore, the report recommends expanding newborn screening and early intervention programs, increasing SCD awareness and education, and improving access to quality care in developing regions.
Sickle Cell Disease Coalition
To address the aforementioned challenges, ASH and more than 20 other organizations launched the Sickle Cell Disease Coalition. The coalition is focused on promoting research, clinical care, education, training, and advocacy.
The aim of the coalition is to provide a platform to encourage stakeholders to work together to implement projects and activities that will ultimately help the SCD community and improve patient outcomes.
The coalition consists of leading patient advocacy groups, people with SCD and their families, researchers, clinicians, policymakers, industry stakeholders, and foundations with an interest in SCD.
Saline comparable to drug therapy for epistaxis in HHT
Photo courtesy of the
University of Utah
Health Sciences Center
Results of a phase 2 study suggest a saline nose spray may be as effective as 3 different medicated sprays for preventing epistaxis in patients with hemorrhagic telangiectasia (HHT).
The study was a comparison of bevacizumab, estriol, tranexamic acid, and saline.
The results showed no significant differences in the frequency or duration of epistaxis, and patients in all 4 groups reported improvements in Epistaxis Severity Scores (ESS).
“This research highlights that there could be a benefit even in the simplest of interventions,” said study author Kevin Whitehead, MD, of the University of Utah School of Medicine in Salt Lake City.
“No drug proved to be any better than the saline placebo, but the majority of patients improved over the course of treatment—even those using saline.”
Dr Whitehead and his colleagues reported these results in JAMA.
The study included 121 HHT patients who had experienced HHT-related epistaxis. They were randomized to twice-daily nose sprays with bevacizumab 1% (4 mg/day), estriol 0.1% (0.4 mg/day), tranexamic acid 10% (40 mg/day), or placebo (0.9% saline) for 12 weeks.
Safety
The investigators said nasal symptoms were the most common adverse events, and they occurred in all 4 treatment groups.
Gastrointestinal symptoms, including abdominal pain, nausea, and vomiting, were most common among patients receiving tranexamic acid.
There were no thrombotic complications, episodes of severe hypertension, serious drug-related adverse events, or deaths in any treatment group.
Efficacy
There was no significant difference in epistaxis frequency between the placebo group and the other treatment groups (P=0.97).
After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 for patients in the bevacizumab group, 8.0 for the estriol group, 7.5 for the tranexamic acid group, and 8.0 for the placebo group. At baseline, the median weekly number of bleeding episodes was 10.0, 7.0, 7.8, and 7.0, respectively.
After 12 weeks of treatment, there was no significant difference in epistaxis duration between the placebo group and the other treatment groups (P=0.09).
The median duration of epistaxis per bleeding episode was 3.0 minutes for the bevacizumab group, 4.0 minutes for the estriol group, 6.2 minutes for the tranexamic acid group, and 5.0 minutes for the placebo group. (Bleeding duration was not recorded at baseline.)
After 12 weeks of treatment, there were no significant differences between the treatment groups when it came to hemoglobin levels (P=0.43), ferritin levels (P=0.10), treatment failure (P=0.08), the need for transfusion (P=0.42), or emergency department visits (P=0.72).
Patients in all 4 treatment groups experienced a significant decline in ESS from baseline to week 12 (P<0.001 for time effect).
The median ESS decreased from 5.71 to 3.74 in the placebo group, 5.16 to 3.54 in the bevacizumab group, 5.19 to 3.56 in the estriol group, and 5.43 to 4.06 in the tranexamic acid group. The investigators said the improvement in ESS was clinically significant.
However, the team also said they cannot completely rule out the possibility that symptoms may have improved because of a placebo effect.
What’s more, it could be that some of the drugs tested would work better if taken at a higher dose, or if applied as a gel or polymer that adheres better to the inside of the nasal cavity.
Nevertheless, the results from this trial were enough to convince Dr Whitehead and his colleagues to routinely recommend saline nasal spray to their patients with HHT.
“We stress the importance of hydration,” Dr Whitehead said. “We tell them that something as simple as a morning and night saline spray could offer them some benefit.”
Photo courtesy of the
University of Utah
Health Sciences Center
Results of a phase 2 study suggest a saline nose spray may be as effective as 3 different medicated sprays for preventing epistaxis in patients with hemorrhagic telangiectasia (HHT).
The study was a comparison of bevacizumab, estriol, tranexamic acid, and saline.
The results showed no significant differences in the frequency or duration of epistaxis, and patients in all 4 groups reported improvements in Epistaxis Severity Scores (ESS).
“This research highlights that there could be a benefit even in the simplest of interventions,” said study author Kevin Whitehead, MD, of the University of Utah School of Medicine in Salt Lake City.
“No drug proved to be any better than the saline placebo, but the majority of patients improved over the course of treatment—even those using saline.”
Dr Whitehead and his colleagues reported these results in JAMA.
The study included 121 HHT patients who had experienced HHT-related epistaxis. They were randomized to twice-daily nose sprays with bevacizumab 1% (4 mg/day), estriol 0.1% (0.4 mg/day), tranexamic acid 10% (40 mg/day), or placebo (0.9% saline) for 12 weeks.
Safety
The investigators said nasal symptoms were the most common adverse events, and they occurred in all 4 treatment groups.
Gastrointestinal symptoms, including abdominal pain, nausea, and vomiting, were most common among patients receiving tranexamic acid.
There were no thrombotic complications, episodes of severe hypertension, serious drug-related adverse events, or deaths in any treatment group.
Efficacy
There was no significant difference in epistaxis frequency between the placebo group and the other treatment groups (P=0.97).
After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 for patients in the bevacizumab group, 8.0 for the estriol group, 7.5 for the tranexamic acid group, and 8.0 for the placebo group. At baseline, the median weekly number of bleeding episodes was 10.0, 7.0, 7.8, and 7.0, respectively.
After 12 weeks of treatment, there was no significant difference in epistaxis duration between the placebo group and the other treatment groups (P=0.09).
The median duration of epistaxis per bleeding episode was 3.0 minutes for the bevacizumab group, 4.0 minutes for the estriol group, 6.2 minutes for the tranexamic acid group, and 5.0 minutes for the placebo group. (Bleeding duration was not recorded at baseline.)
After 12 weeks of treatment, there were no significant differences between the treatment groups when it came to hemoglobin levels (P=0.43), ferritin levels (P=0.10), treatment failure (P=0.08), the need for transfusion (P=0.42), or emergency department visits (P=0.72).
Patients in all 4 treatment groups experienced a significant decline in ESS from baseline to week 12 (P<0.001 for time effect).
The median ESS decreased from 5.71 to 3.74 in the placebo group, 5.16 to 3.54 in the bevacizumab group, 5.19 to 3.56 in the estriol group, and 5.43 to 4.06 in the tranexamic acid group. The investigators said the improvement in ESS was clinically significant.
However, the team also said they cannot completely rule out the possibility that symptoms may have improved because of a placebo effect.
What’s more, it could be that some of the drugs tested would work better if taken at a higher dose, or if applied as a gel or polymer that adheres better to the inside of the nasal cavity.
Nevertheless, the results from this trial were enough to convince Dr Whitehead and his colleagues to routinely recommend saline nasal spray to their patients with HHT.
“We stress the importance of hydration,” Dr Whitehead said. “We tell them that something as simple as a morning and night saline spray could offer them some benefit.”
Photo courtesy of the
University of Utah
Health Sciences Center
Results of a phase 2 study suggest a saline nose spray may be as effective as 3 different medicated sprays for preventing epistaxis in patients with hemorrhagic telangiectasia (HHT).
The study was a comparison of bevacizumab, estriol, tranexamic acid, and saline.
The results showed no significant differences in the frequency or duration of epistaxis, and patients in all 4 groups reported improvements in Epistaxis Severity Scores (ESS).
“This research highlights that there could be a benefit even in the simplest of interventions,” said study author Kevin Whitehead, MD, of the University of Utah School of Medicine in Salt Lake City.
