Therapeutic goals set the tone for the American College of Rheumatology National Research Agenda 2016-2020 by calling for the discovery and development of new therapies for rheumatic disease; finding predictors of response and nonresponse to, and adverse events from therapy; and improving the understanding of how therapies should be used.

Those are the top 3 out of 15 goals facilitated by the ACR’s Committee on Research, which finalized the agenda after seeking input from members of the ACR and Association of Rheumatology Health Professionals (ARHP) living in the United States, and going through several rounds of refining and prioritizing the importance of goals through the input of clinicians, researchers, patients, and stakeholders. The Committee on Research uses the agenda to “set the compass for the organization in terms of research initiatives and facilitate the ACR’s advocacy for the research goals identified.”

©Tashatuvango/Thinkstock

Dr. Alexis R. Ogdie-Beatty, who jointly led the development of the agenda for the Committee on Research along with Dr. S. Louis Bridges, said that while the goals for 2016-2020 had a great deal of overlap with those of 2011-2015, “some of the topics that came up were different. Some of the topics were more specific than in the previous agenda. We have some idea how important these issues were to rheumatologists, given that rheumatologists (and patients) rated the importance of the items. Defining new therapeutic targets and developing new therapies for rheumatic diseases was by far the most highly rated goal by rheumatologists. Next most highly rated was to advocate for increased support for rheumatology research and rheumatology investigators – this was included as a supplementary goal that supports the rest of the agenda. Other newer items were those around determining how the changing health care landscape affects rheumatology patients and clinicians. In addition, nonpharmacologic therapy, adult outcomes of pediatric disease, and optimizing patient engagement were topics that were felt to be important. I think these highlight the input of clinicians in identifying research objectives.”

The 2016-2020 agenda is the third set of goals developed by the committee since 2005, and the first to “crowdsource” the important questions to ACR and ARHP members rather than be assembled solely by the committee.

The agenda arose from a multistage process that began with a web-based survey to the ACR/ARHP membership that asked respondents to “list the five most important research questions that need to be addressed over the next 5 years in order to improve the care for patients with rheumatic disease.” A selected group of 100 individuals representing patients, clinicians (academic and community), research (all types with diverse areas/diseases of interest), allied health professionals, pediatric and adult rheumatology, men and women, all career stages, and all regions of the country, used a Delphi exercise to rate 30 statements generated from the survey on a scale from 1 (not important) to 10 (very important). They had the option to provide comments. At a Leadership Summit, stakeholders from various nonprofit foundations associated with rheumatic diseases, the National Institutes of Health, and the president of the Rheumatology Research Foundation gave comments on a draft agenda to the Committee on Research, after which the committee discussed the results and input and then solicited further 1-10 ratings and comments on preliminary agenda goals from the same group of 100 individuals as in the second phase, plus an additional 17 clinicians.

Up next in the rank-ordering after therapeutic goals were three goals about understanding:

• The etiology, pathogenesis, and genetic basis of rheumatic diseases.

• Early disease states to improve early diagnosis, develop biomarkers for early detection, and determine how earlier treatment changes outcomes.

• The immune system and autoimmunity by defining autoimmunity triggers and determining how epigenetics affect disease susceptibility and inflammation.

The 5-year plan proposed developing improved outcome measures that incorporate patient self-reports, imaging, and measures of clinical response and disease activity. The agenda also seeks to gain better understanding of how patients with rheumatic disease, rheumatologists, and rheumatology health professionals are being affected by the changing U.S. health care landscape.

The plan calls for determining the role of nonpharmacologic therapy in the management of rheumatic disease (promoting and improving adherence to physical activity, finding optimal exercise prescriptions, and determining the role of diet on disease activity), as well as evaluating the role of regenerative medicine.

The agenda spells out the need for better engagement of patients in their care as well as for understanding how comorbidities are influenced by rheumatic disease and how pain and fatigue arise in rheumatic disease.

In two separate goals, committee members listed the importance of determining adult outcomes of pediatric rheumatic diseases and the effect of aging on the development, progression, and management of rheumatic diseases.

The Committee on Research identified three supplemental goals that support the others:

• Advocating for increased support for rheumatology research and rheumatology investigators.

• Harmonizing data from existing cohorts and registries to optimize research capabilities.

• Improving patient research partner involvement in research protocols.

[email protected]

Therapeutic goals set the tone for the American College of Rheumatology National Research Agenda 2016-2020 by calling for the discovery and development of new therapies for rheumatic disease; finding predictors of response and nonresponse to, and adverse events from therapy; and improving the understanding of how therapies should be used.

Those are the top 3 out of 15 goals facilitated by the ACR’s Committee on Research, which finalized the agenda after seeking input from members of the ACR and Association of Rheumatology Health Professionals (ARHP) living in the United States, and going through several rounds of refining and prioritizing the importance of goals through the input of clinicians, researchers, patients, and stakeholders. The Committee on Research uses the agenda to “set the compass for the organization in terms of research initiatives and facilitate the ACR’s advocacy for the research goals identified.”

©Tashatuvango/Thinkstock

Dr. Alexis R. Ogdie-Beatty, who jointly led the development of the agenda for the Committee on Research along with Dr. S. Louis Bridges, said that while the goals for 2016-2020 had a great deal of overlap with those of 2011-2015, “some of the topics that came up were different. Some of the topics were more specific than in the previous agenda. We have some idea how important these issues were to rheumatologists, given that rheumatologists (and patients) rated the importance of the items. Defining new therapeutic targets and developing new therapies for rheumatic diseases was by far the most highly rated goal by rheumatologists. Next most highly rated was to advocate for increased support for rheumatology research and rheumatology investigators – this was included as a supplementary goal that supports the rest of the agenda. Other newer items were those around determining how the changing health care landscape affects rheumatology patients and clinicians. In addition, nonpharmacologic therapy, adult outcomes of pediatric disease, and optimizing patient engagement were topics that were felt to be important. I think these highlight the input of clinicians in identifying research objectives.”

The 2016-2020 agenda is the third set of goals developed by the committee since 2005, and the first to “crowdsource” the important questions to ACR and ARHP members rather than be assembled solely by the committee.

The agenda arose from a multistage process that began with a web-based survey to the ACR/ARHP membership that asked respondents to “list the five most important research questions that need to be addressed over the next 5 years in order to improve the care for patients with rheumatic disease.” A selected group of 100 individuals representing patients, clinicians (academic and community), research (all types with diverse areas/diseases of interest), allied health professionals, pediatric and adult rheumatology, men and women, all career stages, and all regions of the country, used a Delphi exercise to rate 30 statements generated from the survey on a scale from 1 (not important) to 10 (very important). They had the option to provide comments. At a Leadership Summit, stakeholders from various nonprofit foundations associated with rheumatic diseases, the National Institutes of Health, and the president of the Rheumatology Research Foundation gave comments on a draft agenda to the Committee on Research, after which the committee discussed the results and input and then solicited further 1-10 ratings and comments on preliminary agenda goals from the same group of 100 individuals as in the second phase, plus an additional 17 clinicians.

