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Researchers combine genetic and clinical factors in new VTE risk score
MELBOURNE – A venous thromboembolism risk score that combines clinical risk factors, such as lymphoma type and stage, along with genetic variables, could offer a better way to predict venous thromboembolism in patients with lymphoma, according to new findings presented at the International Society on Thrombosis and Haemostasis congress.
Cristina Pascual, MD, of the Hospital Universitario Gregorio Marañon in Madrid presented data from a development and validation study of a clinical-genetic risk model for thrombosis in lymphoma in 208 patients with lymphoma, 31 of whom experienced a venous thromboembolic event.
While the relationship between cancer and increased thrombosis risk is well recognized, lymphoma patients are at particularly high risk, with an estimated thrombosis incidence of 5%-10%, Dr. Pascual said.
Currently, the Khorana score is the most validated risk score for thrombosis in patients with solid tumors, using factors such as tumor site, platelet and leukocyte count, hemoglobin levels, and body mass index. However, Dr. Pascual pointed out that just 10% of the validation cohort for the Khorana score were lymphoma patients, and it had previously been found to be not as useful for that population.
More recently, researchers had developed the ThroLy score for predicting thromboembolic events specifically in patients with lymphoma, incorporating clinical variables such as mediastinal involvement and extranodal localization.
Another group took a different approach by incorporating genetic risk factors for thrombosis to create Thrombo inCode-Oncology (TiC-Onco) for solid tumors. This assessment included four genetic variants known to increase the risk of thromboembolic events in cancer patients, as well as the clinical risk factors of body mass index, family history of thrombosis, primary tumor site, and tumor stage.
Dr. Pascual and colleagues developed a unique risk factor model that combined both the ThroLy and TiC-Onco elements.
In 208 patients with lymphoma who were not receiving anticoagulant treatment, researchers identified five clinical factors that were most predictive of venous thrombosis: a history of thrombosis, immobilization for more than 3 days, lymphoma type, Ann Arbor score for lymphoma stage, and mediastinal extension.
They combined these clinical risk factors with the genetic risk factors from the TiC-Onco score to develop the TiC-Onco–associated lymphoma score (TiC-Lympho).
When validated in the same group of patients, the TiC-Lympho score had a sensitivity of 93.55%, a specificity of 54.49%, positive predictive value of 26.36%, and negative predictive value of 97.94%.
The researchers also compared TiC-Lympho’s performance with that of the ThroLy and TiC-Onco models, and found it performed better on sensitivity and negative predictive value. The area under the curve for TiC-Lympho (0.783) was significantly higher than that seen with the other two risk models.
Session chair Kate Burbury, MBBS, of the Peter MacCallum Cancer Centre in Melbourne, raised the question of how the score – and particularly the genetic risk factor assessment – might be applied in the real-world clinical setting.
In an interview, Dr. Pascual said the findings represented preliminary data only, so the model was not ready to be applied to clinical practice yet. She also stressed that this was based on retrospective data, and needed to be further validated in other cohorts of lymphoma patients.
No conflicts of interest were reported.
SOURCE: Pascual C et al. 2019 ISTH Congress, Abstract OC 41.3.
MELBOURNE – A venous thromboembolism risk score that combines clinical risk factors, such as lymphoma type and stage, along with genetic variables, could offer a better way to predict venous thromboembolism in patients with lymphoma, according to new findings presented at the International Society on Thrombosis and Haemostasis congress.
Cristina Pascual, MD, of the Hospital Universitario Gregorio Marañon in Madrid presented data from a development and validation study of a clinical-genetic risk model for thrombosis in lymphoma in 208 patients with lymphoma, 31 of whom experienced a venous thromboembolic event.
While the relationship between cancer and increased thrombosis risk is well recognized, lymphoma patients are at particularly high risk, with an estimated thrombosis incidence of 5%-10%, Dr. Pascual said.
Currently, the Khorana score is the most validated risk score for thrombosis in patients with solid tumors, using factors such as tumor site, platelet and leukocyte count, hemoglobin levels, and body mass index. However, Dr. Pascual pointed out that just 10% of the validation cohort for the Khorana score were lymphoma patients, and it had previously been found to be not as useful for that population.
More recently, researchers had developed the ThroLy score for predicting thromboembolic events specifically in patients with lymphoma, incorporating clinical variables such as mediastinal involvement and extranodal localization.
Another group took a different approach by incorporating genetic risk factors for thrombosis to create Thrombo inCode-Oncology (TiC-Onco) for solid tumors. This assessment included four genetic variants known to increase the risk of thromboembolic events in cancer patients, as well as the clinical risk factors of body mass index, family history of thrombosis, primary tumor site, and tumor stage.
Dr. Pascual and colleagues developed a unique risk factor model that combined both the ThroLy and TiC-Onco elements.
In 208 patients with lymphoma who were not receiving anticoagulant treatment, researchers identified five clinical factors that were most predictive of venous thrombosis: a history of thrombosis, immobilization for more than 3 days, lymphoma type, Ann Arbor score for lymphoma stage, and mediastinal extension.
They combined these clinical risk factors with the genetic risk factors from the TiC-Onco score to develop the TiC-Onco–associated lymphoma score (TiC-Lympho).
When validated in the same group of patients, the TiC-Lympho score had a sensitivity of 93.55%, a specificity of 54.49%, positive predictive value of 26.36%, and negative predictive value of 97.94%.
The researchers also compared TiC-Lympho’s performance with that of the ThroLy and TiC-Onco models, and found it performed better on sensitivity and negative predictive value. The area under the curve for TiC-Lympho (0.783) was significantly higher than that seen with the other two risk models.
Session chair Kate Burbury, MBBS, of the Peter MacCallum Cancer Centre in Melbourne, raised the question of how the score – and particularly the genetic risk factor assessment – might be applied in the real-world clinical setting.
In an interview, Dr. Pascual said the findings represented preliminary data only, so the model was not ready to be applied to clinical practice yet. She also stressed that this was based on retrospective data, and needed to be further validated in other cohorts of lymphoma patients.
No conflicts of interest were reported.
SOURCE: Pascual C et al. 2019 ISTH Congress, Abstract OC 41.3.
MELBOURNE – A venous thromboembolism risk score that combines clinical risk factors, such as lymphoma type and stage, along with genetic variables, could offer a better way to predict venous thromboembolism in patients with lymphoma, according to new findings presented at the International Society on Thrombosis and Haemostasis congress.
Cristina Pascual, MD, of the Hospital Universitario Gregorio Marañon in Madrid presented data from a development and validation study of a clinical-genetic risk model for thrombosis in lymphoma in 208 patients with lymphoma, 31 of whom experienced a venous thromboembolic event.
While the relationship between cancer and increased thrombosis risk is well recognized, lymphoma patients are at particularly high risk, with an estimated thrombosis incidence of 5%-10%, Dr. Pascual said.
Currently, the Khorana score is the most validated risk score for thrombosis in patients with solid tumors, using factors such as tumor site, platelet and leukocyte count, hemoglobin levels, and body mass index. However, Dr. Pascual pointed out that just 10% of the validation cohort for the Khorana score were lymphoma patients, and it had previously been found to be not as useful for that population.
More recently, researchers had developed the ThroLy score for predicting thromboembolic events specifically in patients with lymphoma, incorporating clinical variables such as mediastinal involvement and extranodal localization.
Another group took a different approach by incorporating genetic risk factors for thrombosis to create Thrombo inCode-Oncology (TiC-Onco) for solid tumors. This assessment included four genetic variants known to increase the risk of thromboembolic events in cancer patients, as well as the clinical risk factors of body mass index, family history of thrombosis, primary tumor site, and tumor stage.
Dr. Pascual and colleagues developed a unique risk factor model that combined both the ThroLy and TiC-Onco elements.
In 208 patients with lymphoma who were not receiving anticoagulant treatment, researchers identified five clinical factors that were most predictive of venous thrombosis: a history of thrombosis, immobilization for more than 3 days, lymphoma type, Ann Arbor score for lymphoma stage, and mediastinal extension.
They combined these clinical risk factors with the genetic risk factors from the TiC-Onco score to develop the TiC-Onco–associated lymphoma score (TiC-Lympho).
When validated in the same group of patients, the TiC-Lympho score had a sensitivity of 93.55%, a specificity of 54.49%, positive predictive value of 26.36%, and negative predictive value of 97.94%.
The researchers also compared TiC-Lympho’s performance with that of the ThroLy and TiC-Onco models, and found it performed better on sensitivity and negative predictive value. The area under the curve for TiC-Lympho (0.783) was significantly higher than that seen with the other two risk models.
Session chair Kate Burbury, MBBS, of the Peter MacCallum Cancer Centre in Melbourne, raised the question of how the score – and particularly the genetic risk factor assessment – might be applied in the real-world clinical setting.
In an interview, Dr. Pascual said the findings represented preliminary data only, so the model was not ready to be applied to clinical practice yet. She also stressed that this was based on retrospective data, and needed to be further validated in other cohorts of lymphoma patients.
No conflicts of interest were reported.
SOURCE: Pascual C et al. 2019 ISTH Congress, Abstract OC 41.3.
REPORTING FROM 2019 ISTH CONGRESS
Concizumab looks feasible in hemophilia A and B treatment
MELBOURNE – A once-daily subcutaneous treatment that inhibits the tissue factor 4 pathway inhibitor has shown significant reductions in bleeding rates in patients with hemophilia A and B, according to findings presented at the International Society on Thrombosis and Haemostasis congress.
Jan Astermark, MD, PhD, of the Centre for Thrombosis and Haemostasis at Lund University in Sweden, presented data from two phase 2, dose-escalation trials of the monoclonal antibody concizumab.
The explorer 5 trial involved 36 adults with severe hemophilia A without inhibitors who were started on 0.15 mg/kg of concizumab for 24 weeks. If they experienced three or more bleeds during that time, they were escalated to 0.20 mg/kg, and then to 0.25mg/kg if they experienced an additional three bleeds. The initial 24-week treatment period was then extended by more than 52 weeks.
In the explorer 4 trial, 16 adults with hemophilia A and 10 adults with hemophilia B – all with inhibitors – were initially randomized 2:1 to either 24 weeks of 0.15mg/kg of concizumab, including a loading dose, or placebo, with similar dose escalation in response to breakthrough bleeds. After 24 weeks, the study continued with a 52-week extension, during which all patients were treated with concizumab.