“No drug proved to be any better than the saline placebo, but the majority of patients improved over the course of treatment—even those using saline.”
Dr Whitehead and his colleagues reported these results in JAMA.
The study included 121 HHT patients who had experienced HHT-related epistaxis. They were randomized to twice-daily nose sprays with bevacizumab 1% (4 mg/day), estriol 0.1% (0.4 mg/day), tranexamic acid 10% (40 mg/day), or placebo (0.9% saline) for 12 weeks.
Safety
The investigators said nasal symptoms were the most common adverse events, and they occurred in all 4 treatment groups.
Gastrointestinal symptoms, including abdominal pain, nausea, and vomiting, were most common among patients receiving tranexamic acid.
There were no thrombotic complications, episodes of severe hypertension, serious drug-related adverse events, or deaths in any treatment group.
Efficacy
There was no significant difference in epistaxis frequency between the placebo group and the other treatment groups (P=0.97).
After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 for patients in the bevacizumab group, 8.0 for the estriol group, 7.5 for the tranexamic acid group, and 8.0 for the placebo group. At baseline, the median weekly number of bleeding episodes was 10.0, 7.0, 7.8, and 7.0, respectively.
After 12 weeks of treatment, there was no significant difference in epistaxis duration between the placebo group and the other treatment groups (P=0.09).
The median duration of epistaxis per bleeding episode was 3.0 minutes for the bevacizumab group, 4.0 minutes for the estriol group, 6.2 minutes for the tranexamic acid group, and 5.0 minutes for the placebo group. (Bleeding duration was not recorded at baseline.)
After 12 weeks of treatment, there were no significant differences between the treatment groups when it came to hemoglobin levels (P=0.43), ferritin levels (P=0.10), treatment failure (P=0.08), the need for transfusion (P=0.42), or emergency department visits (P=0.72).
Patients in all 4 treatment groups experienced a significant decline in ESS from baseline to week 12 (P<0.001 for time effect).
The median ESS decreased from 5.71 to 3.74 in the placebo group, 5.16 to 3.54 in the bevacizumab group, 5.19 to 3.56 in the estriol group, and 5.43 to 4.06 in the tranexamic acid group. The investigators said the improvement in ESS was clinically significant.
However, the team also said they cannot completely rule out the possibility that symptoms may have improved because of a placebo effect.
What’s more, it could be that some of the drugs tested would work better if taken at a higher dose, or if applied as a gel or polymer that adheres better to the inside of the nasal cavity.
Nevertheless, the results from this trial were enough to convince Dr Whitehead and his colleagues to routinely recommend saline nasal spray to their patients with HHT.
“We stress the importance of hydration,” Dr Whitehead said. “We tell them that something as simple as a morning and night saline spray could offer them some benefit.”
FDA grants therapy orphan designation for hemophilia B
Image by Spencer Phillips
The US Food and Drug Administration (FDA) has granted orphan drug designation to SB-FIX, a zinc finger nuclease (ZFN)-mediated genome-editing product candidate for the treatment of hemophilia B.
SB-FIX is designed to be used as a one-time treatment that will provide stable, continuous production of factor IX (FIX) for the lifetime of the patient.
The ZFN-mediated in vivo genome-editing approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic “safe-harbor site,” that can be edited with ZFNs to accept and express therapeutic genes.
The approach is designed is to enable the patient’s liver to permanently produce circulating therapeutic levels of a corrective protein product.
This differs from conventional adeno-associated virus complementary DNA gene therapy approaches, which are non-integrating and may “wash out” of the liver as cells divide and turn over.
Sangamo BioSciences, Inc., the company developing SB-FIX, expects to initiate a phase 1/2 trial of SB-FIX in adults with hemophilia B this year.
“We will enroll adult hemophilia patients into our first clinical trial. However, our goal is to move into pediatric patients, a population we believe could particularly benefit from a treatment that has the potential to provide life-long expression of therapeutic levels of factor IX protein,” said Geoff Nichol, MBChB, Sangamo’s executive vice president of research and development.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Image by Spencer Phillips
The US Food and Drug Administration (FDA) has granted orphan drug designation to SB-FIX, a zinc finger nuclease (ZFN)-mediated genome-editing product candidate for the treatment of hemophilia B.
SB-FIX is designed to be used as a one-time treatment that will provide stable, continuous production of factor IX (FIX) for the lifetime of the patient.
The ZFN-mediated in vivo genome-editing approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic “safe-harbor site,” that can be edited with ZFNs to accept and express therapeutic genes.
The approach is designed is to enable the patient’s liver to permanently produce circulating therapeutic levels of a corrective protein product.
This differs from conventional adeno-associated virus complementary DNA gene therapy approaches, which are non-integrating and may “wash out” of the liver as cells divide and turn over.
Sangamo BioSciences, Inc., the company developing SB-FIX, expects to initiate a phase 1/2 trial of SB-FIX in adults with hemophilia B this year.
“We will enroll adult hemophilia patients into our first clinical trial. However, our goal is to move into pediatric patients, a population we believe could particularly benefit from a treatment that has the potential to provide life-long expression of therapeutic levels of factor IX protein,” said Geoff Nichol, MBChB, Sangamo’s executive vice president of research and development.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Image by Spencer Phillips
The US Food and Drug Administration (FDA) has granted orphan drug designation to SB-FIX, a zinc finger nuclease (ZFN)-mediated genome-editing product candidate for the treatment of hemophilia B.
SB-FIX is designed to be used as a one-time treatment that will provide stable, continuous production of factor IX (FIX) for the lifetime of the patient.
The ZFN-mediated in vivo genome-editing approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic “safe-harbor site,” that can be edited with ZFNs to accept and express therapeutic genes.
The approach is designed is to enable the patient’s liver to permanently produce circulating therapeutic levels of a corrective protein product.
This differs from conventional adeno-associated virus complementary DNA gene therapy approaches, which are non-integrating and may “wash out” of the liver as cells divide and turn over.
Sangamo BioSciences, Inc., the company developing SB-FIX, expects to initiate a phase 1/2 trial of SB-FIX in adults with hemophilia B this year.
“We will enroll adult hemophilia patients into our first clinical trial. However, our goal is to move into pediatric patients, a population we believe could particularly benefit from a treatment that has the potential to provide life-long expression of therapeutic levels of factor IX protein,” said Geoff Nichol, MBChB, Sangamo’s executive vice president of research and development.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
HSCT may age T cells as much as 30 years
Photo by Chad McNeeley
New research suggests hematopoietic stem cell transplant (HSCT) may increase the molecular age of peripheral blood T cells.
The study showed an increase in peripheral blood T-cell senescence in patients with hematologic malignancies who were treated with autologous (auto-) or allogeneic (allo-) HSCT.
The patients had elevated levels of p16INK4a, a known marker of cellular senescence.
Auto-HSCT in particular had a strong effect on p16INK4a, increasing the expression of this marker to a degree comparable to 30 years of chronological aging.
Researchers reported these findings in EBioMedicine.
“We know that transplant is life-prolonging, and, in many cases, it’s life-saving for many patients with blood cancers and other disorders,” said study author William Wood, MD, of the University of North Carolina School of Medicine in Chapel Hill.
“At the same time, we’re increasingly recognizing that survivors of transplant are at risk for long-term health problems, and so there is interest in determining what markers may exist to help predict risk for long-term health problems or even in helping choose which patients are best candidates for transplantation.”
With this in mind, Dr Wood and his colleagues looked at levels of p16INK4a in 63 patients who underwent auto- or allo-HSCT to treat myeloma, lymphoma, or leukemia. The researchers assessed p16INK4a expression in T cells before HSCT and 6 months after.
Among auto-HSCT recipients, there were no baseline characteristics associated with pre-transplant p16INK4a expression.
However, allo-HSCT recipients had significantly higher pre-transplant p16INK4a levels the more cycles of chemotherapy they received before transplant (P=0.003), if they had previously undergone auto-HSCT (P=0.01), and if they had been exposed to alkylating agents (P=0.01).