Up next in the rank-ordering after therapeutic goals were three goals about understanding:

• The etiology, pathogenesis, and genetic basis of rheumatic diseases.

• Early disease states to improve early diagnosis, develop biomarkers for early detection, and determine how earlier treatment changes outcomes.

• The immune system and autoimmunity by defining autoimmunity triggers and determining how epigenetics affect disease susceptibility and inflammation.

The 5-year plan proposed developing improved outcome measures that incorporate patient self-reports, imaging, and measures of clinical response and disease activity. The agenda also seeks to gain better understanding of how patients with rheumatic disease, rheumatologists, and rheumatology health professionals are being affected by the changing U.S. health care landscape.

The plan calls for determining the role of nonpharmacologic therapy in the management of rheumatic disease (promoting and improving adherence to physical activity, finding optimal exercise prescriptions, and determining the role of diet on disease activity), as well as evaluating the role of regenerative medicine.

The agenda spells out the need for better engagement of patients in their care as well as for understanding how comorbidities are influenced by rheumatic disease and how pain and fatigue arise in rheumatic disease.

In two separate goals, committee members listed the importance of determining adult outcomes of pediatric rheumatic diseases and the effect of aging on the development, progression, and management of rheumatic diseases.

The Committee on Research identified three supplemental goals that support the others:

• Advocating for increased support for rheumatology research and rheumatology investigators.

• Harmonizing data from existing cohorts and registries to optimize research capabilities.

• Improving patient research partner involvement in research protocols.

[email protected]

Therapeutic goals set the tone for the American College of Rheumatology National Research Agenda 2016-2020 by calling for the discovery and development of new therapies for rheumatic disease; finding predictors of response and nonresponse to, and adverse events from therapy; and improving the understanding of how therapies should be used.

Those are the top 3 out of 15 goals facilitated by the ACR’s Committee on Research, which finalized the agenda after seeking input from members of the ACR and Association of Rheumatology Health Professionals (ARHP) living in the United States, and going through several rounds of refining and prioritizing the importance of goals through the input of clinicians, researchers, patients, and stakeholders. The Committee on Research uses the agenda to “set the compass for the organization in terms of research initiatives and facilitate the ACR’s advocacy for the research goals identified.”

©Tashatuvango/Thinkstock

Dr. Alexis R. Ogdie-Beatty, who jointly led the development of the agenda for the Committee on Research along with Dr. S. Louis Bridges, said that while the goals for 2016-2020 had a great deal of overlap with those of 2011-2015, “some of the topics that came up were different. Some of the topics were more specific than in the previous agenda. We have some idea how important these issues were to rheumatologists, given that rheumatologists (and patients) rated the importance of the items. Defining new therapeutic targets and developing new therapies for rheumatic diseases was by far the most highly rated goal by rheumatologists. Next most highly rated was to advocate for increased support for rheumatology research and rheumatology investigators – this was included as a supplementary goal that supports the rest of the agenda. Other newer items were those around determining how the changing health care landscape affects rheumatology patients and clinicians. In addition, nonpharmacologic therapy, adult outcomes of pediatric disease, and optimizing patient engagement were topics that were felt to be important. I think these highlight the input of clinicians in identifying research objectives.”

The 2016-2020 agenda is the third set of goals developed by the committee since 2005, and the first to “crowdsource” the important questions to ACR and ARHP members rather than be assembled solely by the committee.

The agenda arose from a multistage process that began with a web-based survey to the ACR/ARHP membership that asked respondents to “list the five most important research questions that need to be addressed over the next 5 years in order to improve the care for patients with rheumatic disease.” A selected group of 100 individuals representing patients, clinicians (academic and community), research (all types with diverse areas/diseases of interest), allied health professionals, pediatric and adult rheumatology, men and women, all career stages, and all regions of the country, used a Delphi exercise to rate 30 statements generated from the survey on a scale from 1 (not important) to 10 (very important). They had the option to provide comments. At a Leadership Summit, stakeholders from various nonprofit foundations associated with rheumatic diseases, the National Institutes of Health, and the president of the Rheumatology Research Foundation gave comments on a draft agenda to the Committee on Research, after which the committee discussed the results and input and then solicited further 1-10 ratings and comments on preliminary agenda goals from the same group of 100 individuals as in the second phase, plus an additional 17 clinicians.

Up next in the rank-ordering after therapeutic goals were three goals about understanding:

• The etiology, pathogenesis, and genetic basis of rheumatic diseases.

• Early disease states to improve early diagnosis, develop biomarkers for early detection, and determine how earlier treatment changes outcomes.

• The immune system and autoimmunity by defining autoimmunity triggers and determining how epigenetics affect disease susceptibility and inflammation.

The 5-year plan proposed developing improved outcome measures that incorporate patient self-reports, imaging, and measures of clinical response and disease activity. The agenda also seeks to gain better understanding of how patients with rheumatic disease, rheumatologists, and rheumatology health professionals are being affected by the changing U.S. health care landscape.

The plan calls for determining the role of nonpharmacologic therapy in the management of rheumatic disease (promoting and improving adherence to physical activity, finding optimal exercise prescriptions, and determining the role of diet on disease activity), as well as evaluating the role of regenerative medicine.

The agenda spells out the need for better engagement of patients in their care as well as for understanding how comorbidities are influenced by rheumatic disease and how pain and fatigue arise in rheumatic disease.

In two separate goals, committee members listed the importance of determining adult outcomes of pediatric rheumatic diseases and the effect of aging on the development, progression, and management of rheumatic diseases.

The Committee on Research identified three supplemental goals that support the others:

• Advocating for increased support for rheumatology research and rheumatology investigators.

• Harmonizing data from existing cohorts and registries to optimize research capabilities.

• Improving patient research partner involvement in research protocols.

[email protected]

Pediatric patients with systemic lupus erythematosus may have greater odds for developing thrombosis if they have a history of vasculitis, antiphospholipid antibody positivity (aPL), and/or avascular necrosis (AVN), according to Dr. Kyla Driest and her associates.

Among 974 pediatric systemic lupus erythematosus (pSLE) patients in the CARRA (Childhood Arthritis & Rheumatology Research Alliance) registry cohort who had available data on thrombosis history, 24 (2.5%) had a history of arterial thrombosis and 35 (3.6%) had a history of venous thrombosis. The researchers conducted a multivariable analysis that found statistically higher odds of thrombosis (P less than .10) among patients with histories of AVN (odds ratio, 4.24; 95% confidence interval, 1.53-11.74), aPL (OR, 2.95; 95% CI, 1.38-6.28), and vasculitis (OR, 2.19; 95% CI, 1.03-4.77), whereas significantly lower odds occurred in patients with a history of renal disease (OR, 0.47; 95% CI, 0.24-0.92). Gender and body-mass index were not statistically significant.