Both studies saw reductions in bleeding rates associated with concizumab treatment.
In patients with hemophilia A and B with inhibitors, the mean annualized bleeding rate for all bleeds declined from 20.4 to 4.5 bleeds, spontaneous bleeds declined from 18.5 to 2.5, and joint bleeds declined from 15 to 3.2. All three of the reductions were statistically significant.
Almost all patients achieved a concizumab concentration of 100 ng/mL, which was the expected level based on data from the phase 1 trial. Some patients showed anticoncizumab antibodies, but these were transient and did not appear to have any effect on clinical outcomes, according to Dr. Astermark.
Most patients also reached a normal level of thrombin generation, although Dr. Astermark noted that there were some patients with hemophilia B with inhibitors who produced a lower amount of thrombin than normal.
Despite the increase in thrombin generation, there were no thromboembolic events, and no significant safety concerns emerged during the study, he reported.
“Importantly and interestingly, all patients completing the main phase went into the extension phase of this trial, indicating that it was something they think was a contribution to their treatment,” Dr. Astermark said.
Earlier in 2019, concizumab was granted breakthrough designation by the Food and Drug Administration for the treatment of patients with hemophilia B and inhibitors, allowing it to receive an accelerated review by the agency.
“What the FDA based their decision on was the B patients with inhibitors, because this is truly a group where we do not have so many options,” Dr. Astermark said in an interview. He also noted that the subcutaneous treatment, delivered via a pen-like device, was much more convenient for patients who, until now, had required repeated intravenous infusions.
Two phase 3 trials are now scheduled, in which patients will receive a higher loading dose than what was used in the phase 2 trials.
Novo Nordisk sponsored both studies. Dr. Astermark reported consultancies and research funding unrelated to the study.
SOURCE: Astermark J et al. 2019 ISTH Congress, Abstract LB 01.1.
MELBOURNE – A once-daily subcutaneous treatment that inhibits the tissue factor 4 pathway inhibitor has shown significant reductions in bleeding rates in patients with hemophilia A and B, according to findings presented at the International Society on Thrombosis and Haemostasis congress.
Jan Astermark, MD, PhD, of the Centre for Thrombosis and Haemostasis at Lund University in Sweden, presented data from two phase 2, dose-escalation trials of the monoclonal antibody concizumab.
The explorer 5 trial involved 36 adults with severe hemophilia A without inhibitors who were started on 0.15 mg/kg of concizumab for 24 weeks. If they experienced three or more bleeds during that time, they were escalated to 0.20 mg/kg, and then to 0.25mg/kg if they experienced an additional three bleeds. The initial 24-week treatment period was then extended by more than 52 weeks.
In the explorer 4 trial, 16 adults with hemophilia A and 10 adults with hemophilia B – all with inhibitors – were initially randomized 2:1 to either 24 weeks of 0.15mg/kg of concizumab, including a loading dose, or placebo, with similar dose escalation in response to breakthrough bleeds. After 24 weeks, the study continued with a 52-week extension, during which all patients were treated with concizumab.
Both studies saw reductions in bleeding rates associated with concizumab treatment.
In patients with hemophilia A and B with inhibitors, the mean annualized bleeding rate for all bleeds declined from 20.4 to 4.5 bleeds, spontaneous bleeds declined from 18.5 to 2.5, and joint bleeds declined from 15 to 3.2. All three of the reductions were statistically significant.
Almost all patients achieved a concizumab concentration of 100 ng/mL, which was the expected level based on data from the phase 1 trial. Some patients showed anticoncizumab antibodies, but these were transient and did not appear to have any effect on clinical outcomes, according to Dr. Astermark.
Most patients also reached a normal level of thrombin generation, although Dr. Astermark noted that there were some patients with hemophilia B with inhibitors who produced a lower amount of thrombin than normal.
Despite the increase in thrombin generation, there were no thromboembolic events, and no significant safety concerns emerged during the study, he reported.
“Importantly and interestingly, all patients completing the main phase went into the extension phase of this trial, indicating that it was something they think was a contribution to their treatment,” Dr. Astermark said.
Earlier in 2019, concizumab was granted breakthrough designation by the Food and Drug Administration for the treatment of patients with hemophilia B and inhibitors, allowing it to receive an accelerated review by the agency.
“What the FDA based their decision on was the B patients with inhibitors, because this is truly a group where we do not have so many options,” Dr. Astermark said in an interview. He also noted that the subcutaneous treatment, delivered via a pen-like device, was much more convenient for patients who, until now, had required repeated intravenous infusions.
Two phase 3 trials are now scheduled, in which patients will receive a higher loading dose than what was used in the phase 2 trials.
Novo Nordisk sponsored both studies. Dr. Astermark reported consultancies and research funding unrelated to the study.
SOURCE: Astermark J et al. 2019 ISTH Congress, Abstract LB 01.1.
MELBOURNE – A once-daily subcutaneous treatment that inhibits the tissue factor 4 pathway inhibitor has shown significant reductions in bleeding rates in patients with hemophilia A and B, according to findings presented at the International Society on Thrombosis and Haemostasis congress.
Jan Astermark, MD, PhD, of the Centre for Thrombosis and Haemostasis at Lund University in Sweden, presented data from two phase 2, dose-escalation trials of the monoclonal antibody concizumab.
The explorer 5 trial involved 36 adults with severe hemophilia A without inhibitors who were started on 0.15 mg/kg of concizumab for 24 weeks. If they experienced three or more bleeds during that time, they were escalated to 0.20 mg/kg, and then to 0.25mg/kg if they experienced an additional three bleeds. The initial 24-week treatment period was then extended by more than 52 weeks.
In the explorer 4 trial, 16 adults with hemophilia A and 10 adults with hemophilia B – all with inhibitors – were initially randomized 2:1 to either 24 weeks of 0.15mg/kg of concizumab, including a loading dose, or placebo, with similar dose escalation in response to breakthrough bleeds. After 24 weeks, the study continued with a 52-week extension, during which all patients were treated with concizumab.
Both studies saw reductions in bleeding rates associated with concizumab treatment.
In patients with hemophilia A and B with inhibitors, the mean annualized bleeding rate for all bleeds declined from 20.4 to 4.5 bleeds, spontaneous bleeds declined from 18.5 to 2.5, and joint bleeds declined from 15 to 3.2. All three of the reductions were statistically significant.
Almost all patients achieved a concizumab concentration of 100 ng/mL, which was the expected level based on data from the phase 1 trial. Some patients showed anticoncizumab antibodies, but these were transient and did not appear to have any effect on clinical outcomes, according to Dr. Astermark.
Most patients also reached a normal level of thrombin generation, although Dr. Astermark noted that there were some patients with hemophilia B with inhibitors who produced a lower amount of thrombin than normal.
Despite the increase in thrombin generation, there were no thromboembolic events, and no significant safety concerns emerged during the study, he reported.
“Importantly and interestingly, all patients completing the main phase went into the extension phase of this trial, indicating that it was something they think was a contribution to their treatment,” Dr. Astermark said.
Earlier in 2019, concizumab was granted breakthrough designation by the Food and Drug Administration for the treatment of patients with hemophilia B and inhibitors, allowing it to receive an accelerated review by the agency.
“What the FDA based their decision on was the B patients with inhibitors, because this is truly a group where we do not have so many options,” Dr. Astermark said in an interview. He also noted that the subcutaneous treatment, delivered via a pen-like device, was much more convenient for patients who, until now, had required repeated intravenous infusions.
Two phase 3 trials are now scheduled, in which patients will receive a higher loading dose than what was used in the phase 2 trials.
Novo Nordisk sponsored both studies. Dr. Astermark reported consultancies and research funding unrelated to the study.
SOURCE: Astermark J et al. 2019 ISTH Congress, Abstract LB 01.1.
REPORTING FROM 2019 ISTH CONGRESS
RNA interference drug fitusiran looks effective in both hemophilia A and B
MELBOURNE – An investigational RNA interference therapeutic that suppresses the production of antithrombin has shown significant reductions in bleeding rates with no major safety events, according to findings presented at the International Society on Thrombosis and Haemostasis congress.
Fitusiran is a once-monthly, fixed-dose subcutaneous therapy that uses RNA interference to silence the gene for the endogenous anticoagulant antithrombin.
“The therapeutic hypothesis is based on the fact that hemophilia A and B are essentially thrombin-deficiency disorders, so if we lack factor VIII or factor IX, we can’t generate enough thrombin and we can’t produce a significant and substantial blood clot,” John Pasi, MBChB, PhD, of the Royal London Haemophilia Centre, Barts Health NHS Trust. “If we, however, administer fitusiran, which will suppress antithrombin production, we can rebalance coagulation, generate more thrombin and form a much more substantial clot.”
Dr. Pasi presented results of an interim analysis of safety and efficacy data from an open-label, phase 2 extension study in 34 individuals with hemophilia A or B, with or without inhibitors, who were treated either with 50-mg or 80-mg doses of fitusiran for a median of at least 2 years.
Researchers saw significant declines in annualized bleeding rates in patients with hemophilia A and B, with and without inhibitors. Among those without inhibitors, the median annualized bleeding rate declined from 2.00 in patients already on hemophilia prophylaxis and 12.00 in those using on-demand treatment to 1.08 overall. In patients with inhibitors, the median annualized bleeding rate dropped from 42.00 to 1.04.
The treatment was also associated with substantial reductions in antithrombin production and increases in thrombin generation.
One patient in the phase 1 study experienced a fatal cerebral venous sinus thrombosis, which subsequently led to introduction of a bleed management protocol.
“Following that last case, we revised and reviewed the bleed management guidelines in view of the fact that there might potentially be an interaction between the amount of replacement therapy and thrombin generation,” Dr. Pasi said. Since introduction of that protocol, there have been no related thrombotic events.
The majority of adverse events reported were mild and deemed not related to the study drug, Dr. Pasi said. These included headache, injection site erythema, and arthralgia. A total of 14 subjects – all of whom were positive for hepatitis C at baseline – experienced rises in ALT levels but these were asymptomatic and resolved spontaneously.
One patient with chronic active hepatitis C infection also showed significant ALT/AST elevation which led to discontinuation of treatment.