After transplant, allo-HSCT recipients had a 1.93-fold increase in p16INK4a expression (P=0.0004), and auto-HSCT recipients had a 3.05-fold increase (P=0.002).
The researchers said the measured change in p16INK4a from pre- to post-HSCT in allogeneic recipients likely underestimates the age-promoting effects of HSCT, given that the pre-HSCT levels were elevated in the recipients from prior therapeutic exposure.
The researchers also pointed out that this study does not show a clear connection between changes in p16INK4a levels and the actual function of peripheral blood T cells, but they did say that p16INK4a is “arguably one of the best in vivo markers of cellular senescence and is directly associated with age-related deterioration.”
So the results of this research suggest the forced bone marrow repopulation associated with HSCT accelerates the molecular aging of peripheral blood T cells.
“Many oncologists would not be surprised by the finding that stem cell transplant accelerates aspects of aging,” said study author Norman Sharpless, MD, of the University of North Carolina School of Medicine.
“We know that, years after a curative transplant, stem cell transplant survivors are at increased risk for blood problems that can occur with aging, such as reduced immunity, increased risk for bone marrow failure, and increased risk of blood cancers. What is important about this work, however, is that it allows us to quantify the effect of stem cell transplant on molecular age.”
Photo by Chad McNeeley
New research suggests hematopoietic stem cell transplant (HSCT) may increase the molecular age of peripheral blood T cells.
The study showed an increase in peripheral blood T-cell senescence in patients with hematologic malignancies who were treated with autologous (auto-) or allogeneic (allo-) HSCT.
The patients had elevated levels of p16INK4a, a known marker of cellular senescence.
Auto-HSCT in particular had a strong effect on p16INK4a, increasing the expression of this marker to a degree comparable to 30 years of chronological aging.
Researchers reported these findings in EBioMedicine.
“We know that transplant is life-prolonging, and, in many cases, it’s life-saving for many patients with blood cancers and other disorders,” said study author William Wood, MD, of the University of North Carolina School of Medicine in Chapel Hill.
“At the same time, we’re increasingly recognizing that survivors of transplant are at risk for long-term health problems, and so there is interest in determining what markers may exist to help predict risk for long-term health problems or even in helping choose which patients are best candidates for transplantation.”
With this in mind, Dr Wood and his colleagues looked at levels of p16INK4a in 63 patients who underwent auto- or allo-HSCT to treat myeloma, lymphoma, or leukemia. The researchers assessed p16INK4a expression in T cells before HSCT and 6 months after.
Among auto-HSCT recipients, there were no baseline characteristics associated with pre-transplant p16INK4a expression.
However, allo-HSCT recipients had significantly higher pre-transplant p16INK4a levels the more cycles of chemotherapy they received before transplant (P=0.003), if they had previously undergone auto-HSCT (P=0.01), and if they had been exposed to alkylating agents (P=0.01).
After transplant, allo-HSCT recipients had a 1.93-fold increase in p16INK4a expression (P=0.0004), and auto-HSCT recipients had a 3.05-fold increase (P=0.002).
The researchers said the measured change in p16INK4a from pre- to post-HSCT in allogeneic recipients likely underestimates the age-promoting effects of HSCT, given that the pre-HSCT levels were elevated in the recipients from prior therapeutic exposure.
The researchers also pointed out that this study does not show a clear connection between changes in p16INK4a levels and the actual function of peripheral blood T cells, but they did say that p16INK4a is “arguably one of the best in vivo markers of cellular senescence and is directly associated with age-related deterioration.”
So the results of this research suggest the forced bone marrow repopulation associated with HSCT accelerates the molecular aging of peripheral blood T cells.
“Many oncologists would not be surprised by the finding that stem cell transplant accelerates aspects of aging,” said study author Norman Sharpless, MD, of the University of North Carolina School of Medicine.
“We know that, years after a curative transplant, stem cell transplant survivors are at increased risk for blood problems that can occur with aging, such as reduced immunity, increased risk for bone marrow failure, and increased risk of blood cancers. What is important about this work, however, is that it allows us to quantify the effect of stem cell transplant on molecular age.”
Photo by Chad McNeeley
New research suggests hematopoietic stem cell transplant (HSCT) may increase the molecular age of peripheral blood T cells.
The study showed an increase in peripheral blood T-cell senescence in patients with hematologic malignancies who were treated with autologous (auto-) or allogeneic (allo-) HSCT.
The patients had elevated levels of p16INK4a, a known marker of cellular senescence.
Auto-HSCT in particular had a strong effect on p16INK4a, increasing the expression of this marker to a degree comparable to 30 years of chronological aging.
Researchers reported these findings in EBioMedicine.
“We know that transplant is life-prolonging, and, in many cases, it’s life-saving for many patients with blood cancers and other disorders,” said study author William Wood, MD, of the University of North Carolina School of Medicine in Chapel Hill.
“At the same time, we’re increasingly recognizing that survivors of transplant are at risk for long-term health problems, and so there is interest in determining what markers may exist to help predict risk for long-term health problems or even in helping choose which patients are best candidates for transplantation.”
With this in mind, Dr Wood and his colleagues looked at levels of p16INK4a in 63 patients who underwent auto- or allo-HSCT to treat myeloma, lymphoma, or leukemia. The researchers assessed p16INK4a expression in T cells before HSCT and 6 months after.
Among auto-HSCT recipients, there were no baseline characteristics associated with pre-transplant p16INK4a expression.
However, allo-HSCT recipients had significantly higher pre-transplant p16INK4a levels the more cycles of chemotherapy they received before transplant (P=0.003), if they had previously undergone auto-HSCT (P=0.01), and if they had been exposed to alkylating agents (P=0.01).
After transplant, allo-HSCT recipients had a 1.93-fold increase in p16INK4a expression (P=0.0004), and auto-HSCT recipients had a 3.05-fold increase (P=0.002).
The researchers said the measured change in p16INK4a from pre- to post-HSCT in allogeneic recipients likely underestimates the age-promoting effects of HSCT, given that the pre-HSCT levels were elevated in the recipients from prior therapeutic exposure.
The researchers also pointed out that this study does not show a clear connection between changes in p16INK4a levels and the actual function of peripheral blood T cells, but they did say that p16INK4a is “arguably one of the best in vivo markers of cellular senescence and is directly associated with age-related deterioration.”
So the results of this research suggest the forced bone marrow repopulation associated with HSCT accelerates the molecular aging of peripheral blood T cells.
“Many oncologists would not be surprised by the finding that stem cell transplant accelerates aspects of aging,” said study author Norman Sharpless, MD, of the University of North Carolina School of Medicine.
“We know that, years after a curative transplant, stem cell transplant survivors are at increased risk for blood problems that can occur with aging, such as reduced immunity, increased risk for bone marrow failure, and increased risk of blood cancers. What is important about this work, however, is that it allows us to quantify the effect of stem cell transplant on molecular age.”
Study reveals higher risk of injuries pre- and post-cancer diagnosis
Photo courtesy of the CDC
Cancer patients have a heightened risk of injuries 16 weeks before and after their diagnosis, according to a large study.
This includes injuries arising from medical complications and treatments, such as infections or bleeding after invasive treatment, and other types of injuries, such as bruising or fractures from self-harm and accidents.
Fang Fang, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in The BMJ.
The researchers analyzed all injury-related hospital admissions in Swedish patients with cancer between 1990 and 2010. The team compared a diagnostic period—16 weeks before and after diagnosis—with a control period the year before diagnosis.
Among 720,901 patients, there were 7306 injuries from medical complications and drug treatments and 8331 injuries from accidents and self-harm that resulted in hospital admission during the diagnostic period.
Patients with central nervous system cancers had the highest risk of medical-related injuries—a 14.7-fold higher risk during the diagnostic period than the control period.
Patients with lymphatic or hematopoietic cancers had a 4-fold higher risk of such injuries during the diagnostic period than during the control period.