“This study adds to our understanding of which pSLE patients are at the most risk for thrombosis,” the researchers concluded. “These results may prompt discussion concerning potential measures to prevent thrombosis in high-risk patients.”

Find the full study in Lupus (doi: 10.1177/0961203316638164).

[email protected]

Pediatric patients with systemic lupus erythematosus may have greater odds for developing thrombosis if they have a history of vasculitis, antiphospholipid antibody positivity (aPL), and/or avascular necrosis (AVN), according to Dr. Kyla Driest and her associates.

Among 974 pediatric systemic lupus erythematosus (pSLE) patients in the CARRA (Childhood Arthritis & Rheumatology Research Alliance) registry cohort who had available data on thrombosis history, 24 (2.5%) had a history of arterial thrombosis and 35 (3.6%) had a history of venous thrombosis. The researchers conducted a multivariable analysis that found statistically higher odds of thrombosis (P less than .10) among patients with histories of AVN (odds ratio, 4.24; 95% confidence interval, 1.53-11.74), aPL (OR, 2.95; 95% CI, 1.38-6.28), and vasculitis (OR, 2.19; 95% CI, 1.03-4.77), whereas significantly lower odds occurred in patients with a history of renal disease (OR, 0.47; 95% CI, 0.24-0.92). Gender and body-mass index were not statistically significant.

“This study adds to our understanding of which pSLE patients are at the most risk for thrombosis,” the researchers concluded. “These results may prompt discussion concerning potential measures to prevent thrombosis in high-risk patients.”

Find the full study in Lupus (doi: 10.1177/0961203316638164).

[email protected]

Pediatric patients with systemic lupus erythematosus may have greater odds for developing thrombosis if they have a history of vasculitis, antiphospholipid antibody positivity (aPL), and/or avascular necrosis (AVN), according to Dr. Kyla Driest and her associates.

Among 974 pediatric systemic lupus erythematosus (pSLE) patients in the CARRA (Childhood Arthritis & Rheumatology Research Alliance) registry cohort who had available data on thrombosis history, 24 (2.5%) had a history of arterial thrombosis and 35 (3.6%) had a history of venous thrombosis. The researchers conducted a multivariable analysis that found statistically higher odds of thrombosis (P less than .10) among patients with histories of AVN (odds ratio, 4.24; 95% confidence interval, 1.53-11.74), aPL (OR, 2.95; 95% CI, 1.38-6.28), and vasculitis (OR, 2.19; 95% CI, 1.03-4.77), whereas significantly lower odds occurred in patients with a history of renal disease (OR, 0.47; 95% CI, 0.24-0.92). Gender and body-mass index were not statistically significant.

“This study adds to our understanding of which pSLE patients are at the most risk for thrombosis,” the researchers concluded. “These results may prompt discussion concerning potential measures to prevent thrombosis in high-risk patients.”

Find the full study in Lupus (doi: 10.1177/0961203316638164).

[email protected]

Clinical question: In cardiopulmonary resuscitation, do continuous chest compressions improve survival or neurologic outcome compared to chest compressions interrupted for ventilation?

Background: Animal models have demonstrated that interruptions in chest compressions are associated with decreased survival and worse neurologic outcome in cardiac arrests. Observational studies in humans have suggested that for out-of-hospital cardiac arrests, continuous compressions result in improved survival.

Study Design: Unblinded, randomized, cluster design with crossover.

Setting: One hundred fourteen emergency medical service (EMS) agencies across eight clinical sites in North America.

Synopsis: Patients with out-of-hospital cardiac arrest received either continuous chest compressions with asynchronous positive-pressure ventilations or interrupted compressions at a rate of 30 compressions to two ventilations. EMS agencies were divided into clusters and randomly assigned to deliver either resuscitation strategy. Twice per year, each cluster switched treatment strategies.

During the active enrollment phase, 12,653 patients were enrolled in the intervention arm and 11,058 were enrolled in the control arm. The primary outcome of survival to hospital discharge was comparable between the two groups, with 9.0% survival rate in the intervention group as compared to 9.7% in the control group (P=0.07). The secondary outcome of survivorship with favorable neurologic status was similar at 7.0% in the intervention group and 7.7% in the control group.

There was only a small difference in the proportion of minutes devoted to compressions between the two groups, so the similarity in outcomes may be reflective of high-quality chest compressions. Additional limitations include a lack of standardization of post-resuscitation care and a lack of measurement of oxygen or ventilation delivered.

Bottom line: For out-of-hospital cardiac arrests, continuous chest compressions with positive-pressure ventilation did not increase survival or improve neurologic outcome compared to interrupted chest compressions.

Citation: Nichol G, Lerou B, Wang H, et al. Trial of continuous or interrupted chest compressions during CPR. N Engl J Med. 2015;373(23):2203-2214.

Clinical question: In cardiopulmonary resuscitation, do continuous chest compressions improve survival or neurologic outcome compared to chest compressions interrupted for ventilation?

Background: Animal models have demonstrated that interruptions in chest compressions are associated with decreased survival and worse neurologic outcome in cardiac arrests. Observational studies in humans have suggested that for out-of-hospital cardiac arrests, continuous compressions result in improved survival.

Study Design: Unblinded, randomized, cluster design with crossover.

Setting: One hundred fourteen emergency medical service (EMS) agencies across eight clinical sites in North America.

Synopsis: Patients with out-of-hospital cardiac arrest received either continuous chest compressions with asynchronous positive-pressure ventilations or interrupted compressions at a rate of 30 compressions to two ventilations. EMS agencies were divided into clusters and randomly assigned to deliver either resuscitation strategy. Twice per year, each cluster switched treatment strategies.

During the active enrollment phase, 12,653 patients were enrolled in the intervention arm and 11,058 were enrolled in the control arm. The primary outcome of survival to hospital discharge was comparable between the two groups, with 9.0% survival rate in the intervention group as compared to 9.7% in the control group (P=0.07). The secondary outcome of survivorship with favorable neurologic status was similar at 7.0% in the intervention group and 7.7% in the control group.

There was only a small difference in the proportion of minutes devoted to compressions between the two groups, so the similarity in outcomes may be reflective of high-quality chest compressions. Additional limitations include a lack of standardization of post-resuscitation care and a lack of measurement of oxygen or ventilation delivered.

Bottom line: For out-of-hospital cardiac arrests, continuous chest compressions with positive-pressure ventilation did not increase survival or improve neurologic outcome compared to interrupted chest compressions.

Citation: Nichol G, Lerou B, Wang H, et al. Trial of continuous or interrupted chest compressions during CPR. N Engl J Med. 2015;373(23):2203-2214.

Clinical question: In cardiopulmonary resuscitation, do continuous chest compressions improve survival or neurologic outcome compared to chest compressions interrupted for ventilation?