In an interview, Dr. Pasi said one of the biggest advantages of fitusiran was that it could be used in patients with hemophilia A and B. “You’ve got patients with hemophilia B who’ve got no options at the moment. That would be an obvious specific group that would gain from this.”
Another advantage was fitusiran’s stability and dosing, he said, pointing out that the treatment was fixed dosing and stable at room temperature. Fitusiran is now undergoing phase 3 trials.
The study was funded by Sanofi Genzyme and Alnylam Pharmaceuticals, and six authors were employees of Sanofi Genzyme. Dr. Pasi reported financial relationships with pharmaceutical companies, including Alnylam.
SOURCE: Pasi J et al. 2019 ISTH Congress, Abstract OC 11.3.
MELBOURNE – An investigational RNA interference therapeutic that suppresses the production of antithrombin has shown significant reductions in bleeding rates with no major safety events, according to findings presented at the International Society on Thrombosis and Haemostasis congress.
Fitusiran is a once-monthly, fixed-dose subcutaneous therapy that uses RNA interference to silence the gene for the endogenous anticoagulant antithrombin.
“The therapeutic hypothesis is based on the fact that hemophilia A and B are essentially thrombin-deficiency disorders, so if we lack factor VIII or factor IX, we can’t generate enough thrombin and we can’t produce a significant and substantial blood clot,” John Pasi, MBChB, PhD, of the Royal London Haemophilia Centre, Barts Health NHS Trust. “If we, however, administer fitusiran, which will suppress antithrombin production, we can rebalance coagulation, generate more thrombin and form a much more substantial clot.”
Dr. Pasi presented results of an interim analysis of safety and efficacy data from an open-label, phase 2 extension study in 34 individuals with hemophilia A or B, with or without inhibitors, who were treated either with 50-mg or 80-mg doses of fitusiran for a median of at least 2 years.
Researchers saw significant declines in annualized bleeding rates in patients with hemophilia A and B, with and without inhibitors. Among those without inhibitors, the median annualized bleeding rate declined from 2.00 in patients already on hemophilia prophylaxis and 12.00 in those using on-demand treatment to 1.08 overall. In patients with inhibitors, the median annualized bleeding rate dropped from 42.00 to 1.04.
The treatment was also associated with substantial reductions in antithrombin production and increases in thrombin generation.
One patient in the phase 1 study experienced a fatal cerebral venous sinus thrombosis, which subsequently led to introduction of a bleed management protocol.
“Following that last case, we revised and reviewed the bleed management guidelines in view of the fact that there might potentially be an interaction between the amount of replacement therapy and thrombin generation,” Dr. Pasi said. Since introduction of that protocol, there have been no related thrombotic events.
The majority of adverse events reported were mild and deemed not related to the study drug, Dr. Pasi said. These included headache, injection site erythema, and arthralgia. A total of 14 subjects – all of whom were positive for hepatitis C at baseline – experienced rises in ALT levels but these were asymptomatic and resolved spontaneously.
One patient with chronic active hepatitis C infection also showed significant ALT/AST elevation which led to discontinuation of treatment.
In an interview, Dr. Pasi said one of the biggest advantages of fitusiran was that it could be used in patients with hemophilia A and B. “You’ve got patients with hemophilia B who’ve got no options at the moment. That would be an obvious specific group that would gain from this.”
Another advantage was fitusiran’s stability and dosing, he said, pointing out that the treatment was fixed dosing and stable at room temperature. Fitusiran is now undergoing phase 3 trials.
The study was funded by Sanofi Genzyme and Alnylam Pharmaceuticals, and six authors were employees of Sanofi Genzyme. Dr. Pasi reported financial relationships with pharmaceutical companies, including Alnylam.
SOURCE: Pasi J et al. 2019 ISTH Congress, Abstract OC 11.3.
MELBOURNE – An investigational RNA interference therapeutic that suppresses the production of antithrombin has shown significant reductions in bleeding rates with no major safety events, according to findings presented at the International Society on Thrombosis and Haemostasis congress.
Fitusiran is a once-monthly, fixed-dose subcutaneous therapy that uses RNA interference to silence the gene for the endogenous anticoagulant antithrombin.
“The therapeutic hypothesis is based on the fact that hemophilia A and B are essentially thrombin-deficiency disorders, so if we lack factor VIII or factor IX, we can’t generate enough thrombin and we can’t produce a significant and substantial blood clot,” John Pasi, MBChB, PhD, of the Royal London Haemophilia Centre, Barts Health NHS Trust. “If we, however, administer fitusiran, which will suppress antithrombin production, we can rebalance coagulation, generate more thrombin and form a much more substantial clot.”
Dr. Pasi presented results of an interim analysis of safety and efficacy data from an open-label, phase 2 extension study in 34 individuals with hemophilia A or B, with or without inhibitors, who were treated either with 50-mg or 80-mg doses of fitusiran for a median of at least 2 years.
Researchers saw significant declines in annualized bleeding rates in patients with hemophilia A and B, with and without inhibitors. Among those without inhibitors, the median annualized bleeding rate declined from 2.00 in patients already on hemophilia prophylaxis and 12.00 in those using on-demand treatment to 1.08 overall. In patients with inhibitors, the median annualized bleeding rate dropped from 42.00 to 1.04.
The treatment was also associated with substantial reductions in antithrombin production and increases in thrombin generation.
One patient in the phase 1 study experienced a fatal cerebral venous sinus thrombosis, which subsequently led to introduction of a bleed management protocol.
“Following that last case, we revised and reviewed the bleed management guidelines in view of the fact that there might potentially be an interaction between the amount of replacement therapy and thrombin generation,” Dr. Pasi said. Since introduction of that protocol, there have been no related thrombotic events.
The majority of adverse events reported were mild and deemed not related to the study drug, Dr. Pasi said. These included headache, injection site erythema, and arthralgia. A total of 14 subjects – all of whom were positive for hepatitis C at baseline – experienced rises in ALT levels but these were asymptomatic and resolved spontaneously.
One patient with chronic active hepatitis C infection also showed significant ALT/AST elevation which led to discontinuation of treatment.
In an interview, Dr. Pasi said one of the biggest advantages of fitusiran was that it could be used in patients with hemophilia A and B. “You’ve got patients with hemophilia B who’ve got no options at the moment. That would be an obvious specific group that would gain from this.”
Another advantage was fitusiran’s stability and dosing, he said, pointing out that the treatment was fixed dosing and stable at room temperature. Fitusiran is now undergoing phase 3 trials.
The study was funded by Sanofi Genzyme and Alnylam Pharmaceuticals, and six authors were employees of Sanofi Genzyme. Dr. Pasi reported financial relationships with pharmaceutical companies, including Alnylam.
SOURCE: Pasi J et al. 2019 ISTH Congress, Abstract OC 11.3.
REPORTING FROM 2019 ISTH CONGRESS
Early phase trial shows durable responses to gene therapy for hemophilia A
MELBOURNE – A gene therapy treatment for hemophilia A has shown sustained reductions in bleeding rates 3 years after treatment, with no major safety issues, according to findings presented at the International Society on Thrombosis and Haemostasis congress.
Valoctocogene roxaparvovec is an investigational gene therapy that involves using an adenovirus-associated virus to deliver the gene for clotting factor VIII.
John Pasi, MBChB, PhD, of the Royal London Haemophilia Centre, Barts Health NHS Trust, presented the 3-year efficacy and safety results from the phase 1/2 trial of the therapy, involving 15 men with hemophilia A without inhibitors who received a single intravenous dose – either 4 x 1013 vector genomes (vg) per kg or 6 x 1013 vg/kg – of the therapy.
Participants’ mean annualized bleeding rate at baseline ranged from 6.5 among men who had been receiving prophylactic therapy to 25 among those who had been historically been treated on demand.
The treatment was associated with a substantial, significant reduction in mean annualized bleed rates; a 96% reduction in the 6 x 1013 vg/kg group by year 3, and 92% reduction in the 4 x 1013 vg/kg group by year 2.
By year 3, 86% of patients in the higher dose group had not experienced a bleed in the prior 12 months, all patients were off prophylaxis, and all had experienced resolution of target joints.
Mean factor VIII usage also decreased significantly, with a 96% reduction by year 3 in the higher dose cohort, and a 97% reduction by year 2 in the lower dose cohort.
The study also showed significant improvements in quality of life across all domains, Dr. Pasi reported.
There were no significant safety concerns raised during the study. Several patients experienced mild to moderate, transient rises in alanine aminotransferase levels at around 8-16 weeks after treatment, but there was no significant impact on liver function or on corticosteroid use. Two patients reported mild infusion reactions, which resolved within 48 hours with altering treatment.
The researchers also examined durability of factor VIII activity levels following the gene therapy, which was monitored using chromogenic assays. This revealed that after the initial increase following therapy, the factor VIII levels plateaued between years 2 and 3.
“We’ve got what we feel is really good clinical evidence of a persistent effect and we think this is dramatic,” Dr. Pasi said. A phase 3 trial is now underway.
A commenter from the audience, who remarked that the data were incredible and would make a huge difference for patients, asked about whether this represented a possible cure for the disease.
It’s premature to talk about a cure, Dr. Pasi said.
“It’s like watching paint dry; it’s going to take years before we know where we are,” he said in an interview.
However, this could represent massive and transformational change in the management of hemophilia A, he added.
On the question of whether this approach might also work in patients with inhibitors, Dr. Pasi said there were animal data suggesting that gene therapy could work in individuals with inhibitors, but the focus for the moment was on patients without inhibitors.
“But for patients that previously had a history of inhibitors and are now tolerant, that’s quite a significant group of patients that we were going to have to think about how we deal with that in due course,” he said.
The study was sponsored by manufacturer BioMarin Pharmaceutical. Dr. Pasi reported financial relationships with the study sponsor and other companies.
SOURCE: Pasi KJ et al. 2019 ISTH Congress, Abstract LB 01.2.
MELBOURNE – A gene therapy treatment for hemophilia A has shown sustained reductions in bleeding rates 3 years after treatment, with no major safety issues, according to findings presented at the International Society on Thrombosis and Haemostasis congress.
Valoctocogene roxaparvovec is an investigational gene therapy that involves using an adenovirus-associated virus to deliver the gene for clotting factor VIII.