Patients who were younger, were cohabiting, had a higher socioeconomic status or education, and had no pre-existing psychiatric disorder had a higher risk of medical-related injuries during the diagnostic period than other groups of patients.
The risk of other types of injuries from self-harm and accidents was also higher during the diagnostic period. There was a 5.3-fold increased risk during the 2 weeks before diagnosis. The researchers said this suggests that psychological stress is high when patients are expecting a diagnosis.
Patients with lymphatic or hematopoietic cancers and patients with central nervous system cancers had the highest risk of self-harm and accidental injuries—a 2.8-fold increased risk during the diagnostic period compared to the control period (for both groups).
Older patients and those with lower socioeconomic status or education had slightly greater increases in the risk of self-harm and accidental injuries compared to other groups.
The researchers said the estimates of risk in this study are conservative because the team did not account for injuries that failed to result in a hospital admission or for those that were fatal.
Furthermore, this was an observational study, so no firm conclusions about cause and effect can be made.
Still, the researchers said this study sheds light on which patients might be at an increased risk of injuries, providing evidence for clinicians and policy makers to develop targeted prevention strategies.
Photo courtesy of the CDC
Cancer patients have a heightened risk of injuries 16 weeks before and after their diagnosis, according to a large study.
This includes injuries arising from medical complications and treatments, such as infections or bleeding after invasive treatment, and other types of injuries, such as bruising or fractures from self-harm and accidents.
Fang Fang, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in The BMJ.
The researchers analyzed all injury-related hospital admissions in Swedish patients with cancer between 1990 and 2010. The team compared a diagnostic period—16 weeks before and after diagnosis—with a control period the year before diagnosis.
Among 720,901 patients, there were 7306 injuries from medical complications and drug treatments and 8331 injuries from accidents and self-harm that resulted in hospital admission during the diagnostic period.
Patients with central nervous system cancers had the highest risk of medical-related injuries—a 14.7-fold higher risk during the diagnostic period than the control period.
Patients with lymphatic or hematopoietic cancers had a 4-fold higher risk of such injuries during the diagnostic period than during the control period.
Patients who were younger, were cohabiting, had a higher socioeconomic status or education, and had no pre-existing psychiatric disorder had a higher risk of medical-related injuries during the diagnostic period than other groups of patients.
The risk of other types of injuries from self-harm and accidents was also higher during the diagnostic period. There was a 5.3-fold increased risk during the 2 weeks before diagnosis. The researchers said this suggests that psychological stress is high when patients are expecting a diagnosis.
Patients with lymphatic or hematopoietic cancers and patients with central nervous system cancers had the highest risk of self-harm and accidental injuries—a 2.8-fold increased risk during the diagnostic period compared to the control period (for both groups).
Older patients and those with lower socioeconomic status or education had slightly greater increases in the risk of self-harm and accidental injuries compared to other groups.
The researchers said the estimates of risk in this study are conservative because the team did not account for injuries that failed to result in a hospital admission or for those that were fatal.
Furthermore, this was an observational study, so no firm conclusions about cause and effect can be made.
Still, the researchers said this study sheds light on which patients might be at an increased risk of injuries, providing evidence for clinicians and policy makers to develop targeted prevention strategies.
Photo courtesy of the CDC
Cancer patients have a heightened risk of injuries 16 weeks before and after their diagnosis, according to a large study.
This includes injuries arising from medical complications and treatments, such as infections or bleeding after invasive treatment, and other types of injuries, such as bruising or fractures from self-harm and accidents.
Fang Fang, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in The BMJ.
The researchers analyzed all injury-related hospital admissions in Swedish patients with cancer between 1990 and 2010. The team compared a diagnostic period—16 weeks before and after diagnosis—with a control period the year before diagnosis.
Among 720,901 patients, there were 7306 injuries from medical complications and drug treatments and 8331 injuries from accidents and self-harm that resulted in hospital admission during the diagnostic period.
Patients with central nervous system cancers had the highest risk of medical-related injuries—a 14.7-fold higher risk during the diagnostic period than the control period.
Patients with lymphatic or hematopoietic cancers had a 4-fold higher risk of such injuries during the diagnostic period than during the control period.
Patients who were younger, were cohabiting, had a higher socioeconomic status or education, and had no pre-existing psychiatric disorder had a higher risk of medical-related injuries during the diagnostic period than other groups of patients.
The risk of other types of injuries from self-harm and accidents was also higher during the diagnostic period. There was a 5.3-fold increased risk during the 2 weeks before diagnosis. The researchers said this suggests that psychological stress is high when patients are expecting a diagnosis.
Patients with lymphatic or hematopoietic cancers and patients with central nervous system cancers had the highest risk of self-harm and accidental injuries—a 2.8-fold increased risk during the diagnostic period compared to the control period (for both groups).
Older patients and those with lower socioeconomic status or education had slightly greater increases in the risk of self-harm and accidental injuries compared to other groups.
The researchers said the estimates of risk in this study are conservative because the team did not account for injuries that failed to result in a hospital admission or for those that were fatal.
Furthermore, this was an observational study, so no firm conclusions about cause and effect can be made.
Still, the researchers said this study sheds light on which patients might be at an increased risk of injuries, providing evidence for clinicians and policy makers to develop targeted prevention strategies.
Blood cells emerge through internal struggle, study suggests
Image by Volker Brinkmann
Developing blood cells are caught in a tug of war between competing gene regulatory networks before finally deciding what type of cell to become, according to a study published in Nature.
Researchers found that, as developing blood cells are triggered by a multitude of genetic signals firing on and off, they are pulled back and forth in fluctuating multi-lineage states before finally becoming specific cell types.
The team still doesn’t understand exactly what drives the cells to an eventual fate, but their work suggests that competing gene networks induce dynamic instability, resulting in mixed-lineage states that are necessary to prime newly forming cells for that decision.
“It is somewhat chaotic, but, from that chaos, results order,” said study author Harinder Singh, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“It’s a finding that helps us address a fundamental question of developmental biology: What are the nature of the intermediate states and the networks of regulatory genes that underlie cell-type specification?”
Although the finding requires additional study to better understand the back-and-forth nature of this process, the research may eventually provide new insights into developmental miscues that cause disease, according to study author H. Leighton Grimes, PhD, of Cincinnati Children’s.
“How do blood cells know to become neutrophils or monocytes?” Dr Grimes asked. “Two thirds of your bone marrow is taken up with this activity, and the number of cells has to be exquisitely balanced. Too many or too few of either can kill you.”
For this study, Dr Grimes and his colleagues looked specifically at the formation of neutrophils and macrophages. The researchers studied mouse cells as they developed in a natural state using single-cell RNA sequencing.
The team also used a bioinformatics computer program known as iterative clustering and guide-gene selection (ICGS). They used ICGS to process and analyze sequencing and biological data to identify the various transitioning or shifting genomic and cellular states of developing blood cells.
Dynamic instability
Researchers previously proposed that neutrophils and macrophages result from a bi-stable gene regulatory network—one that can manifest either of 2 stable states. But the different cellular transition states and underlying molecular dynamics of development have remained unknown.
Dr Grimes and his colleagues said their analysis of developing blood cells captured a prevalent mixed-lineage intermediate.
These intermediates expressed a combination of genes, including those typical of hematopoietic stem and progenitor cells and some genes that are specific for red blood cells, platelets, macrophages, and neutrophils. This seemed to reflect competing genetic programs.
The researchers also observed the developing cells moving through a rare state where they encountered turbulence known as dynamic instability. This was caused by 2 counteracting myeloid gene regulatory networks.
Two key components of the counteracting gene networks were Irf8 and Gfi1, genes that are involved in blood cell formation. When Irf8 and Gfi1 were eliminated from the picture, the rare cells could be trapped in an intermediate state.
As they continue this work, the researchers want to gain a clearer understanding of what finally causes cells in intermediate states of dynamic instability to assume specific fates.