Background: Animal models have demonstrated that interruptions in chest compressions are associated with decreased survival and worse neurologic outcome in cardiac arrests. Observational studies in humans have suggested that for out-of-hospital cardiac arrests, continuous compressions result in improved survival.

Study Design: Unblinded, randomized, cluster design with crossover.

Setting: One hundred fourteen emergency medical service (EMS) agencies across eight clinical sites in North America.

Synopsis: Patients with out-of-hospital cardiac arrest received either continuous chest compressions with asynchronous positive-pressure ventilations or interrupted compressions at a rate of 30 compressions to two ventilations. EMS agencies were divided into clusters and randomly assigned to deliver either resuscitation strategy. Twice per year, each cluster switched treatment strategies.

During the active enrollment phase, 12,653 patients were enrolled in the intervention arm and 11,058 were enrolled in the control arm. The primary outcome of survival to hospital discharge was comparable between the two groups, with 9.0% survival rate in the intervention group as compared to 9.7% in the control group (P=0.07). The secondary outcome of survivorship with favorable neurologic status was similar at 7.0% in the intervention group and 7.7% in the control group.

There was only a small difference in the proportion of minutes devoted to compressions between the two groups, so the similarity in outcomes may be reflective of high-quality chest compressions. Additional limitations include a lack of standardization of post-resuscitation care and a lack of measurement of oxygen or ventilation delivered.

Bottom line: For out-of-hospital cardiac arrests, continuous chest compressions with positive-pressure ventilation did not increase survival or improve neurologic outcome compared to interrupted chest compressions.

Citation: Nichol G, Lerou B, Wang H, et al. Trial of continuous or interrupted chest compressions during CPR. N Engl J Med. 2015;373(23):2203-2214.

Clinical question: Does the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score more accurately identify patients with atrial fibrillation (Afib) who are at low risk for ischemic stroke than the CHADS2 or CHA2DS2-VASc score?

Background: More accurate and reliable stroke risk prediction tools are needed to optimize anticoagulation decision making in patients with Afib. Recently, a new clinically based risk score, the ATRIA, has been developed and validated. This risk score assigns points based on four age categories (as well as an interaction of age and prior stroke); female gender; renal function; and history of diabetes, congestive heart failure, and hypertension. This study compared the predictive ability of the ATRIA risk score with the CHADS2 and CHA2DS2-VASc risk scores and their implications for anticoagulant treatment in Afib patients.

Study Design: Retrospective cohort study.

Setting: Afib patients not using warfarin from the United Kingdom’s Clinical Practice Research Datalink (CPRD) database, January 1998 to January 2012.

Synopsis: A total of 60,594 patients with Afib were followed until occurrence of ischemic stroke, prescription of warfarin, death, or the study’s end. The annualized stroke rate was 2.99%. Patients with moderate and high-risk CHA2DS2-VASc scores had lower event rates than those with corresponding ATRIA and CHADS2 scores. C-statistics for full point scores were 0.70 (95% CI, 0.69–0.71) for ATRIA and 0.68 (95% CI, 0.67–0.69) for both CHADS2 and CHA2DS2-VASc scores. The net reclassification index of ATRIA compared with CHADS2 and CHA2DS2-VASc risk scores were 0.137 and 0.233, respectively, reflecting that the ATRIA risk score better categorizes patients developing an event.

ATRIA risk score more accurately identified low-risk patients than the CHA2DS2-VASc score assigned to higher-risk categories. The results persisted even after restricting analysis to more recent follow-up, excluding unspecified strokes and excluding renal dysfunction as a predictor. Most improvements with ATRIA were the result of “down classification,” suggesting that using the CHA2DS2-VASc risk score could lead to overtreatment of patients at very low risk of stroke.

Bottom line: The ATRIA risk score better identifies Afib patients who are at low risk for stroke compared to CHADS2 and CHA2DS2-VASc scores.

Citation: van den Ham HA, Klungel OH, Singer DE, Leufkens HG, van Staa TP. Comparative performance of ATRIA, CHADS2, and CHA2DS2-VASc risk scores predicting stroke in patients with atrial fibrillation: results from a national primary care database. J Am Coll Cardiol. 2015;66(17):1851-1959.

Clinical question: Does the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score more accurately identify patients with atrial fibrillation (Afib) who are at low risk for ischemic stroke than the CHADS2 or CHA2DS2-VASc score?

Background: More accurate and reliable stroke risk prediction tools are needed to optimize anticoagulation decision making in patients with Afib. Recently, a new clinically based risk score, the ATRIA, has been developed and validated. This risk score assigns points based on four age categories (as well as an interaction of age and prior stroke); female gender; renal function; and history of diabetes, congestive heart failure, and hypertension. This study compared the predictive ability of the ATRIA risk score with the CHADS2 and CHA2DS2-VASc risk scores and their implications for anticoagulant treatment in Afib patients.

Study Design: Retrospective cohort study.

Setting: Afib patients not using warfarin from the United Kingdom’s Clinical Practice Research Datalink (CPRD) database, January 1998 to January 2012.

Synopsis: A total of 60,594 patients with Afib were followed until occurrence of ischemic stroke, prescription of warfarin, death, or the study’s end. The annualized stroke rate was 2.99%. Patients with moderate and high-risk CHA2DS2-VASc scores had lower event rates than those with corresponding ATRIA and CHADS2 scores. C-statistics for full point scores were 0.70 (95% CI, 0.69–0.71) for ATRIA and 0.68 (95% CI, 0.67–0.69) for both CHADS2 and CHA2DS2-VASc scores. The net reclassification index of ATRIA compared with CHADS2 and CHA2DS2-VASc risk scores were 0.137 and 0.233, respectively, reflecting that the ATRIA risk score better categorizes patients developing an event.

ATRIA risk score more accurately identified low-risk patients than the CHA2DS2-VASc score assigned to higher-risk categories. The results persisted even after restricting analysis to more recent follow-up, excluding unspecified strokes and excluding renal dysfunction as a predictor. Most improvements with ATRIA were the result of “down classification,” suggesting that using the CHA2DS2-VASc risk score could lead to overtreatment of patients at very low risk of stroke.

Bottom line: The ATRIA risk score better identifies Afib patients who are at low risk for stroke compared to CHADS2 and CHA2DS2-VASc scores.

Citation: van den Ham HA, Klungel OH, Singer DE, Leufkens HG, van Staa TP. Comparative performance of ATRIA, CHADS2, and CHA2DS2-VASc risk scores predicting stroke in patients with atrial fibrillation: results from a national primary care database. J Am Coll Cardiol. 2015;66(17):1851-1959.

Clinical question: Does the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score more accurately identify patients with atrial fibrillation (Afib) who are at low risk for ischemic stroke than the CHADS2 or CHA2DS2-VASc score?