John Pasi, MBChB, PhD, of the Royal London Haemophilia Centre, Barts Health NHS Trust, presented the 3-year efficacy and safety results from the phase 1/2 trial of the therapy, involving 15 men with hemophilia A without inhibitors who received a single intravenous dose – either 4 x 1013 vector genomes (vg) per kg or 6 x 1013 vg/kg – of the therapy.
Participants’ mean annualized bleeding rate at baseline ranged from 6.5 among men who had been receiving prophylactic therapy to 25 among those who had been historically been treated on demand.
The treatment was associated with a substantial, significant reduction in mean annualized bleed rates; a 96% reduction in the 6 x 1013 vg/kg group by year 3, and 92% reduction in the 4 x 1013 vg/kg group by year 2.
By year 3, 86% of patients in the higher dose group had not experienced a bleed in the prior 12 months, all patients were off prophylaxis, and all had experienced resolution of target joints.
Mean factor VIII usage also decreased significantly, with a 96% reduction by year 3 in the higher dose cohort, and a 97% reduction by year 2 in the lower dose cohort.
The study also showed significant improvements in quality of life across all domains, Dr. Pasi reported.
There were no significant safety concerns raised during the study. Several patients experienced mild to moderate, transient rises in alanine aminotransferase levels at around 8-16 weeks after treatment, but there was no significant impact on liver function or on corticosteroid use. Two patients reported mild infusion reactions, which resolved within 48 hours with altering treatment.
The researchers also examined durability of factor VIII activity levels following the gene therapy, which was monitored using chromogenic assays. This revealed that after the initial increase following therapy, the factor VIII levels plateaued between years 2 and 3.
“We’ve got what we feel is really good clinical evidence of a persistent effect and we think this is dramatic,” Dr. Pasi said. A phase 3 trial is now underway.
A commenter from the audience, who remarked that the data were incredible and would make a huge difference for patients, asked about whether this represented a possible cure for the disease.
It’s premature to talk about a cure, Dr. Pasi said.
“It’s like watching paint dry; it’s going to take years before we know where we are,” he said in an interview.
However, this could represent massive and transformational change in the management of hemophilia A, he added.
On the question of whether this approach might also work in patients with inhibitors, Dr. Pasi said there were animal data suggesting that gene therapy could work in individuals with inhibitors, but the focus for the moment was on patients without inhibitors.
“But for patients that previously had a history of inhibitors and are now tolerant, that’s quite a significant group of patients that we were going to have to think about how we deal with that in due course,” he said.
The study was sponsored by manufacturer BioMarin Pharmaceutical. Dr. Pasi reported financial relationships with the study sponsor and other companies.
SOURCE: Pasi KJ et al. 2019 ISTH Congress, Abstract LB 01.2.
MELBOURNE – A gene therapy treatment for hemophilia A has shown sustained reductions in bleeding rates 3 years after treatment, with no major safety issues, according to findings presented at the International Society on Thrombosis and Haemostasis congress.
Valoctocogene roxaparvovec is an investigational gene therapy that involves using an adenovirus-associated virus to deliver the gene for clotting factor VIII.
John Pasi, MBChB, PhD, of the Royal London Haemophilia Centre, Barts Health NHS Trust, presented the 3-year efficacy and safety results from the phase 1/2 trial of the therapy, involving 15 men with hemophilia A without inhibitors who received a single intravenous dose – either 4 x 1013 vector genomes (vg) per kg or 6 x 1013 vg/kg – of the therapy.
Participants’ mean annualized bleeding rate at baseline ranged from 6.5 among men who had been receiving prophylactic therapy to 25 among those who had been historically been treated on demand.
The treatment was associated with a substantial, significant reduction in mean annualized bleed rates; a 96% reduction in the 6 x 1013 vg/kg group by year 3, and 92% reduction in the 4 x 1013 vg/kg group by year 2.
By year 3, 86% of patients in the higher dose group had not experienced a bleed in the prior 12 months, all patients were off prophylaxis, and all had experienced resolution of target joints.
Mean factor VIII usage also decreased significantly, with a 96% reduction by year 3 in the higher dose cohort, and a 97% reduction by year 2 in the lower dose cohort.
The study also showed significant improvements in quality of life across all domains, Dr. Pasi reported.
There were no significant safety concerns raised during the study. Several patients experienced mild to moderate, transient rises in alanine aminotransferase levels at around 8-16 weeks after treatment, but there was no significant impact on liver function or on corticosteroid use. Two patients reported mild infusion reactions, which resolved within 48 hours with altering treatment.
The researchers also examined durability of factor VIII activity levels following the gene therapy, which was monitored using chromogenic assays. This revealed that after the initial increase following therapy, the factor VIII levels plateaued between years 2 and 3.
“We’ve got what we feel is really good clinical evidence of a persistent effect and we think this is dramatic,” Dr. Pasi said. A phase 3 trial is now underway.
A commenter from the audience, who remarked that the data were incredible and would make a huge difference for patients, asked about whether this represented a possible cure for the disease.
It’s premature to talk about a cure, Dr. Pasi said.
“It’s like watching paint dry; it’s going to take years before we know where we are,” he said in an interview.
However, this could represent massive and transformational change in the management of hemophilia A, he added.
On the question of whether this approach might also work in patients with inhibitors, Dr. Pasi said there were animal data suggesting that gene therapy could work in individuals with inhibitors, but the focus for the moment was on patients without inhibitors.
“But for patients that previously had a history of inhibitors and are now tolerant, that’s quite a significant group of patients that we were going to have to think about how we deal with that in due course,” he said.
The study was sponsored by manufacturer BioMarin Pharmaceutical. Dr. Pasi reported financial relationships with the study sponsor and other companies.
SOURCE: Pasi KJ et al. 2019 ISTH Congress, Abstract LB 01.2.
REPORTING FROM 2019 ISTH CONGRESS
Emicizumab follow-up shows further bleeding declines
MELBOURNE – according to data presented at the International Society on Thrombosis and Haemostasis congress.
Michael Callaghan, MD, of the Children’s Hospital of Michigan, Detroit, reported on a pooled analysis of data from 399 patients with hemophilia A who were treated with emicizumab (Hemlibra) for a median duration of 83.1 weeks, representing 650 patient-years of exposure. The studies included pediatric and adult patients, both with and without factor VIII inhibitors.
Patients enrolled in the studies had a median of eight bleeds in the 24 weeks before enrollment, but in the first 24 weeks of treatment with emicizumab, the mean annualized bleed rate dropped to 1.9. During weeks 25-48, this dropped further to 0.8, remained at that level in weeks 49-72, then declined further to 0.3 during weeks 73-96.
During the first 24 weeks of treatment, 70.8% of patients experienced zero bleeds, and 22.5% experienced 1-3 bleeds. By week 96, the number of patients experiencing zero bleeds had increased to 88.6% and nearly 100% of patients had had fewer than three bleeds during that 24-week period.
The study also reported on target joint bleeds and showed the mean annualized bleed rate in target joints decreased from 1.4 in the first 24 weeks of treatment to 0.3 in weeks 73-96, by which time 90.4% of patients reported no target joint bleeds at all. Overall, 99.2% of target joints resolved, which was defined as two or fewer spontaneous bleeding events into a target joint in a year.
“The bleed rate seemed to converge on a low number, suggesting that maybe patients that came with preexisting synovitis or inflamed joints improved over time to resemble the patients who had better joint health at the beginning of the study,” Dr. Callaghan said.
The long-term follow-up did not reveal any major safety concerns. The most common drug-related adverse event was injection site reactions, which just over one-quarter of patients reported. The main serious adverse events were bleeding related.
“With any biologic agent, we were concerned about antidrug antibodies,” Dr. Callaghan told the conference. “At this follow-up point, less than 1% of patients treated with emicizumab in this group have had neutralizing antidrug antibodies.” Most of these antibodies were detected with routine screening, but there was one patient with antidrug antibodies who developed breakthrough bleeding during the study.
In an interview, Dr. Callaghan said emicizumab was “game-changing” therapy, and that the data showed it was efficacious even long term. However, he said there were still some questions to be answered about which patients were most likely to benefit.
“How early do we start this? Do we put previously untreated patients on this, and if we do, how do we expose them to factor VIII?” he said. Other challenging questions are whether to do immune tolerance induction for patients with factor VIII inhibitors and how the drug would work for other patient groups, such as those with comorbidities or who were very active.
The study was sponsored by F. Hoffman-La Roche and Chugai Pharmaceutical. Dr. Callaghan declared consultancies, grants, clinical trial involvement, speakers bureau engagements, and shares with the pharmaceutical sector.
SOURCE: Callaghan M et al. 2019 ISTH Congress, Abstract OC 60.2.
MELBOURNE – according to data presented at the International Society on Thrombosis and Haemostasis congress.
Michael Callaghan, MD, of the Children’s Hospital of Michigan, Detroit, reported on a pooled analysis of data from 399 patients with hemophilia A who were treated with emicizumab (Hemlibra) for a median duration of 83.1 weeks, representing 650 patient-years of exposure. The studies included pediatric and adult patients, both with and without factor VIII inhibitors.
Patients enrolled in the studies had a median of eight bleeds in the 24 weeks before enrollment, but in the first 24 weeks of treatment with emicizumab, the mean annualized bleed rate dropped to 1.9. During weeks 25-48, this dropped further to 0.8, remained at that level in weeks 49-72, then declined further to 0.3 during weeks 73-96.
During the first 24 weeks of treatment, 70.8% of patients experienced zero bleeds, and 22.5% experienced 1-3 bleeds. By week 96, the number of patients experiencing zero bleeds had increased to 88.6% and nearly 100% of patients had had fewer than three bleeds during that 24-week period.
The study also reported on target joint bleeds and showed the mean annualized bleed rate in target joints decreased from 1.4 in the first 24 weeks of treatment to 0.3 in weeks 73-96, by which time 90.4% of patients reported no target joint bleeds at all. Overall, 99.2% of target joints resolved, which was defined as two or fewer spontaneous bleeding events into a target joint in a year.
“The bleed rate seemed to converge on a low number, suggesting that maybe patients that came with preexisting synovitis or inflamed joints improved over time to resemble the patients who had better joint health at the beginning of the study,” Dr. Callaghan said.
The long-term follow-up did not reveal any major safety concerns. The most common drug-related adverse event was injection site reactions, which just over one-quarter of patients reported. The main serious adverse events were bleeding related.