The team suggests the influence of 2 simultaneous and counteracting gene networks generates internal oscillations that are eventually stabilized by unknown mechanisms to generate 1 of 2 different cell fates.
Image by Volker Brinkmann
Developing blood cells are caught in a tug of war between competing gene regulatory networks before finally deciding what type of cell to become, according to a study published in Nature.
Researchers found that, as developing blood cells are triggered by a multitude of genetic signals firing on and off, they are pulled back and forth in fluctuating multi-lineage states before finally becoming specific cell types.
The team still doesn’t understand exactly what drives the cells to an eventual fate, but their work suggests that competing gene networks induce dynamic instability, resulting in mixed-lineage states that are necessary to prime newly forming cells for that decision.
“It is somewhat chaotic, but, from that chaos, results order,” said study author Harinder Singh, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“It’s a finding that helps us address a fundamental question of developmental biology: What are the nature of the intermediate states and the networks of regulatory genes that underlie cell-type specification?”
Although the finding requires additional study to better understand the back-and-forth nature of this process, the research may eventually provide new insights into developmental miscues that cause disease, according to study author H. Leighton Grimes, PhD, of Cincinnati Children’s.
“How do blood cells know to become neutrophils or monocytes?” Dr Grimes asked. “Two thirds of your bone marrow is taken up with this activity, and the number of cells has to be exquisitely balanced. Too many or too few of either can kill you.”
For this study, Dr Grimes and his colleagues looked specifically at the formation of neutrophils and macrophages. The researchers studied mouse cells as they developed in a natural state using single-cell RNA sequencing.
The team also used a bioinformatics computer program known as iterative clustering and guide-gene selection (ICGS). They used ICGS to process and analyze sequencing and biological data to identify the various transitioning or shifting genomic and cellular states of developing blood cells.
Dynamic instability
Researchers previously proposed that neutrophils and macrophages result from a bi-stable gene regulatory network—one that can manifest either of 2 stable states. But the different cellular transition states and underlying molecular dynamics of development have remained unknown.
Dr Grimes and his colleagues said their analysis of developing blood cells captured a prevalent mixed-lineage intermediate.
These intermediates expressed a combination of genes, including those typical of hematopoietic stem and progenitor cells and some genes that are specific for red blood cells, platelets, macrophages, and neutrophils. This seemed to reflect competing genetic programs.
The researchers also observed the developing cells moving through a rare state where they encountered turbulence known as dynamic instability. This was caused by 2 counteracting myeloid gene regulatory networks.
Two key components of the counteracting gene networks were Irf8 and Gfi1, genes that are involved in blood cell formation. When Irf8 and Gfi1 were eliminated from the picture, the rare cells could be trapped in an intermediate state.
As they continue this work, the researchers want to gain a clearer understanding of what finally causes cells in intermediate states of dynamic instability to assume specific fates.
The team suggests the influence of 2 simultaneous and counteracting gene networks generates internal oscillations that are eventually stabilized by unknown mechanisms to generate 1 of 2 different cell fates.
Image by Volker Brinkmann
Developing blood cells are caught in a tug of war between competing gene regulatory networks before finally deciding what type of cell to become, according to a study published in Nature.
Researchers found that, as developing blood cells are triggered by a multitude of genetic signals firing on and off, they are pulled back and forth in fluctuating multi-lineage states before finally becoming specific cell types.
The team still doesn’t understand exactly what drives the cells to an eventual fate, but their work suggests that competing gene networks induce dynamic instability, resulting in mixed-lineage states that are necessary to prime newly forming cells for that decision.
“It is somewhat chaotic, but, from that chaos, results order,” said study author Harinder Singh, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“It’s a finding that helps us address a fundamental question of developmental biology: What are the nature of the intermediate states and the networks of regulatory genes that underlie cell-type specification?”
Although the finding requires additional study to better understand the back-and-forth nature of this process, the research may eventually provide new insights into developmental miscues that cause disease, according to study author H. Leighton Grimes, PhD, of Cincinnati Children’s.
“How do blood cells know to become neutrophils or monocytes?” Dr Grimes asked. “Two thirds of your bone marrow is taken up with this activity, and the number of cells has to be exquisitely balanced. Too many or too few of either can kill you.”
For this study, Dr Grimes and his colleagues looked specifically at the formation of neutrophils and macrophages. The researchers studied mouse cells as they developed in a natural state using single-cell RNA sequencing.
The team also used a bioinformatics computer program known as iterative clustering and guide-gene selection (ICGS). They used ICGS to process and analyze sequencing and biological data to identify the various transitioning or shifting genomic and cellular states of developing blood cells.
Dynamic instability
Researchers previously proposed that neutrophils and macrophages result from a bi-stable gene regulatory network—one that can manifest either of 2 stable states. But the different cellular transition states and underlying molecular dynamics of development have remained unknown.
Dr Grimes and his colleagues said their analysis of developing blood cells captured a prevalent mixed-lineage intermediate.
These intermediates expressed a combination of genes, including those typical of hematopoietic stem and progenitor cells and some genes that are specific for red blood cells, platelets, macrophages, and neutrophils. This seemed to reflect competing genetic programs.
The researchers also observed the developing cells moving through a rare state where they encountered turbulence known as dynamic instability. This was caused by 2 counteracting myeloid gene regulatory networks.
Two key components of the counteracting gene networks were Irf8 and Gfi1, genes that are involved in blood cell formation. When Irf8 and Gfi1 were eliminated from the picture, the rare cells could be trapped in an intermediate state.
As they continue this work, the researchers want to gain a clearer understanding of what finally causes cells in intermediate states of dynamic instability to assume specific fates.
The team suggests the influence of 2 simultaneous and counteracting gene networks generates internal oscillations that are eventually stabilized by unknown mechanisms to generate 1 of 2 different cell fates.
Longer DAPT better for PAD, study suggests
Photo by Sage Ross
ROME—A subanalysis of the PRODIGY study suggests a longer duration of dual antiplatelet therapy (DAPT) improves outcomes after percutaneous coronary intervention (PCI) for patients with peripheral arterial disease (PAD).
Receiving long-term DAPT after PCI reduced the risk of atherothrombotic events and death in patients with PAD, without increasing the risk of actionable bleeding episodes.
However, patients without PAD fared better with short-term DAPT.
These results were presented at ESC Congress 2016 (abstract 5154) and published in JAMA Cardiology.
Marco Valgimigli, MD, PhD, of Bern University Hospital in Bern, Switzerland, and his colleagues performed this analysis of PRODIGY data.
The study included patients from tertiary care hospitals who had stable coronary artery disease or acute coronary syndromes, with or without concomitant PAD, and were undergoing PCI.
There were 246 patients with PAD—118 who were randomized to receive DAPT for 24 months after PCI and 128 who were randomized to DAPT for 6 months or less.
There were 1724 patients without PAD—869 who were randomized to receive DAPT for 24 months after PCI and 855 who were randomized to DAPT for 6 months or less.
The patients with PAD were older and more frequently underwent multivessel intervention. They were also more likely to have hypertension, type 1 or 2 diabetes, previous myocardial infarction, previous coronary artery bypass grafting, non-ST-segment elevation myocardial infarction, and more complex coronary artery disease.
At 30 days, patients with PAD were more often taking diuretics, and patients without PAD were more often taking beta-blockers and statins.
Patients with PAD who were randomized to long-term DAPT were younger, had a higher body mass index, and less frequently underwent PCI of the left main coronary artery than PAD patients randomized to short-term DAPT.
Having PAD was associated with a higher risk of death and ischemic events, with a hazard ratio (HR) of 2.80 (95% CI, 2.05-3.83; P<0.001).
Results
The primary efficacy endpoint of this study was a composite of death, myocardial infarction, and cerebrovascular accidents.
Among patients with PAD, those who received long-term DAPT had a lower risk of this endpoint than those who received short-term DAPT—16.1% and 27.3%, respectively. The HR was 0.54 (95% CI, 0.31-0.95; P=0.03).