Background: More accurate and reliable stroke risk prediction tools are needed to optimize anticoagulation decision making in patients with Afib. Recently, a new clinically based risk score, the ATRIA, has been developed and validated. This risk score assigns points based on four age categories (as well as an interaction of age and prior stroke); female gender; renal function; and history of diabetes, congestive heart failure, and hypertension. This study compared the predictive ability of the ATRIA risk score with the CHADS2 and CHA2DS2-VASc risk scores and their implications for anticoagulant treatment in Afib patients.

Study Design: Retrospective cohort study.

Setting: Afib patients not using warfarin from the United Kingdom’s Clinical Practice Research Datalink (CPRD) database, January 1998 to January 2012.

Synopsis: A total of 60,594 patients with Afib were followed until occurrence of ischemic stroke, prescription of warfarin, death, or the study’s end. The annualized stroke rate was 2.99%. Patients with moderate and high-risk CHA2DS2-VASc scores had lower event rates than those with corresponding ATRIA and CHADS2 scores. C-statistics for full point scores were 0.70 (95% CI, 0.69–0.71) for ATRIA and 0.68 (95% CI, 0.67–0.69) for both CHADS2 and CHA2DS2-VASc scores. The net reclassification index of ATRIA compared with CHADS2 and CHA2DS2-VASc risk scores were 0.137 and 0.233, respectively, reflecting that the ATRIA risk score better categorizes patients developing an event.

ATRIA risk score more accurately identified low-risk patients than the CHA2DS2-VASc score assigned to higher-risk categories. The results persisted even after restricting analysis to more recent follow-up, excluding unspecified strokes and excluding renal dysfunction as a predictor. Most improvements with ATRIA were the result of “down classification,” suggesting that using the CHA2DS2-VASc risk score could lead to overtreatment of patients at very low risk of stroke.

Bottom line: The ATRIA risk score better identifies Afib patients who are at low risk for stroke compared to CHADS2 and CHA2DS2-VASc scores.

Citation: van den Ham HA, Klungel OH, Singer DE, Leufkens HG, van Staa TP. Comparative performance of ATRIA, CHADS2, and CHA2DS2-VASc risk scores predicting stroke in patients with atrial fibrillation: results from a national primary care database. J Am Coll Cardiol. 2015;66(17):1851-1959.

Micrograph showing MDS

Results of a phase 3 trial suggest the small-molecule inhibitor rigosertib may improve overall survival (OS) in some patients with higher-risk myelodysplastic syndromes (HR-MDS).

Overall, researchers found no significant difference in OS between patients who received rigosertib and those who received best supportive care (BSC).

However, the data indicate that rigosertib can confer a survival benefit in certain subgroups of HR-MDS patients.

The results of this trial, known as ONTIME, were published in The Lancet Oncology. The trial was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

The trial enrolled 299 HR-MDS patients. They had refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia based on local site assessment. They had all failed treatment with a hypomethylating agent (HMA) in the past 2 years.

The patients were randomized (2:1) to receive rigosertib at 1800 mg per 24 hours via 72-hour continuous intravenous (IV) infusion, administered every other week (n=199), or BSC with or without low-dose cytarabine (n=100).

At a median follow-up of 19.5 months, there was no significant difference in OS between the treatment arms. The median OS was 8.2 months in the rigosertib arm and 5.9 months in the BSC arm. The hazard ratio (HR) was 0.87 (P=0.33).

However, the researchers said that subgroup analyses suggested rigosertib may provide a survival benefit over BSC in some HR-MDS patients. This includes:

• Patients younger than 75 years of age (HR=0.55, P=0.0010)
• Patients who received HMA therapy for 9 months or fewer (HR=0.54, P=0.0016)
• Patients with primary, rather than secondary, HMA failure (HR=0.72, P=0.060)
• Patients who were classified as “very high risk” according to the Revised International Prognostic Scoring System (HR=0.61, P=0.015)
• Patients with monosomy 7 (HR=0.26, P=0.0041)
• Patients with trisomy 8 (HR=0.28, P=0.0083).

The most common grade 3 or higher adverse events—in the rigosertib and BSC arms, respectively—were anemia (18% vs 8%), thrombocytopenia (19% vs 7%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%).

Twenty-two percent of patients in the rigosertib arm and 33% in the BSC arm died due to adverse events. Three deaths were attributed to rigosertib.

“Rigosertib was well-tolerated in patients with a high unmet medical need who have no approved therapeutic options,” said study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients.”

INSPIRE is a randomized, controlled study designed to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months of HMA treatment initiation.

The trial is expected to enroll approximately 225 patients, who will be randomized at a 2:1 ratio into 2 treatment arms: IV rigosertib plus BSC versus physician’s choice plus BSC. The primary endpoint is OS. Full details on the trial can be found on clinicaltrials.gov (NCT02562443).

Micrograph showing MDS

Results of a phase 3 trial suggest the small-molecule inhibitor rigosertib may improve overall survival (OS) in some patients with higher-risk myelodysplastic syndromes (HR-MDS).

Overall, researchers found no significant difference in OS between patients who received rigosertib and those who received best supportive care (BSC).

However, the data indicate that rigosertib can confer a survival benefit in certain subgroups of HR-MDS patients.

The results of this trial, known as ONTIME, were published in The Lancet Oncology. The trial was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

The trial enrolled 299 HR-MDS patients. They had refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia based on local site assessment. They had all failed treatment with a hypomethylating agent (HMA) in the past 2 years.

The patients were randomized (2:1) to receive rigosertib at 1800 mg per 24 hours via 72-hour continuous intravenous (IV) infusion, administered every other week (n=199), or BSC with or without low-dose cytarabine (n=100).

At a median follow-up of 19.5 months, there was no significant difference in OS between the treatment arms. The median OS was 8.2 months in the rigosertib arm and 5.9 months in the BSC arm. The hazard ratio (HR) was 0.87 (P=0.33).

However, the researchers said that subgroup analyses suggested rigosertib may provide a survival benefit over BSC in some HR-MDS patients. This includes:

• Patients younger than 75 years of age (HR=0.55, P=0.0010)
• Patients who received HMA therapy for 9 months or fewer (HR=0.54, P=0.0016)
• Patients with primary, rather than secondary, HMA failure (HR=0.72, P=0.060)
• Patients who were classified as “very high risk” according to the Revised International Prognostic Scoring System (HR=0.61, P=0.015)
• Patients with monosomy 7 (HR=0.26, P=0.0041)
• Patients with trisomy 8 (HR=0.28, P=0.0083).

The most common grade 3 or higher adverse events—in the rigosertib and BSC arms, respectively—were anemia (18% vs 8%), thrombocytopenia (19% vs 7%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%).

Twenty-two percent of patients in the rigosertib arm and 33% in the BSC arm died due to adverse events. Three deaths were attributed to rigosertib.

“Rigosertib was well-tolerated in patients with a high unmet medical need who have no approved therapeutic options,” said study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients.”