“With any biologic agent, we were concerned about antidrug antibodies,” Dr. Callaghan told the conference. “At this follow-up point, less than 1% of patients treated with emicizumab in this group have had neutralizing antidrug antibodies.” Most of these antibodies were detected with routine screening, but there was one patient with antidrug antibodies who developed breakthrough bleeding during the study.
In an interview, Dr. Callaghan said emicizumab was “game-changing” therapy, and that the data showed it was efficacious even long term. However, he said there were still some questions to be answered about which patients were most likely to benefit.
“How early do we start this? Do we put previously untreated patients on this, and if we do, how do we expose them to factor VIII?” he said. Other challenging questions are whether to do immune tolerance induction for patients with factor VIII inhibitors and how the drug would work for other patient groups, such as those with comorbidities or who were very active.
The study was sponsored by F. Hoffman-La Roche and Chugai Pharmaceutical. Dr. Callaghan declared consultancies, grants, clinical trial involvement, speakers bureau engagements, and shares with the pharmaceutical sector.
SOURCE: Callaghan M et al. 2019 ISTH Congress, Abstract OC 60.2.
MELBOURNE – according to data presented at the International Society on Thrombosis and Haemostasis congress.
Michael Callaghan, MD, of the Children’s Hospital of Michigan, Detroit, reported on a pooled analysis of data from 399 patients with hemophilia A who were treated with emicizumab (Hemlibra) for a median duration of 83.1 weeks, representing 650 patient-years of exposure. The studies included pediatric and adult patients, both with and without factor VIII inhibitors.
Patients enrolled in the studies had a median of eight bleeds in the 24 weeks before enrollment, but in the first 24 weeks of treatment with emicizumab, the mean annualized bleed rate dropped to 1.9. During weeks 25-48, this dropped further to 0.8, remained at that level in weeks 49-72, then declined further to 0.3 during weeks 73-96.
During the first 24 weeks of treatment, 70.8% of patients experienced zero bleeds, and 22.5% experienced 1-3 bleeds. By week 96, the number of patients experiencing zero bleeds had increased to 88.6% and nearly 100% of patients had had fewer than three bleeds during that 24-week period.
The study also reported on target joint bleeds and showed the mean annualized bleed rate in target joints decreased from 1.4 in the first 24 weeks of treatment to 0.3 in weeks 73-96, by which time 90.4% of patients reported no target joint bleeds at all. Overall, 99.2% of target joints resolved, which was defined as two or fewer spontaneous bleeding events into a target joint in a year.
“The bleed rate seemed to converge on a low number, suggesting that maybe patients that came with preexisting synovitis or inflamed joints improved over time to resemble the patients who had better joint health at the beginning of the study,” Dr. Callaghan said.
The long-term follow-up did not reveal any major safety concerns. The most common drug-related adverse event was injection site reactions, which just over one-quarter of patients reported. The main serious adverse events were bleeding related.
“With any biologic agent, we were concerned about antidrug antibodies,” Dr. Callaghan told the conference. “At this follow-up point, less than 1% of patients treated with emicizumab in this group have had neutralizing antidrug antibodies.” Most of these antibodies were detected with routine screening, but there was one patient with antidrug antibodies who developed breakthrough bleeding during the study.
In an interview, Dr. Callaghan said emicizumab was “game-changing” therapy, and that the data showed it was efficacious even long term. However, he said there were still some questions to be answered about which patients were most likely to benefit.
“How early do we start this? Do we put previously untreated patients on this, and if we do, how do we expose them to factor VIII?” he said. Other challenging questions are whether to do immune tolerance induction for patients with factor VIII inhibitors and how the drug would work for other patient groups, such as those with comorbidities or who were very active.
The study was sponsored by F. Hoffman-La Roche and Chugai Pharmaceutical. Dr. Callaghan declared consultancies, grants, clinical trial involvement, speakers bureau engagements, and shares with the pharmaceutical sector.
SOURCE: Callaghan M et al. 2019 ISTH Congress, Abstract OC 60.2.
REPORTING FROM 2019 ISTH CONGRESS
Minor surgeries appear safe for hemophilia patients on emicizumab
MELBOURNE – A majority of minor surgeries can be performed in hemophilia A patients receiving emicizumab therapy without requiring prophylactic treatment with coagulation factors, according to data presented at the International Society on Thrombosis and Haemostasis congress.
Elena Santagostino, MD, PhD, from the Hemophilia and Thrombosis Center at Ospedale Maggiore Policlinico in Milan presented data from 399 patients involved in the four HAVEN trials of the humanized bispecific monoclonal antibody emicizumab (Hemlibra), which is Food and Drug Administration–approved for the prevention of bleeding episodes in individuals with hemophilia A, with or without inhibitors.
The analysis focused on the 126 patients (31.6%) who underwent at least one surgical procedure during the studies. Of the 233 surgeries, there were 215 minor procedures performed in 115 patients, and 18 major surgeries in 18 patients. All patients were receiving ongoing treatment with emicizumab, and there was no change to that treatment regimen during surgery.
“It is clear that surgery is a challenge for hemophilia,” Dr. Santagostino said. “It is a challenge for bleeding, it is a challenge for thrombosis, it is a challenge for any new drug, and this is why there is a lot of interest around this topic.”
Overall, 65.6% of minor surgeries were performed without any prophylactic coagulation factor treatment, and 90.8% of minor surgeries were conducted without postoperative bleeds requiring treatment. There were no cases of thrombosis reported.
The surgeries that did not require prophylactic coagulation factor included 42 dental procedures, 25 central venous access devices, 17 endoscopic procedures, and 12 joint procedures.
While the HAVEN studies did not allow for elective major surgery, there were still 18 unplanned major surgical situations that arose during the course of the studies. These included three hip, one knee, and one ankle arthroplasties; three synovectomies; and some dental, central venous line, and endoscopic biopsy procedures.
Of these, 15 involved prophylactic coagulant factor administration, but three procedures – including one synovectomy – were performed without prophylaxis and none resulted in a bleed.
There was one complicated bleed that occurred in a patient undergoing multiple procedures including a synovectomy, joint debridement and chondroplasty, who received prolonged treatment with recombinant Factor VIIa.
Dr. Santagostino said the findings showed surgery could be safely performed in patients who were being treated with emicizumab, both with and without inhibitors.
“A large number of minor procedures can be done without adding coagulation factors,” she said in an interview. “This is true for less invasive surgeries, such as catheter-related central venous line procedures. Even several endoscopic procedures, like a single biopsy, can be done reasonably safely.”
However she said there was still a lack of experience in dealing with hemophilia A patients who were undergoing cancer surgery, or who had significant comorbidities that might put them at higher risk of thrombosis.
“These are special patients populations that are still not investigated in the trial setting,” she said.
Commenting on the data, session cochair Liane Khoo, MD, from the Haemophilia Treatment Centre at Royal Prince Alfred Hospital in Sydney, said the results showed surgery could be performed in hemophilia A patients with and without inhibitors.
“The more we have the medication and the more experience we have, then we become more confident in using it,” she said.
The study was funded by F. Hoffman-La Roche and Chugai Pharmaceutical. Dr. Santagostino reported consultancies and speakers bureau engagements with the pharmaceutical sector.
SOURCE: Santagostino E et al. 2019 ISTH Congress, Abstract OC 60.1.
MELBOURNE – A majority of minor surgeries can be performed in hemophilia A patients receiving emicizumab therapy without requiring prophylactic treatment with coagulation factors, according to data presented at the International Society on Thrombosis and Haemostasis congress.
Elena Santagostino, MD, PhD, from the Hemophilia and Thrombosis Center at Ospedale Maggiore Policlinico in Milan presented data from 399 patients involved in the four HAVEN trials of the humanized bispecific monoclonal antibody emicizumab (Hemlibra), which is Food and Drug Administration–approved for the prevention of bleeding episodes in individuals with hemophilia A, with or without inhibitors.
The analysis focused on the 126 patients (31.6%) who underwent at least one surgical procedure during the studies. Of the 233 surgeries, there were 215 minor procedures performed in 115 patients, and 18 major surgeries in 18 patients. All patients were receiving ongoing treatment with emicizumab, and there was no change to that treatment regimen during surgery.
“It is clear that surgery is a challenge for hemophilia,” Dr. Santagostino said. “It is a challenge for bleeding, it is a challenge for thrombosis, it is a challenge for any new drug, and this is why there is a lot of interest around this topic.”
Overall, 65.6% of minor surgeries were performed without any prophylactic coagulation factor treatment, and 90.8% of minor surgeries were conducted without postoperative bleeds requiring treatment. There were no cases of thrombosis reported.
The surgeries that did not require prophylactic coagulation factor included 42 dental procedures, 25 central venous access devices, 17 endoscopic procedures, and 12 joint procedures.
While the HAVEN studies did not allow for elective major surgery, there were still 18 unplanned major surgical situations that arose during the course of the studies. These included three hip, one knee, and one ankle arthroplasties; three synovectomies; and some dental, central venous line, and endoscopic biopsy procedures.
Of these, 15 involved prophylactic coagulant factor administration, but three procedures – including one synovectomy – were performed without prophylaxis and none resulted in a bleed.
There was one complicated bleed that occurred in a patient undergoing multiple procedures including a synovectomy, joint debridement and chondroplasty, who received prolonged treatment with recombinant Factor VIIa.
Dr. Santagostino said the findings showed surgery could be safely performed in patients who were being treated with emicizumab, both with and without inhibitors.
“A large number of minor procedures can be done without adding coagulation factors,” she said in an interview. “This is true for less invasive surgeries, such as catheter-related central venous line procedures. Even several endoscopic procedures, like a single biopsy, can be done reasonably safely.”
However she said there was still a lack of experience in dealing with hemophilia A patients who were undergoing cancer surgery, or who had significant comorbidities that might put them at higher risk of thrombosis.
“These are special patients populations that are still not investigated in the trial setting,” she said.
Commenting on the data, session cochair Liane Khoo, MD, from the Haemophilia Treatment Centre at Royal Prince Alfred Hospital in Sydney, said the results showed surgery could be performed in hemophilia A patients with and without inhibitors.
“The more we have the medication and the more experience we have, then we become more confident in using it,” she said.
The study was funded by F. Hoffman-La Roche and Chugai Pharmaceutical. Dr. Santagostino reported consultancies and speakers bureau engagements with the pharmaceutical sector.