Among patients without PAD, there was no significant difference in the incidence of the primary endpoint according to DAPT duration. It occurred in 9.3% of patients who received long-term DAPT and 7.4% of patients who received short-term DAPT. The HR was 1.28 (95% CI, 0.92-1.77; P=0.15).
The key safety endpoint was a composite of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding.
There was no significant difference in this endpoint according to DAPT duration for patients with PAD, but long-term DAPT was associated with a significant increase in this endpoint for patients without PAD.
Among patients with PAD, BARC type 2, 3, or 5 bleeding occurred in 5.2% of those receiving long-term DAPT and 6.9% of those receiving short-term DAPT. The HR was 0.77 (95% CI, 0.27-2.21; P=0.62).
Among patients without PAD, BARC type 2, 3, or 5 bleeding occurred in 8% of those receiving long-term DAPT and 3.1% of those receiving short-term DAPT. The HR was 2.61 (95% CI, 0.27-2.21; P<0.001).
The researchers said the apparent neutral effect of long-term DAPT on bleeding risk in PAD patients requires further evaluation in adequately powered studies, but this research suggests patients with PAD will benefit from prolonged DAPT after PCI.
Photo by Sage Ross
ROME—A subanalysis of the PRODIGY study suggests a longer duration of dual antiplatelet therapy (DAPT) improves outcomes after percutaneous coronary intervention (PCI) for patients with peripheral arterial disease (PAD).
Receiving long-term DAPT after PCI reduced the risk of atherothrombotic events and death in patients with PAD, without increasing the risk of actionable bleeding episodes.
However, patients without PAD fared better with short-term DAPT.
These results were presented at ESC Congress 2016 (abstract 5154) and published in JAMA Cardiology.
Marco Valgimigli, MD, PhD, of Bern University Hospital in Bern, Switzerland, and his colleagues performed this analysis of PRODIGY data.
The study included patients from tertiary care hospitals who had stable coronary artery disease or acute coronary syndromes, with or without concomitant PAD, and were undergoing PCI.
There were 246 patients with PAD—118 who were randomized to receive DAPT for 24 months after PCI and 128 who were randomized to DAPT for 6 months or less.
There were 1724 patients without PAD—869 who were randomized to receive DAPT for 24 months after PCI and 855 who were randomized to DAPT for 6 months or less.
The patients with PAD were older and more frequently underwent multivessel intervention. They were also more likely to have hypertension, type 1 or 2 diabetes, previous myocardial infarction, previous coronary artery bypass grafting, non-ST-segment elevation myocardial infarction, and more complex coronary artery disease.
At 30 days, patients with PAD were more often taking diuretics, and patients without PAD were more often taking beta-blockers and statins.
Patients with PAD who were randomized to long-term DAPT were younger, had a higher body mass index, and less frequently underwent PCI of the left main coronary artery than PAD patients randomized to short-term DAPT.
Having PAD was associated with a higher risk of death and ischemic events, with a hazard ratio (HR) of 2.80 (95% CI, 2.05-3.83; P<0.001).
Results
The primary efficacy endpoint of this study was a composite of death, myocardial infarction, and cerebrovascular accidents.
Among patients with PAD, those who received long-term DAPT had a lower risk of this endpoint than those who received short-term DAPT—16.1% and 27.3%, respectively. The HR was 0.54 (95% CI, 0.31-0.95; P=0.03).
Among patients without PAD, there was no significant difference in the incidence of the primary endpoint according to DAPT duration. It occurred in 9.3% of patients who received long-term DAPT and 7.4% of patients who received short-term DAPT. The HR was 1.28 (95% CI, 0.92-1.77; P=0.15).
The key safety endpoint was a composite of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding.
There was no significant difference in this endpoint according to DAPT duration for patients with PAD, but long-term DAPT was associated with a significant increase in this endpoint for patients without PAD.
Among patients with PAD, BARC type 2, 3, or 5 bleeding occurred in 5.2% of those receiving long-term DAPT and 6.9% of those receiving short-term DAPT. The HR was 0.77 (95% CI, 0.27-2.21; P=0.62).
Among patients without PAD, BARC type 2, 3, or 5 bleeding occurred in 8% of those receiving long-term DAPT and 3.1% of those receiving short-term DAPT. The HR was 2.61 (95% CI, 0.27-2.21; P<0.001).
The researchers said the apparent neutral effect of long-term DAPT on bleeding risk in PAD patients requires further evaluation in adequately powered studies, but this research suggests patients with PAD will benefit from prolonged DAPT after PCI.
Photo by Sage Ross
ROME—A subanalysis of the PRODIGY study suggests a longer duration of dual antiplatelet therapy (DAPT) improves outcomes after percutaneous coronary intervention (PCI) for patients with peripheral arterial disease (PAD).
Receiving long-term DAPT after PCI reduced the risk of atherothrombotic events and death in patients with PAD, without increasing the risk of actionable bleeding episodes.
However, patients without PAD fared better with short-term DAPT.
These results were presented at ESC Congress 2016 (abstract 5154) and published in JAMA Cardiology.
Marco Valgimigli, MD, PhD, of Bern University Hospital in Bern, Switzerland, and his colleagues performed this analysis of PRODIGY data.
The study included patients from tertiary care hospitals who had stable coronary artery disease or acute coronary syndromes, with or without concomitant PAD, and were undergoing PCI.
There were 246 patients with PAD—118 who were randomized to receive DAPT for 24 months after PCI and 128 who were randomized to DAPT for 6 months or less.
There were 1724 patients without PAD—869 who were randomized to receive DAPT for 24 months after PCI and 855 who were randomized to DAPT for 6 months or less.
The patients with PAD were older and more frequently underwent multivessel intervention. They were also more likely to have hypertension, type 1 or 2 diabetes, previous myocardial infarction, previous coronary artery bypass grafting, non-ST-segment elevation myocardial infarction, and more complex coronary artery disease.
At 30 days, patients with PAD were more often taking diuretics, and patients without PAD were more often taking beta-blockers and statins.
Patients with PAD who were randomized to long-term DAPT were younger, had a higher body mass index, and less frequently underwent PCI of the left main coronary artery than PAD patients randomized to short-term DAPT.
Having PAD was associated with a higher risk of death and ischemic events, with a hazard ratio (HR) of 2.80 (95% CI, 2.05-3.83; P<0.001).
Results
The primary efficacy endpoint of this study was a composite of death, myocardial infarction, and cerebrovascular accidents.
Among patients with PAD, those who received long-term DAPT had a lower risk of this endpoint than those who received short-term DAPT—16.1% and 27.3%, respectively. The HR was 0.54 (95% CI, 0.31-0.95; P=0.03).
Among patients without PAD, there was no significant difference in the incidence of the primary endpoint according to DAPT duration. It occurred in 9.3% of patients who received long-term DAPT and 7.4% of patients who received short-term DAPT. The HR was 1.28 (95% CI, 0.92-1.77; P=0.15).
The key safety endpoint was a composite of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding.
There was no significant difference in this endpoint according to DAPT duration for patients with PAD, but long-term DAPT was associated with a significant increase in this endpoint for patients without PAD.
Among patients with PAD, BARC type 2, 3, or 5 bleeding occurred in 5.2% of those receiving long-term DAPT and 6.9% of those receiving short-term DAPT. The HR was 0.77 (95% CI, 0.27-2.21; P=0.62).
Among patients without PAD, BARC type 2, 3, or 5 bleeding occurred in 8% of those receiving long-term DAPT and 3.1% of those receiving short-term DAPT. The HR was 2.61 (95% CI, 0.27-2.21; P<0.001).
The researchers said the apparent neutral effect of long-term DAPT on bleeding risk in PAD patients requires further evaluation in adequately powered studies, but this research suggests patients with PAD will benefit from prolonged DAPT after PCI.
FDA expands approval of blinatumomab
and solution for infusion
Photo courtesy of Amgen
The US Food and Drug Administration (FDA) has granted accelerated approval for blinatumomab (Blincyto®) to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
The approval is based on results from a phase 1/2 study.