INSPIRE is a randomized, controlled study designed to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months of HMA treatment initiation.

The trial is expected to enroll approximately 225 patients, who will be randomized at a 2:1 ratio into 2 treatment arms: IV rigosertib plus BSC versus physician’s choice plus BSC. The primary endpoint is OS. Full details on the trial can be found on clinicaltrials.gov (NCT02562443).

Micrograph showing MDS

Results of a phase 3 trial suggest the small-molecule inhibitor rigosertib may improve overall survival (OS) in some patients with higher-risk myelodysplastic syndromes (HR-MDS).

Overall, researchers found no significant difference in OS between patients who received rigosertib and those who received best supportive care (BSC).

However, the data indicate that rigosertib can confer a survival benefit in certain subgroups of HR-MDS patients.

The results of this trial, known as ONTIME, were published in The Lancet Oncology. The trial was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

The trial enrolled 299 HR-MDS patients. They had refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia based on local site assessment. They had all failed treatment with a hypomethylating agent (HMA) in the past 2 years.

The patients were randomized (2:1) to receive rigosertib at 1800 mg per 24 hours via 72-hour continuous intravenous (IV) infusion, administered every other week (n=199), or BSC with or without low-dose cytarabine (n=100).

At a median follow-up of 19.5 months, there was no significant difference in OS between the treatment arms. The median OS was 8.2 months in the rigosertib arm and 5.9 months in the BSC arm. The hazard ratio (HR) was 0.87 (P=0.33).

However, the researchers said that subgroup analyses suggested rigosertib may provide a survival benefit over BSC in some HR-MDS patients. This includes:

• Patients younger than 75 years of age (HR=0.55, P=0.0010)
• Patients who received HMA therapy for 9 months or fewer (HR=0.54, P=0.0016)
• Patients with primary, rather than secondary, HMA failure (HR=0.72, P=0.060)
• Patients who were classified as “very high risk” according to the Revised International Prognostic Scoring System (HR=0.61, P=0.015)
• Patients with monosomy 7 (HR=0.26, P=0.0041)
• Patients with trisomy 8 (HR=0.28, P=0.0083).

The most common grade 3 or higher adverse events—in the rigosertib and BSC arms, respectively—were anemia (18% vs 8%), thrombocytopenia (19% vs 7%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%).

Twenty-two percent of patients in the rigosertib arm and 33% in the BSC arm died due to adverse events. Three deaths were attributed to rigosertib.

“Rigosertib was well-tolerated in patients with a high unmet medical need who have no approved therapeutic options,” said study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients.”

INSPIRE is a randomized, controlled study designed to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months of HMA treatment initiation.

The trial is expected to enroll approximately 225 patients, who will be randomized at a 2:1 ratio into 2 treatment arms: IV rigosertib plus BSC versus physician’s choice plus BSC. The primary endpoint is OS. Full details on the trial can be found on clinicaltrials.gov (NCT02562443).

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the recombinant antihemophilic factor Kovaltry for the treatment of adults and children with hemophilia A.

Kovaltry is an unmodified, full-length factor VIII compound indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes.

Dosing of Kovaltry should be individualized based on each patient’s clinical response.

The recommended dosing for adults and adolescents is 20 to 40 IU per kg of body weight 2 or 3 times per week. The recommended dosing for children age 12 and younger is 25 to 50 IU per kg of body weight twice weekly, 3 times weekly, or every other day, according to individual requirements.

For more details, see the full prescribing information.

The FDA’s approval of Kovaltry is based on results from the LEOPOLD trials—3 multinational trials of patients with severe hemophilia A. The trials were supported by Bayer HealthCare AG, the company developing Kovaltry.

LEOPOLD I

LEOPOLD I is an open-label, cross-over, phase 3 study of males, ages 12 to 65, with severe hemophilia A. Sixty-two patients were assigned to either 2- or 3-times-weekly dosing with Kovaltry, based on each patient’s phenotype, prior bleeding history, and other factors.

The median annualized bleeding rate (ABR) was 1.0 for all the patients who received Kovaltry prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD II

LEOPOLD II is a randomized, cross-over, open-label trial conducted in males ages 12 to 65. In this phase 3 study, 80 subjects were randomized to receive Kovaltry as a low-dose prophylaxis regimen (n=28) twice per week, high-dose prophylaxis (n=31) 3 times a week, or on-demand treatment (n=21).

The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD Kids

LEOPOLD Kids is an open-label, non-randomized, phase 3 study designed to evaluate Kovaltry in children age 12 and younger. The study is divided into 2 parts. Part A enrolled only previously treated children, and part B, which is ongoing, includes only untreated children.

For part A, 51 children received Kovaltry twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days. The median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.

Safety results

For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with at least a reasonable suspected causal relationship to Kovaltry.

The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.

The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).

None of the patients developed factor VIII inhibitors.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the recombinant antihemophilic factor Kovaltry for the treatment of adults and children with hemophilia A.

Kovaltry is an unmodified, full-length factor VIII compound indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes.

Dosing of Kovaltry should be individualized based on each patient’s clinical response.

The recommended dosing for adults and adolescents is 20 to 40 IU per kg of body weight 2 or 3 times per week. The recommended dosing for children age 12 and younger is 25 to 50 IU per kg of body weight twice weekly, 3 times weekly, or every other day, according to individual requirements.

For more details, see the full prescribing information.

The FDA’s approval of Kovaltry is based on results from the LEOPOLD trials—3 multinational trials of patients with severe hemophilia A. The trials were supported by Bayer HealthCare AG, the company developing Kovaltry.

LEOPOLD I

LEOPOLD I is an open-label, cross-over, phase 3 study of males, ages 12 to 65, with severe hemophilia A. Sixty-two patients were assigned to either 2- or 3-times-weekly dosing with Kovaltry, based on each patient’s phenotype, prior bleeding history, and other factors.

The median annualized bleeding rate (ABR) was 1.0 for all the patients who received Kovaltry prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD II

LEOPOLD II is a randomized, cross-over, open-label trial conducted in males ages 12 to 65. In this phase 3 study, 80 subjects were randomized to receive Kovaltry as a low-dose prophylaxis regimen (n=28) twice per week, high-dose prophylaxis (n=31) 3 times a week, or on-demand treatment (n=21).

The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD Kids

LEOPOLD Kids is an open-label, non-randomized, phase 3 study designed to evaluate Kovaltry in children age 12 and younger. The study is divided into 2 parts. Part A enrolled only previously treated children, and part B, which is ongoing, includes only untreated children.

For part A, 51 children received Kovaltry twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days. The median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.

Safety results

For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with at least a reasonable suspected causal relationship to Kovaltry.

The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.

The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).

None of the patients developed factor VIII inhibitors.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the recombinant antihemophilic factor Kovaltry for the treatment of adults and children with hemophilia A.