SOURCE: Santagostino E et al. 2019 ISTH Congress, Abstract OC 60.1.
MELBOURNE – A majority of minor surgeries can be performed in hemophilia A patients receiving emicizumab therapy without requiring prophylactic treatment with coagulation factors, according to data presented at the International Society on Thrombosis and Haemostasis congress.
Elena Santagostino, MD, PhD, from the Hemophilia and Thrombosis Center at Ospedale Maggiore Policlinico in Milan presented data from 399 patients involved in the four HAVEN trials of the humanized bispecific monoclonal antibody emicizumab (Hemlibra), which is Food and Drug Administration–approved for the prevention of bleeding episodes in individuals with hemophilia A, with or without inhibitors.
The analysis focused on the 126 patients (31.6%) who underwent at least one surgical procedure during the studies. Of the 233 surgeries, there were 215 minor procedures performed in 115 patients, and 18 major surgeries in 18 patients. All patients were receiving ongoing treatment with emicizumab, and there was no change to that treatment regimen during surgery.
“It is clear that surgery is a challenge for hemophilia,” Dr. Santagostino said. “It is a challenge for bleeding, it is a challenge for thrombosis, it is a challenge for any new drug, and this is why there is a lot of interest around this topic.”
Overall, 65.6% of minor surgeries were performed without any prophylactic coagulation factor treatment, and 90.8% of minor surgeries were conducted without postoperative bleeds requiring treatment. There were no cases of thrombosis reported.
The surgeries that did not require prophylactic coagulation factor included 42 dental procedures, 25 central venous access devices, 17 endoscopic procedures, and 12 joint procedures.
While the HAVEN studies did not allow for elective major surgery, there were still 18 unplanned major surgical situations that arose during the course of the studies. These included three hip, one knee, and one ankle arthroplasties; three synovectomies; and some dental, central venous line, and endoscopic biopsy procedures.
Of these, 15 involved prophylactic coagulant factor administration, but three procedures – including one synovectomy – were performed without prophylaxis and none resulted in a bleed.
There was one complicated bleed that occurred in a patient undergoing multiple procedures including a synovectomy, joint debridement and chondroplasty, who received prolonged treatment with recombinant Factor VIIa.
Dr. Santagostino said the findings showed surgery could be safely performed in patients who were being treated with emicizumab, both with and without inhibitors.
“A large number of minor procedures can be done without adding coagulation factors,” she said in an interview. “This is true for less invasive surgeries, such as catheter-related central venous line procedures. Even several endoscopic procedures, like a single biopsy, can be done reasonably safely.”
However she said there was still a lack of experience in dealing with hemophilia A patients who were undergoing cancer surgery, or who had significant comorbidities that might put them at higher risk of thrombosis.
“These are special patients populations that are still not investigated in the trial setting,” she said.
Commenting on the data, session cochair Liane Khoo, MD, from the Haemophilia Treatment Centre at Royal Prince Alfred Hospital in Sydney, said the results showed surgery could be performed in hemophilia A patients with and without inhibitors.
“The more we have the medication and the more experience we have, then we become more confident in using it,” she said.
The study was funded by F. Hoffman-La Roche and Chugai Pharmaceutical. Dr. Santagostino reported consultancies and speakers bureau engagements with the pharmaceutical sector.
SOURCE: Santagostino E et al. 2019 ISTH Congress, Abstract OC 60.1.
REPORTING FROM 2019 ISTH CONGRESS
Risk of atrial fibrillation 900% higher with cancer
MELBOURNE – The overall prevalence of atrial fibrillation in people who have or have had cancer is 10 times that of individuals without cancer, according to a study presented at the International Society on Thrombosis and Haemostasis congress.
Cihan Ay, MD, of the division of hematology and hemostaseology at the Medical University of Vienna reported on a nationwide cohort study using health insurance data from more than 8.3 million people in Austria, including roughly 159,000 with a diagnosis of cancer and 113,000 with a diagnosis of atrial fibrillation.
The analysis found that, in individuals whose records showed a diagnosis of cancer, there was a 950% higher relative risk of also having a diagnosis of atrial fibrillation, compared with those with no cancer diagnosis.
The overall prevalence of atrial fibrillation among individuals with a cancer diagnosis was 9.8%, compared with 1.2% in those without cancer.
There was significant variation in relative risk according to age. Although the prevalence of atrial fibrillation increased with age, the highest relative risks were seen in the youngest age groups.
In those aged 12 years or under with a cancer diagnosis, the relative risk of atrial fibrillation was 150 times greater than in those without cancer, and in those aged 13-18 years, it was 200 times higher. At the other end of the age spectrum, individuals aged 70-79 years with a recorded cancer diagnosis, the relative risk of atrial fibrillation was still 130% higher than the noncancer population, and in those aged 80-90 years it was a significant 54% higher.
However, the analysis did not find any effect of gender on the risk of atrial fibrillation associated with cancer, regardless of the age group.
Researchers also examined the influence of different cancer types. They found the highest relative risk of atrial fibrillation was in persons with hematologic malignancies – at nine times the risk in the noncancer population – and the lowest was in the endocrine cancer patients, who had three times the risk.
Dr. Ay told the conference that the association between cancer and atrial fibrillation had been suggested in the literature, but it was still an unexplored field. “The exact magnitude of this association between cancer and atrial fibrillation is still unclear.”
There was also the question of what mechanisms might underlie the association. Dr. Ay pointed out that the health insurance database did not allow researchers to explore the temporal relationship between the two diagnoses, and therefore could not tell which came first.
One audience member queried whether the fact that cancer patients were likely to be visiting a clinician more frequently might mean that the atrial fibrillation would be more likely to be diagnosed.
To that, Dr. Ay suggested the significantly higher relative risk in children was supportive of the notion that cancer itself, or treatment effects, were influencing atrial fibrillation risk.
“There is evidence suggesting that cancer treatments are triggering atrial fibrillation,” he said in an interview. “Also, patients with cancer have situations of in which they are sick – they have neutropenia or sepsis and so on – which can also trigger atrial fibrillation.”
Given the limitations of the retrospective cohort study, Dr. Ay said he was hoping to do a prospective study that would enable baseline measurements of cancer patients to determine how much of the atrial fibrillation was preexisting.
“We have also more and more cancer survivors, and over the years they’re living longer and the likelihood of getting atrial fibrillation increases,” he added.
Commenting on the data, Gerald Soff, MD, chief of hematology at the Memorial Sloan Kettering Cancer Center in New York, said it was very important to quantify the association between cancer and atrial fibrillation.
“What’s striking to me is how many people with cancer come in with preexisting atrial fibrillation,” he said. “It could be that they have cancer and they’re already messed up, but we have, on a given day, several people coming in with newly diagnosed cancers, already on warfarin or apixaban or rivaroxaban because they have atrial fibrillation.”
Dr. Ay reported advisory board positions and speaking engagements for the pharmaceutical sector.
MELBOURNE – The overall prevalence of atrial fibrillation in people who have or have had cancer is 10 times that of individuals without cancer, according to a study presented at the International Society on Thrombosis and Haemostasis congress.
Cihan Ay, MD, of the division of hematology and hemostaseology at the Medical University of Vienna reported on a nationwide cohort study using health insurance data from more than 8.3 million people in Austria, including roughly 159,000 with a diagnosis of cancer and 113,000 with a diagnosis of atrial fibrillation.
The analysis found that, in individuals whose records showed a diagnosis of cancer, there was a 950% higher relative risk of also having a diagnosis of atrial fibrillation, compared with those with no cancer diagnosis.
The overall prevalence of atrial fibrillation among individuals with a cancer diagnosis was 9.8%, compared with 1.2% in those without cancer.
There was significant variation in relative risk according to age. Although the prevalence of atrial fibrillation increased with age, the highest relative risks were seen in the youngest age groups.
In those aged 12 years or under with a cancer diagnosis, the relative risk of atrial fibrillation was 150 times greater than in those without cancer, and in those aged 13-18 years, it was 200 times higher. At the other end of the age spectrum, individuals aged 70-79 years with a recorded cancer diagnosis, the relative risk of atrial fibrillation was still 130% higher than the noncancer population, and in those aged 80-90 years it was a significant 54% higher.
However, the analysis did not find any effect of gender on the risk of atrial fibrillation associated with cancer, regardless of the age group.
Researchers also examined the influence of different cancer types. They found the highest relative risk of atrial fibrillation was in persons with hematologic malignancies – at nine times the risk in the noncancer population – and the lowest was in the endocrine cancer patients, who had three times the risk.
Dr. Ay told the conference that the association between cancer and atrial fibrillation had been suggested in the literature, but it was still an unexplored field. “The exact magnitude of this association between cancer and atrial fibrillation is still unclear.”
There was also the question of what mechanisms might underlie the association. Dr. Ay pointed out that the health insurance database did not allow researchers to explore the temporal relationship between the two diagnoses, and therefore could not tell which came first.
One audience member queried whether the fact that cancer patients were likely to be visiting a clinician more frequently might mean that the atrial fibrillation would be more likely to be diagnosed.
To that, Dr. Ay suggested the significantly higher relative risk in children was supportive of the notion that cancer itself, or treatment effects, were influencing atrial fibrillation risk.
“There is evidence suggesting that cancer treatments are triggering atrial fibrillation,” he said in an interview. “Also, patients with cancer have situations of in which they are sick – they have neutropenia or sepsis and so on – which can also trigger atrial fibrillation.”
Given the limitations of the retrospective cohort study, Dr. Ay said he was hoping to do a prospective study that would enable baseline measurements of cancer patients to determine how much of the atrial fibrillation was preexisting.
“We have also more and more cancer survivors, and over the years they’re living longer and the likelihood of getting atrial fibrillation increases,” he added.
Commenting on the data, Gerald Soff, MD, chief of hematology at the Memorial Sloan Kettering Cancer Center in New York, said it was very important to quantify the association between cancer and atrial fibrillation.
“What’s striking to me is how many people with cancer come in with preexisting atrial fibrillation,” he said. “It could be that they have cancer and they’re already messed up, but we have, on a given day, several people coming in with newly diagnosed cancers, already on warfarin or apixaban or rivaroxaban because they have atrial fibrillation.”
Dr. Ay reported advisory board positions and speaking engagements for the pharmaceutical sector.