Continued approval of blinatumomab for this indication may be contingent upon verification of clinical benefit in subsequent trials.
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
In 2014, blinatumomab received accelerated approval from the FDA to treat adults with Ph- relapsed or refractory BCP-ALL. The FDA has also granted the drug priority review, breakthrough therapy designation, and orphan drug designation.
Blinatumomab is being developed by Amgen. Full prescribing information is available at www.blincyto.com.
‘205 trial
The latest accelerated approval of blinatumomab is based on results from the phase 1/2 ‘205 trial, in which researchers evaluated blinatumomab in 93 pediatric patients with relapsed or refractory BCP-ALL.
Amgen said treatment in this study has been completed, subjects are being monitored for long-term efficacy, and the data will be submitted for publication.
Initial results from this study were presented at ASH 2014. The abstract included data on 39 patients with relapsed/refractory BCP-ALL and a median age of 9 (range, 2-16).
The patients received blinatumomab at a dose of 5-15 µg/m²/day. Nineteen patients completed 1 cycle of blinatumomab, 4 completed 2 cycles, and 2 completed 3 cycles.
During the first 2 treatment cycles, 12 patients achieved a complete response, 5 of whom were negative for minimal residual disease.
Six of the complete responders went on to transplant. The median relapse-free survival for complete responders was 5.6 months.
At 6 months of follow-up, the median overall survival for all 39 patients was 4.3 months.
All of the patients experienced adverse events. The most common were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%).
The most common grade 3 or higher events were anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%).
Three patients developed cytokine release syndrome (2 grade 3).
and solution for infusion
Photo courtesy of Amgen
The US Food and Drug Administration (FDA) has granted accelerated approval for blinatumomab (Blincyto®) to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
The approval is based on results from a phase 1/2 study.
Continued approval of blinatumomab for this indication may be contingent upon verification of clinical benefit in subsequent trials.
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
In 2014, blinatumomab received accelerated approval from the FDA to treat adults with Ph- relapsed or refractory BCP-ALL. The FDA has also granted the drug priority review, breakthrough therapy designation, and orphan drug designation.
Blinatumomab is being developed by Amgen. Full prescribing information is available at www.blincyto.com.
‘205 trial
The latest accelerated approval of blinatumomab is based on results from the phase 1/2 ‘205 trial, in which researchers evaluated blinatumomab in 93 pediatric patients with relapsed or refractory BCP-ALL.
Amgen said treatment in this study has been completed, subjects are being monitored for long-term efficacy, and the data will be submitted for publication.
Initial results from this study were presented at ASH 2014. The abstract included data on 39 patients with relapsed/refractory BCP-ALL and a median age of 9 (range, 2-16).
The patients received blinatumomab at a dose of 5-15 µg/m²/day. Nineteen patients completed 1 cycle of blinatumomab, 4 completed 2 cycles, and 2 completed 3 cycles.
During the first 2 treatment cycles, 12 patients achieved a complete response, 5 of whom were negative for minimal residual disease.
Six of the complete responders went on to transplant. The median relapse-free survival for complete responders was 5.6 months.
At 6 months of follow-up, the median overall survival for all 39 patients was 4.3 months.
All of the patients experienced adverse events. The most common were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%).
The most common grade 3 or higher events were anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%).
Three patients developed cytokine release syndrome (2 grade 3).
and solution for infusion
Photo courtesy of Amgen
The US Food and Drug Administration (FDA) has granted accelerated approval for blinatumomab (Blincyto®) to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
The approval is based on results from a phase 1/2 study.
Continued approval of blinatumomab for this indication may be contingent upon verification of clinical benefit in subsequent trials.
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
In 2014, blinatumomab received accelerated approval from the FDA to treat adults with Ph- relapsed or refractory BCP-ALL. The FDA has also granted the drug priority review, breakthrough therapy designation, and orphan drug designation.
Blinatumomab is being developed by Amgen. Full prescribing information is available at www.blincyto.com.
‘205 trial
The latest accelerated approval of blinatumomab is based on results from the phase 1/2 ‘205 trial, in which researchers evaluated blinatumomab in 93 pediatric patients with relapsed or refractory BCP-ALL.
Amgen said treatment in this study has been completed, subjects are being monitored for long-term efficacy, and the data will be submitted for publication.
Initial results from this study were presented at ASH 2014. The abstract included data on 39 patients with relapsed/refractory BCP-ALL and a median age of 9 (range, 2-16).
The patients received blinatumomab at a dose of 5-15 µg/m²/day. Nineteen patients completed 1 cycle of blinatumomab, 4 completed 2 cycles, and 2 completed 3 cycles.
During the first 2 treatment cycles, 12 patients achieved a complete response, 5 of whom were negative for minimal residual disease.
Six of the complete responders went on to transplant. The median relapse-free survival for complete responders was 5.6 months.
At 6 months of follow-up, the median overall survival for all 39 patients was 4.3 months.
All of the patients experienced adverse events. The most common were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%).
The most common grade 3 or higher events were anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%).
Three patients developed cytokine release syndrome (2 grade 3).
Simple algorithm can rule out PE, team says
Image courtesy of
Medical College of Georgia
ROME—A new study suggests the YEARS algorithm may provide a simple method for ruling out pulmonary embolism (PE) and therefore reduce the need for computed tomography pulmonary angiography (CTPA).
“[The YEARS algorithm] can replace current diagnostic algorithms, which, although safe and accurate, are often not used in busy emergency departments because they are too complex,” said study investigator Tom Van der Hulle, MD, of Leiden University Medical Center in the Netherlands.
“The advantage of the YEARS algorithm over existing algorithms is a 14% reduction in the need for CTPA imaging and, with that, reduced potential for radiation-induced harm and overdiagnosis.”
Dr Van der Hulle described his team’s results with the YEARS algorithm at ESC Congress 2016 (abstract 5727).
About the algorithm
The YEARS algorithm consists of a blood test and 3 items of the original Wells rule.
Patients presenting to the emergency department can be evaluated based on:
- Clinical signs of deep vein thrombosis (eg, swelling, edema)
- Hemoptysis
- Whether the clinician considers PE to be “the most likely diagnosis.”
Using this information combined with results of a blood test measuring D-dimer, clinicians can either exclude PE or recommend CTPA for definitive diagnosis.
Based on the algorithm, PE can be excluded in patients who have either:
- None of the 3 YEARS items and a D-dimer level <1000 ng/mL
- One or more YEARS items and a D-dimer level <500 ng/mL.
Testing the algorithm
Dr Van der Hulle and his colleagues prospectively evaluated the YEARS algorithm in 3465 patients. They had a mean age of 53, and 88% were outpatients.
If patients did not have PE excluded via the algorithm, they went on to CTPA. If PE was confirmed, patients received anticoagulant therapy.
Most of the patients in whom PE was excluded (either by algorithm or CTPA) were left untreated and were followed for 3 months, although 60 patients who had PE excluded received anticoagulants anyway.
In all, 1651 patients had PE excluded with the YEARS algorithm, and 1633 of them did not receive anticoagulation.
A total of 1814 patients did not have PE excluded via the YEARS algorithm and went on to CTPA. Of these patients, 456 had PE, 42 had PE excluded via CTPA but received anticoagulation, and 1316 had PE excluded but did not receive anticoagulation.
Five patients were lost to follow-up—4 with PE excluded via the YEARS algorithm and 1 who went on to CTPA.
Patient outcomes
The primary outcome of this study was the 3-month incidence of symptomatic venous thromboembolism (VTE).
A total of 2944 patients were evaluable (because they had PE excluded, did not receive anticoagulation, and were not lost to follow-up)—1629 who had PE excluded via the YEARS algorithm and 1315 who had PE excluded via CTPA.
Symptomatic VTE occurred in 0.61% of all evaluable patients, 0.43% of patients who had PE excluded via YEARS, and 0.84% of patients who had PE excluded via CTPA.