Kovaltry is an unmodified, full-length factor VIII compound indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes.

Dosing of Kovaltry should be individualized based on each patient’s clinical response.

The recommended dosing for adults and adolescents is 20 to 40 IU per kg of body weight 2 or 3 times per week. The recommended dosing for children age 12 and younger is 25 to 50 IU per kg of body weight twice weekly, 3 times weekly, or every other day, according to individual requirements.

For more details, see the full prescribing information.

The FDA’s approval of Kovaltry is based on results from the LEOPOLD trials—3 multinational trials of patients with severe hemophilia A. The trials were supported by Bayer HealthCare AG, the company developing Kovaltry.

LEOPOLD I

LEOPOLD I is an open-label, cross-over, phase 3 study of males, ages 12 to 65, with severe hemophilia A. Sixty-two patients were assigned to either 2- or 3-times-weekly dosing with Kovaltry, based on each patient’s phenotype, prior bleeding history, and other factors.

The median annualized bleeding rate (ABR) was 1.0 for all the patients who received Kovaltry prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD II

LEOPOLD II is a randomized, cross-over, open-label trial conducted in males ages 12 to 65. In this phase 3 study, 80 subjects were randomized to receive Kovaltry as a low-dose prophylaxis regimen (n=28) twice per week, high-dose prophylaxis (n=31) 3 times a week, or on-demand treatment (n=21).

The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD Kids

LEOPOLD Kids is an open-label, non-randomized, phase 3 study designed to evaluate Kovaltry in children age 12 and younger. The study is divided into 2 parts. Part A enrolled only previously treated children, and part B, which is ongoing, includes only untreated children.

For part A, 51 children received Kovaltry twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days. The median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.

Safety results

For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with at least a reasonable suspected causal relationship to Kovaltry.

The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.

The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).

None of the patients developed factor VIII inhibitors.

Lab mouse

Preclinical research indicates that a novel inhibitor can overcome resistance-conferring FLT3 mutations in acute myeloid leukemia (AML).

The MERTK/FLT3 inhibitor MRX-2843 induced apoptosis and inhibited colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD.

MRX-2843 also improved survival in mouse models of AML, including cases where tumors were resistant to the FLT3 inhibitor quizartinib.

Douglas Graham, MD, PhD, of the University of Colorado in Aurora, and his colleagues conducted this research and reported the results in JCI Insight.

The researchers previously showed that the receptor tyrosine kinase MERTK is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis.

With the current study, they showed that MRX-2843 abrogates activation of MERTK, FLT3, and their downstream effectors. And this translates to antileukemic activity in vitro and in vivo.

MRX-2843 inhibited MERTK signaling, induced cell death, and abolished oncogenic phenotypes in AML cells. The drug also exhibited therapeutic activity in a MERTK-dependent xenograft model.

MRX-2843 was able to stop the activation of FLT3 and its signaling pathways almost completely. The researchers said this suggests the drug has somewhat higher cellular potency against FLT3 relative to MERTK.

In mouse models of FLT3-ITD AML, MRX-2843 significantly prolonged survival when compared to vehicle control.

The researchers also said MRX-2843 selectively inhibited colony formation in primary AML patient samples. Primary human MERTK-expressing leukemic blasts, with or without FLT3-ITD mutations, proved sensitive to treatment with MRX-2843.

In addition, MRX-2843 increased survival and decreased peripheral disease burden in patient-derived xenograft models of AML—both MERTK⁺FLT3-WT and MERTK⁺FLT3-ITD models.

Finally, the researchers found that MRX-2843 was active against quizartinib-resistant FLT3-mutant proteins, induced apoptosis and inhibited colony formation in quizartinib-resistant FLT3-ITD cell lines, and prolonged survival in quizartinib-resistant FLT3-ITD xenograft models.

Lab mouse

Preclinical research indicates that a novel inhibitor can overcome resistance-conferring FLT3 mutations in acute myeloid leukemia (AML).

The MERTK/FLT3 inhibitor MRX-2843 induced apoptosis and inhibited colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD.

MRX-2843 also improved survival in mouse models of AML, including cases where tumors were resistant to the FLT3 inhibitor quizartinib.

Douglas Graham, MD, PhD, of the University of Colorado in Aurora, and his colleagues conducted this research and reported the results in JCI Insight.

The researchers previously showed that the receptor tyrosine kinase MERTK is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis.

With the current study, they showed that MRX-2843 abrogates activation of MERTK, FLT3, and their downstream effectors. And this translates to antileukemic activity in vitro and in vivo.

MRX-2843 inhibited MERTK signaling, induced cell death, and abolished oncogenic phenotypes in AML cells. The drug also exhibited therapeutic activity in a MERTK-dependent xenograft model.

MRX-2843 was able to stop the activation of FLT3 and its signaling pathways almost completely. The researchers said this suggests the drug has somewhat higher cellular potency against FLT3 relative to MERTK.

In mouse models of FLT3-ITD AML, MRX-2843 significantly prolonged survival when compared to vehicle control.

The researchers also said MRX-2843 selectively inhibited colony formation in primary AML patient samples. Primary human MERTK-expressing leukemic blasts, with or without FLT3-ITD mutations, proved sensitive to treatment with MRX-2843.

In addition, MRX-2843 increased survival and decreased peripheral disease burden in patient-derived xenograft models of AML—both MERTK⁺FLT3-WT and MERTK⁺FLT3-ITD models.

Finally, the researchers found that MRX-2843 was active against quizartinib-resistant FLT3-mutant proteins, induced apoptosis and inhibited colony formation in quizartinib-resistant FLT3-ITD cell lines, and prolonged survival in quizartinib-resistant FLT3-ITD xenograft models.

Lab mouse

Preclinical research indicates that a novel inhibitor can overcome resistance-conferring FLT3 mutations in acute myeloid leukemia (AML).

The MERTK/FLT3 inhibitor MRX-2843 induced apoptosis and inhibited colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD.

MRX-2843 also improved survival in mouse models of AML, including cases where tumors were resistant to the FLT3 inhibitor quizartinib.

Douglas Graham, MD, PhD, of the University of Colorado in Aurora, and his colleagues conducted this research and reported the results in JCI Insight.

The researchers previously showed that the receptor tyrosine kinase MERTK is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis.

With the current study, they showed that MRX-2843 abrogates activation of MERTK, FLT3, and their downstream effectors. And this translates to antileukemic activity in vitro and in vivo.

MRX-2843 inhibited MERTK signaling, induced cell death, and abolished oncogenic phenotypes in AML cells. The drug also exhibited therapeutic activity in a MERTK-dependent xenograft model.

MRX-2843 was able to stop the activation of FLT3 and its signaling pathways almost completely. The researchers said this suggests the drug has somewhat higher cellular potency against FLT3 relative to MERTK.

In mouse models of FLT3-ITD AML, MRX-2843 significantly prolonged survival when compared to vehicle control.