MELBOURNE – The overall prevalence of atrial fibrillation in people who have or have had cancer is 10 times that of individuals without cancer, according to a study presented at the International Society on Thrombosis and Haemostasis congress.
Cihan Ay, MD, of the division of hematology and hemostaseology at the Medical University of Vienna reported on a nationwide cohort study using health insurance data from more than 8.3 million people in Austria, including roughly 159,000 with a diagnosis of cancer and 113,000 with a diagnosis of atrial fibrillation.
The analysis found that, in individuals whose records showed a diagnosis of cancer, there was a 950% higher relative risk of also having a diagnosis of atrial fibrillation, compared with those with no cancer diagnosis.
The overall prevalence of atrial fibrillation among individuals with a cancer diagnosis was 9.8%, compared with 1.2% in those without cancer.
There was significant variation in relative risk according to age. Although the prevalence of atrial fibrillation increased with age, the highest relative risks were seen in the youngest age groups.
In those aged 12 years or under with a cancer diagnosis, the relative risk of atrial fibrillation was 150 times greater than in those without cancer, and in those aged 13-18 years, it was 200 times higher. At the other end of the age spectrum, individuals aged 70-79 years with a recorded cancer diagnosis, the relative risk of atrial fibrillation was still 130% higher than the noncancer population, and in those aged 80-90 years it was a significant 54% higher.
However, the analysis did not find any effect of gender on the risk of atrial fibrillation associated with cancer, regardless of the age group.
Researchers also examined the influence of different cancer types. They found the highest relative risk of atrial fibrillation was in persons with hematologic malignancies – at nine times the risk in the noncancer population – and the lowest was in the endocrine cancer patients, who had three times the risk.
Dr. Ay told the conference that the association between cancer and atrial fibrillation had been suggested in the literature, but it was still an unexplored field. “The exact magnitude of this association between cancer and atrial fibrillation is still unclear.”
There was also the question of what mechanisms might underlie the association. Dr. Ay pointed out that the health insurance database did not allow researchers to explore the temporal relationship between the two diagnoses, and therefore could not tell which came first.
One audience member queried whether the fact that cancer patients were likely to be visiting a clinician more frequently might mean that the atrial fibrillation would be more likely to be diagnosed.
To that, Dr. Ay suggested the significantly higher relative risk in children was supportive of the notion that cancer itself, or treatment effects, were influencing atrial fibrillation risk.
“There is evidence suggesting that cancer treatments are triggering atrial fibrillation,” he said in an interview. “Also, patients with cancer have situations of in which they are sick – they have neutropenia or sepsis and so on – which can also trigger atrial fibrillation.”
Given the limitations of the retrospective cohort study, Dr. Ay said he was hoping to do a prospective study that would enable baseline measurements of cancer patients to determine how much of the atrial fibrillation was preexisting.
“We have also more and more cancer survivors, and over the years they’re living longer and the likelihood of getting atrial fibrillation increases,” he added.
Commenting on the data, Gerald Soff, MD, chief of hematology at the Memorial Sloan Kettering Cancer Center in New York, said it was very important to quantify the association between cancer and atrial fibrillation.
“What’s striking to me is how many people with cancer come in with preexisting atrial fibrillation,” he said. “It could be that they have cancer and they’re already messed up, but we have, on a given day, several people coming in with newly diagnosed cancers, already on warfarin or apixaban or rivaroxaban because they have atrial fibrillation.”
Dr. Ay reported advisory board positions and speaking engagements for the pharmaceutical sector.
REPORTING FROM 2019 ISTH CONGRESS
Subcutaneous marstacimab appears safe in hemophilia A and B
MELBOURNE – Subcutaneous administration of the monoclonal antibody marstacimab (PF-06741086) provides significant reductions in bleeding rates for patients with hemophilia A and B, with reasonably safety and tolerability, according to research presented at the International Society on Thrombosis and Haemostasis congress.
Johnny Mahlangu, MBBCh, of the University of Witwatersrand in Johannesburg, South Africa, presented data from a multicenter, international phase 1B/2 open-label study involving 26 patients with severe hemophilia, who had experienced at least six acute bleeding episodes in the 6 months prior to enrollment. Twenty-three patients had hemophilia A, the remaining three patients had hemophilia B, and all were receiving on-demand treatment.
Patients were divided into one of four cohorts. Cohort 1 received a weekly 300-mg dose subcutaneously for 30 days, cohort 2 received a 300-mg loading dose followed by 150 mg weekly for 30 days, cohort 3 received 450 mg weekly for 30 days, and cohort 4 also received a 300-mg weekly dose for 30 days but consisted of patients with inhibitors.
With the primary outcome being safety, the researchers reported no treatment-related serious adverse events. There were four grade 3/4 adverse events, including two subjects who reported injection site reactions, and some generalized pruritus and erythematous rash.
Two patients discontinued treatment after reaching prespecified dose-limiting toxicity related to decreasing fibrinogen levels, compared with baseline. However, Dr. Mahlangu pointed out that, in one of these patients, the fibrinogen levels were still within normal levels but protocol required removing the patient from the study.
The study did see a significant 85%-97% reduction in annualized bleed rates across the four cohorts, including among patients with inhibitors.
“Most patients who were exposed to marstacimab actually did not bleed at all when they were receiving marstacimab, compared to when they weren’t receiving marstacimab,” Dr. Mahlangu said.
While three patients developed antidrug antibodies, this did not appear to impact the pharmacokinetics, pharmacodynamics, or safety, he said. No patients developed neutralizing antibodies, and the pharmacodynamics showed no difference between patients with hemophilia A and B.
“I would like to believe that the results of this study are fairly promising in terms of the safety, the efficacy, the pharmoacokinetics, and the pharmacodynamics,” Dr. Mahlangu said.
There is an unmet need for therapies that can be used in patients with either hemophilia A or B, and with or without inhibitors, Dr. Mahlangu said in an interview. Another unmet need that marstacimab could potentially address is for subcutaneous treatment options, he added.
“We are particularly pleased by the fact that injection-site reactions are very low, and they seem not to carry on every time the patients have injected,” Dr. Mahlangu said.
Commenting on the presentation, session cochair Julia Phillips, MD, from PathLab in Waikato, New Zealand, said subcutaneous treatments offered a huge advantage to patients with hemophilia and their families.
“Often more than one member of the family is affected. So [for] a family with children, if they have several sons with hemophilia, then doing IV injections before school on a regular basis can be quite a big burden on the family,” she said in an interview.
The study was sponsored by Pfizer. Dr. Mahlangu reported research support from and scientific advisory board and speakers bureau roles with several pharmaceutical companies, including Pfizer.
SOURCE: Mahlangu J et al. 2019. ISTH CONGRESS, Abstract OC 11.2.
MELBOURNE – Subcutaneous administration of the monoclonal antibody marstacimab (PF-06741086) provides significant reductions in bleeding rates for patients with hemophilia A and B, with reasonably safety and tolerability, according to research presented at the International Society on Thrombosis and Haemostasis congress.
Johnny Mahlangu, MBBCh, of the University of Witwatersrand in Johannesburg, South Africa, presented data from a multicenter, international phase 1B/2 open-label study involving 26 patients with severe hemophilia, who had experienced at least six acute bleeding episodes in the 6 months prior to enrollment. Twenty-three patients had hemophilia A, the remaining three patients had hemophilia B, and all were receiving on-demand treatment.
Patients were divided into one of four cohorts. Cohort 1 received a weekly 300-mg dose subcutaneously for 30 days, cohort 2 received a 300-mg loading dose followed by 150 mg weekly for 30 days, cohort 3 received 450 mg weekly for 30 days, and cohort 4 also received a 300-mg weekly dose for 30 days but consisted of patients with inhibitors.
With the primary outcome being safety, the researchers reported no treatment-related serious adverse events. There were four grade 3/4 adverse events, including two subjects who reported injection site reactions, and some generalized pruritus and erythematous rash.
Two patients discontinued treatment after reaching prespecified dose-limiting toxicity related to decreasing fibrinogen levels, compared with baseline. However, Dr. Mahlangu pointed out that, in one of these patients, the fibrinogen levels were still within normal levels but protocol required removing the patient from the study.
The study did see a significant 85%-97% reduction in annualized bleed rates across the four cohorts, including among patients with inhibitors.
“Most patients who were exposed to marstacimab actually did not bleed at all when they were receiving marstacimab, compared to when they weren’t receiving marstacimab,” Dr. Mahlangu said.
While three patients developed antidrug antibodies, this did not appear to impact the pharmacokinetics, pharmacodynamics, or safety, he said. No patients developed neutralizing antibodies, and the pharmacodynamics showed no difference between patients with hemophilia A and B.
“I would like to believe that the results of this study are fairly promising in terms of the safety, the efficacy, the pharmoacokinetics, and the pharmacodynamics,” Dr. Mahlangu said.
There is an unmet need for therapies that can be used in patients with either hemophilia A or B, and with or without inhibitors, Dr. Mahlangu said in an interview. Another unmet need that marstacimab could potentially address is for subcutaneous treatment options, he added.
“We are particularly pleased by the fact that injection-site reactions are very low, and they seem not to carry on every time the patients have injected,” Dr. Mahlangu said.
Commenting on the presentation, session cochair Julia Phillips, MD, from PathLab in Waikato, New Zealand, said subcutaneous treatments offered a huge advantage to patients with hemophilia and their families.
“Often more than one member of the family is affected. So [for] a family with children, if they have several sons with hemophilia, then doing IV injections before school on a regular basis can be quite a big burden on the family,” she said in an interview.
The study was sponsored by Pfizer. Dr. Mahlangu reported research support from and scientific advisory board and speakers bureau roles with several pharmaceutical companies, including Pfizer.
SOURCE: Mahlangu J et al. 2019. ISTH CONGRESS, Abstract OC 11.2.
MELBOURNE – Subcutaneous administration of the monoclonal antibody marstacimab (PF-06741086) provides significant reductions in bleeding rates for patients with hemophilia A and B, with reasonably safety and tolerability, according to research presented at the International Society on Thrombosis and Haemostasis congress.
Johnny Mahlangu, MBBCh, of the University of Witwatersrand in Johannesburg, South Africa, presented data from a multicenter, international phase 1B/2 open-label study involving 26 patients with severe hemophilia, who had experienced at least six acute bleeding episodes in the 6 months prior to enrollment. Twenty-three patients had hemophilia A, the remaining three patients had hemophilia B, and all were receiving on-demand treatment.