Fatal PE occurred in 0.20% of all evaluable patients, 0.12% of patients who had PE excluded via YEARS, and 0.30% of patients who had PE excluded via CTPA.
“This is fully in line with that observed in studies using traditional, sequential algorithms such as the 2-level Wells score and a fixed cut-off level of D-dimer of 500 ng/mL,” Dr Van der Hulle said.
“Using the YEARS algorithm, CTPA was not indicated in 48% of our patients at baseline, but this would have been only 34% of patients using the traditional algorithm. This shows that the YEARS algorithm can safely exclude PE and resulted in an absolute reduction of required CTPA of 14%.”
“We expect that the YEARS algorithm can be easily implemented outside the participating study sites and that these safety and efficacy outcomes are representative of what could be expected in regular clinical settings.”
Image courtesy of
Medical College of Georgia
ROME—A new study suggests the YEARS algorithm may provide a simple method for ruling out pulmonary embolism (PE) and therefore reduce the need for computed tomography pulmonary angiography (CTPA).
“[The YEARS algorithm] can replace current diagnostic algorithms, which, although safe and accurate, are often not used in busy emergency departments because they are too complex,” said study investigator Tom Van der Hulle, MD, of Leiden University Medical Center in the Netherlands.
“The advantage of the YEARS algorithm over existing algorithms is a 14% reduction in the need for CTPA imaging and, with that, reduced potential for radiation-induced harm and overdiagnosis.”
Dr Van der Hulle described his team’s results with the YEARS algorithm at ESC Congress 2016 (abstract 5727).
About the algorithm
The YEARS algorithm consists of a blood test and 3 items of the original Wells rule.
Patients presenting to the emergency department can be evaluated based on:
- Clinical signs of deep vein thrombosis (eg, swelling, edema)
- Hemoptysis
- Whether the clinician considers PE to be “the most likely diagnosis.”
Using this information combined with results of a blood test measuring D-dimer, clinicians can either exclude PE or recommend CTPA for definitive diagnosis.
Based on the algorithm, PE can be excluded in patients who have either:
- None of the 3 YEARS items and a D-dimer level <1000 ng/mL
- One or more YEARS items and a D-dimer level <500 ng/mL.
Testing the algorithm
Dr Van der Hulle and his colleagues prospectively evaluated the YEARS algorithm in 3465 patients. They had a mean age of 53, and 88% were outpatients.
If patients did not have PE excluded via the algorithm, they went on to CTPA. If PE was confirmed, patients received anticoagulant therapy.
Most of the patients in whom PE was excluded (either by algorithm or CTPA) were left untreated and were followed for 3 months, although 60 patients who had PE excluded received anticoagulants anyway.
In all, 1651 patients had PE excluded with the YEARS algorithm, and 1633 of them did not receive anticoagulation.
A total of 1814 patients did not have PE excluded via the YEARS algorithm and went on to CTPA. Of these patients, 456 had PE, 42 had PE excluded via CTPA but received anticoagulation, and 1316 had PE excluded but did not receive anticoagulation.
Five patients were lost to follow-up—4 with PE excluded via the YEARS algorithm and 1 who went on to CTPA.
Patient outcomes
The primary outcome of this study was the 3-month incidence of symptomatic venous thromboembolism (VTE).
A total of 2944 patients were evaluable (because they had PE excluded, did not receive anticoagulation, and were not lost to follow-up)—1629 who had PE excluded via the YEARS algorithm and 1315 who had PE excluded via CTPA.
Symptomatic VTE occurred in 0.61% of all evaluable patients, 0.43% of patients who had PE excluded via YEARS, and 0.84% of patients who had PE excluded via CTPA.
Fatal PE occurred in 0.20% of all evaluable patients, 0.12% of patients who had PE excluded via YEARS, and 0.30% of patients who had PE excluded via CTPA.
“This is fully in line with that observed in studies using traditional, sequential algorithms such as the 2-level Wells score and a fixed cut-off level of D-dimer of 500 ng/mL,” Dr Van der Hulle said.
“Using the YEARS algorithm, CTPA was not indicated in 48% of our patients at baseline, but this would have been only 34% of patients using the traditional algorithm. This shows that the YEARS algorithm can safely exclude PE and resulted in an absolute reduction of required CTPA of 14%.”
“We expect that the YEARS algorithm can be easily implemented outside the participating study sites and that these safety and efficacy outcomes are representative of what could be expected in regular clinical settings.”
Image courtesy of
Medical College of Georgia
ROME—A new study suggests the YEARS algorithm may provide a simple method for ruling out pulmonary embolism (PE) and therefore reduce the need for computed tomography pulmonary angiography (CTPA).
“[The YEARS algorithm] can replace current diagnostic algorithms, which, although safe and accurate, are often not used in busy emergency departments because they are too complex,” said study investigator Tom Van der Hulle, MD, of Leiden University Medical Center in the Netherlands.
“The advantage of the YEARS algorithm over existing algorithms is a 14% reduction in the need for CTPA imaging and, with that, reduced potential for radiation-induced harm and overdiagnosis.”
Dr Van der Hulle described his team’s results with the YEARS algorithm at ESC Congress 2016 (abstract 5727).
About the algorithm
The YEARS algorithm consists of a blood test and 3 items of the original Wells rule.
Patients presenting to the emergency department can be evaluated based on:
- Clinical signs of deep vein thrombosis (eg, swelling, edema)
- Hemoptysis
- Whether the clinician considers PE to be “the most likely diagnosis.”
Using this information combined with results of a blood test measuring D-dimer, clinicians can either exclude PE or recommend CTPA for definitive diagnosis.
Based on the algorithm, PE can be excluded in patients who have either:
- None of the 3 YEARS items and a D-dimer level <1000 ng/mL
- One or more YEARS items and a D-dimer level <500 ng/mL.
Testing the algorithm
Dr Van der Hulle and his colleagues prospectively evaluated the YEARS algorithm in 3465 patients. They had a mean age of 53, and 88% were outpatients.
If patients did not have PE excluded via the algorithm, they went on to CTPA. If PE was confirmed, patients received anticoagulant therapy.
Most of the patients in whom PE was excluded (either by algorithm or CTPA) were left untreated and were followed for 3 months, although 60 patients who had PE excluded received anticoagulants anyway.
In all, 1651 patients had PE excluded with the YEARS algorithm, and 1633 of them did not receive anticoagulation.
A total of 1814 patients did not have PE excluded via the YEARS algorithm and went on to CTPA. Of these patients, 456 had PE, 42 had PE excluded via CTPA but received anticoagulation, and 1316 had PE excluded but did not receive anticoagulation.
Five patients were lost to follow-up—4 with PE excluded via the YEARS algorithm and 1 who went on to CTPA.
Patient outcomes
The primary outcome of this study was the 3-month incidence of symptomatic venous thromboembolism (VTE).
A total of 2944 patients were evaluable (because they had PE excluded, did not receive anticoagulation, and were not lost to follow-up)—1629 who had PE excluded via the YEARS algorithm and 1315 who had PE excluded via CTPA.
Symptomatic VTE occurred in 0.61% of all evaluable patients, 0.43% of patients who had PE excluded via YEARS, and 0.84% of patients who had PE excluded via CTPA.
Fatal PE occurred in 0.20% of all evaluable patients, 0.12% of patients who had PE excluded via YEARS, and 0.30% of patients who had PE excluded via CTPA.
“This is fully in line with that observed in studies using traditional, sequential algorithms such as the 2-level Wells score and a fixed cut-off level of D-dimer of 500 ng/mL,” Dr Van der Hulle said.
“Using the YEARS algorithm, CTPA was not indicated in 48% of our patients at baseline, but this would have been only 34% of patients using the traditional algorithm. This shows that the YEARS algorithm can safely exclude PE and resulted in an absolute reduction of required CTPA of 14%.”
“We expect that the YEARS algorithm can be easily implemented outside the participating study sites and that these safety and efficacy outcomes are representative of what could be expected in regular clinical settings.”