The researchers also said MRX-2843 selectively inhibited colony formation in primary AML patient samples. Primary human MERTK-expressing leukemic blasts, with or without FLT3-ITD mutations, proved sensitive to treatment with MRX-2843.

In addition, MRX-2843 increased survival and decreased peripheral disease burden in patient-derived xenograft models of AML—both MERTK⁺FLT3-WT and MERTK⁺FLT3-ITD models.

Finally, the researchers found that MRX-2843 was active against quizartinib-resistant FLT3-mutant proteins, induced apoptosis and inhibited colony formation in quizartinib-resistant FLT3-ITD cell lines, and prolonged survival in quizartinib-resistant FLT3-ITD xenograft models.

Ondansetron

Researchers say they have discovered the source of a bloodstream infection observed in more than 50 South American cancer patients.

Using whole-genome sequence typing (WGST), the team was able to link infection with the fungus Sarocladium kiliense to a tainted antinausea medication, ondansetron, that was given to cancer patients in Chile and Colombia.

This work is described in Emerging Infectious Diseases.

“Contamination of medical products, particularly with environmental fungi, poses growing concern and a public health threat, especially in vulnerable populations such as cancer patients,” said study author David Engelthaler, PhD, of The Translational Genomics Research Institute in Flagstaff, Arizona.

“Increased vigilance and the use of advanced technologies are needed to rapidly identify the likely sources of infection to efficiently guide epidemiologic investigations and initiate appropriate control measures.”

The S kiliense bloodstream-infection outbreak, which occurred from June 2013 through January 2014, included a cluster of cases at 8 hospitals in Santiago, Chile.

All of the patients received the same 4 intravenous medications. But only the antinausea medication ondansetron was given exclusively to cancer patients.

All of the patients infected with S kiliense received ondansetron from the same source, a pharmaceutical company called Vitrofarma SA (specifically, Plant No. 8 in Bogotá, Colombia). The drug was imported by LabVitales Chile SA and distributed by Pharma Isa Ltda.

Two of 3 lots of unopened ondansetron, tested by the Chilean Ministry of Health, yielded vials contaminated with S kiliense, forcing a recall of all ondansetron in Chile that was made by Vitrofarma SA.

Subsequently, Colombian officials discovered 14 other cases in which patients who were given ondansetron from Vitrofarma SA were infected with S kiliense.

S kiliense has been implicated in healthcare-related infections before, but the lack of available typing methods has precluded the ability to substantiate sources.

“The use of WGST to investigate fungal outbreaks has become integral to epidemiologic investigations,” Dr Engelthaler said. “Our WGST analysis demonstrated that the patient isolates from Chile and Colombia were nearly genetically indistinguishable from those recovered from the unopened medication vials, indicating the likely presence of a single-source infection.”

Ondansetron

Researchers say they have discovered the source of a bloodstream infection observed in more than 50 South American cancer patients.

Using whole-genome sequence typing (WGST), the team was able to link infection with the fungus Sarocladium kiliense to a tainted antinausea medication, ondansetron, that was given to cancer patients in Chile and Colombia.

This work is described in Emerging Infectious Diseases.

“Contamination of medical products, particularly with environmental fungi, poses growing concern and a public health threat, especially in vulnerable populations such as cancer patients,” said study author David Engelthaler, PhD, of The Translational Genomics Research Institute in Flagstaff, Arizona.

“Increased vigilance and the use of advanced technologies are needed to rapidly identify the likely sources of infection to efficiently guide epidemiologic investigations and initiate appropriate control measures.”

The S kiliense bloodstream-infection outbreak, which occurred from June 2013 through January 2014, included a cluster of cases at 8 hospitals in Santiago, Chile.

All of the patients received the same 4 intravenous medications. But only the antinausea medication ondansetron was given exclusively to cancer patients.

All of the patients infected with S kiliense received ondansetron from the same source, a pharmaceutical company called Vitrofarma SA (specifically, Plant No. 8 in Bogotá, Colombia). The drug was imported by LabVitales Chile SA and distributed by Pharma Isa Ltda.

Two of 3 lots of unopened ondansetron, tested by the Chilean Ministry of Health, yielded vials contaminated with S kiliense, forcing a recall of all ondansetron in Chile that was made by Vitrofarma SA.

Subsequently, Colombian officials discovered 14 other cases in which patients who were given ondansetron from Vitrofarma SA were infected with S kiliense.

S kiliense has been implicated in healthcare-related infections before, but the lack of available typing methods has precluded the ability to substantiate sources.

“The use of WGST to investigate fungal outbreaks has become integral to epidemiologic investigations,” Dr Engelthaler said. “Our WGST analysis demonstrated that the patient isolates from Chile and Colombia were nearly genetically indistinguishable from those recovered from the unopened medication vials, indicating the likely presence of a single-source infection.”

Ondansetron

Researchers say they have discovered the source of a bloodstream infection observed in more than 50 South American cancer patients.

Using whole-genome sequence typing (WGST), the team was able to link infection with the fungus Sarocladium kiliense to a tainted antinausea medication, ondansetron, that was given to cancer patients in Chile and Colombia.

This work is described in Emerging Infectious Diseases.

“Contamination of medical products, particularly with environmental fungi, poses growing concern and a public health threat, especially in vulnerable populations such as cancer patients,” said study author David Engelthaler, PhD, of The Translational Genomics Research Institute in Flagstaff, Arizona.

“Increased vigilance and the use of advanced technologies are needed to rapidly identify the likely sources of infection to efficiently guide epidemiologic investigations and initiate appropriate control measures.”

The S kiliense bloodstream-infection outbreak, which occurred from June 2013 through January 2014, included a cluster of cases at 8 hospitals in Santiago, Chile.

All of the patients received the same 4 intravenous medications. But only the antinausea medication ondansetron was given exclusively to cancer patients.

All of the patients infected with S kiliense received ondansetron from the same source, a pharmaceutical company called Vitrofarma SA (specifically, Plant No. 8 in Bogotá, Colombia). The drug was imported by LabVitales Chile SA and distributed by Pharma Isa Ltda.

Two of 3 lots of unopened ondansetron, tested by the Chilean Ministry of Health, yielded vials contaminated with S kiliense, forcing a recall of all ondansetron in Chile that was made by Vitrofarma SA.

Subsequently, Colombian officials discovered 14 other cases in which patients who were given ondansetron from Vitrofarma SA were infected with S kiliense.

S kiliense has been implicated in healthcare-related infections before, but the lack of available typing methods has precluded the ability to substantiate sources.

“The use of WGST to investigate fungal outbreaks has become integral to epidemiologic investigations,” Dr Engelthaler said. “Our WGST analysis demonstrated that the patient isolates from Chile and Colombia were nearly genetically indistinguishable from those recovered from the unopened medication vials, indicating the likely presence of a single-source infection.”