Patients were divided into one of four cohorts. Cohort 1 received a weekly 300-mg dose subcutaneously for 30 days, cohort 2 received a 300-mg loading dose followed by 150 mg weekly for 30 days, cohort 3 received 450 mg weekly for 30 days, and cohort 4 also received a 300-mg weekly dose for 30 days but consisted of patients with inhibitors.
With the primary outcome being safety, the researchers reported no treatment-related serious adverse events. There were four grade 3/4 adverse events, including two subjects who reported injection site reactions, and some generalized pruritus and erythematous rash.
Two patients discontinued treatment after reaching prespecified dose-limiting toxicity related to decreasing fibrinogen levels, compared with baseline. However, Dr. Mahlangu pointed out that, in one of these patients, the fibrinogen levels were still within normal levels but protocol required removing the patient from the study.
The study did see a significant 85%-97% reduction in annualized bleed rates across the four cohorts, including among patients with inhibitors.
“Most patients who were exposed to marstacimab actually did not bleed at all when they were receiving marstacimab, compared to when they weren’t receiving marstacimab,” Dr. Mahlangu said.
While three patients developed antidrug antibodies, this did not appear to impact the pharmacokinetics, pharmacodynamics, or safety, he said. No patients developed neutralizing antibodies, and the pharmacodynamics showed no difference between patients with hemophilia A and B.
“I would like to believe that the results of this study are fairly promising in terms of the safety, the efficacy, the pharmoacokinetics, and the pharmacodynamics,” Dr. Mahlangu said.
There is an unmet need for therapies that can be used in patients with either hemophilia A or B, and with or without inhibitors, Dr. Mahlangu said in an interview. Another unmet need that marstacimab could potentially address is for subcutaneous treatment options, he added.
“We are particularly pleased by the fact that injection-site reactions are very low, and they seem not to carry on every time the patients have injected,” Dr. Mahlangu said.
Commenting on the presentation, session cochair Julia Phillips, MD, from PathLab in Waikato, New Zealand, said subcutaneous treatments offered a huge advantage to patients with hemophilia and their families.
“Often more than one member of the family is affected. So [for] a family with children, if they have several sons with hemophilia, then doing IV injections before school on a regular basis can be quite a big burden on the family,” she said in an interview.
The study was sponsored by Pfizer. Dr. Mahlangu reported research support from and scientific advisory board and speakers bureau roles with several pharmaceutical companies, including Pfizer.
SOURCE: Mahlangu J et al. 2019. ISTH CONGRESS, Abstract OC 11.2.
REPORTING FROM 2019 ISTH CONGRESS
No reduction in PE risk with vena cava filters after severe injury
MELBOURNE – Use of a prophylactic vena cava filter to trap blood clots in severely injured patients does not appear to reduce the risk of pulmonary embolism or death, according to data presented at the International Society on Thrombosis and Haemostasis congress.
The researchers reported the outcomes of a multicenter, controlled trial in which 240 severely injured patients with a contraindication to anticoagulants were randomized to receive a vena cava filter within 72 hours of admission, or no filter. The findings were published simultaneously in the New England Journal of Medicine.
The study showed no significant differences between the filter and no-filter groups in the primary outcome of a composite of symptomatic pulmonary embolism or death from any cause at 90 days after enrollment (13.9% vs. 14.4% respectively, P = .98).
In a prespecified subgroup analysis, researchers examined patients who survived 7 days after injury and did not receive prophylactic anticoagulation in those 7 days. Among this group of patients, none of those who received the vena cava filter experienced a symptomatic pulmonary embolism between day 8 and day 90, but five patients (14.7%) in the no-filter group did.
Filters were left in place for a median duration of 27 days (11-90 days). Among the 122 patients who received a filter – which included two patients in the control group – researchers found trapped thrombi in the filter in six patients.
Transfusion requirements, and the incidence of major and nonmajor bleeding and leg deep vein thrombosis, were similar between the filter and no-filter groups. Seven patients in the filter group (5.7%) required more than one attempt to remove the filter, and in one patient the filter had to be removed surgically.
Kwok M. Ho, PhD, of the department of intensive care medicine at Royal Perth Hospital, Australia, and coauthors wrote that while vena cava filters are widely used in trauma centers to prevent pulmonary embolism in patients at high risk of bleeding, there are conflicting recommendations regarding their use, and most studies so far have been observational.
“Given the cost and risks associated with a vena cava filter, our data suggest that there is no urgency to insert the filter in patients who can be treated with prophylactic anticoagulation within 7 days after injury,” they wrote. “Unnecessary insertion of a vena cava filter has the potential to cause harm.”
However, they noted that patients with multiple, large intracranial hematomas were particularly at risk from bleeding with anticoagulant therapy, and therefore may benefit from the use of a vena cava filter.
The Medical Research Foundation of Royal Perth Hospital and the Western Australian Department of Health funded the study. Dr. Ho reported funding from the Western Australian Department of Health and the Raine Medical Research Foundation to conduct the study, as well as serving as an adviser to Medtronic and Cardinal Health.
SOURCE: Ho KM et al. N Engl J Med. 2019 Jul 7. doi: 10.156/NEJMoa1806515.
MELBOURNE – Use of a prophylactic vena cava filter to trap blood clots in severely injured patients does not appear to reduce the risk of pulmonary embolism or death, according to data presented at the International Society on Thrombosis and Haemostasis congress.
The researchers reported the outcomes of a multicenter, controlled trial in which 240 severely injured patients with a contraindication to anticoagulants were randomized to receive a vena cava filter within 72 hours of admission, or no filter. The findings were published simultaneously in the New England Journal of Medicine.
The study showed no significant differences between the filter and no-filter groups in the primary outcome of a composite of symptomatic pulmonary embolism or death from any cause at 90 days after enrollment (13.9% vs. 14.4% respectively, P = .98).
In a prespecified subgroup analysis, researchers examined patients who survived 7 days after injury and did not receive prophylactic anticoagulation in those 7 days. Among this group of patients, none of those who received the vena cava filter experienced a symptomatic pulmonary embolism between day 8 and day 90, but five patients (14.7%) in the no-filter group did.
Filters were left in place for a median duration of 27 days (11-90 days). Among the 122 patients who received a filter – which included two patients in the control group – researchers found trapped thrombi in the filter in six patients.
Transfusion requirements, and the incidence of major and nonmajor bleeding and leg deep vein thrombosis, were similar between the filter and no-filter groups. Seven patients in the filter group (5.7%) required more than one attempt to remove the filter, and in one patient the filter had to be removed surgically.
Kwok M. Ho, PhD, of the department of intensive care medicine at Royal Perth Hospital, Australia, and coauthors wrote that while vena cava filters are widely used in trauma centers to prevent pulmonary embolism in patients at high risk of bleeding, there are conflicting recommendations regarding their use, and most studies so far have been observational.
“Given the cost and risks associated with a vena cava filter, our data suggest that there is no urgency to insert the filter in patients who can be treated with prophylactic anticoagulation within 7 days after injury,” they wrote. “Unnecessary insertion of a vena cava filter has the potential to cause harm.”
However, they noted that patients with multiple, large intracranial hematomas were particularly at risk from bleeding with anticoagulant therapy, and therefore may benefit from the use of a vena cava filter.
The Medical Research Foundation of Royal Perth Hospital and the Western Australian Department of Health funded the study. Dr. Ho reported funding from the Western Australian Department of Health and the Raine Medical Research Foundation to conduct the study, as well as serving as an adviser to Medtronic and Cardinal Health.
SOURCE: Ho KM et al. N Engl J Med. 2019 Jul 7. doi: 10.156/NEJMoa1806515.
MELBOURNE – Use of a prophylactic vena cava filter to trap blood clots in severely injured patients does not appear to reduce the risk of pulmonary embolism or death, according to data presented at the International Society on Thrombosis and Haemostasis congress.
The researchers reported the outcomes of a multicenter, controlled trial in which 240 severely injured patients with a contraindication to anticoagulants were randomized to receive a vena cava filter within 72 hours of admission, or no filter. The findings were published simultaneously in the New England Journal of Medicine.
The study showed no significant differences between the filter and no-filter groups in the primary outcome of a composite of symptomatic pulmonary embolism or death from any cause at 90 days after enrollment (13.9% vs. 14.4% respectively, P = .98).
In a prespecified subgroup analysis, researchers examined patients who survived 7 days after injury and did not receive prophylactic anticoagulation in those 7 days. Among this group of patients, none of those who received the vena cava filter experienced a symptomatic pulmonary embolism between day 8 and day 90, but five patients (14.7%) in the no-filter group did.
Filters were left in place for a median duration of 27 days (11-90 days). Among the 122 patients who received a filter – which included two patients in the control group – researchers found trapped thrombi in the filter in six patients.
Transfusion requirements, and the incidence of major and nonmajor bleeding and leg deep vein thrombosis, were similar between the filter and no-filter groups. Seven patients in the filter group (5.7%) required more than one attempt to remove the filter, and in one patient the filter had to be removed surgically.
Kwok M. Ho, PhD, of the department of intensive care medicine at Royal Perth Hospital, Australia, and coauthors wrote that while vena cava filters are widely used in trauma centers to prevent pulmonary embolism in patients at high risk of bleeding, there are conflicting recommendations regarding their use, and most studies so far have been observational.
“Given the cost and risks associated with a vena cava filter, our data suggest that there is no urgency to insert the filter in patients who can be treated with prophylactic anticoagulation within 7 days after injury,” they wrote. “Unnecessary insertion of a vena cava filter has the potential to cause harm.”
However, they noted that patients with multiple, large intracranial hematomas were particularly at risk from bleeding with anticoagulant therapy, and therefore may benefit from the use of a vena cava filter.
The Medical Research Foundation of Royal Perth Hospital and the Western Australian Department of Health funded the study. Dr. Ho reported funding from the Western Australian Department of Health and the Raine Medical Research Foundation to conduct the study, as well as serving as an adviser to Medtronic and Cardinal Health.
SOURCE: Ho KM et al. N Engl J Med. 2019 Jul 7. doi: 10.156/NEJMoa1806515.
REPORTING FROM 2019 ISTH CONGRESS
Consider bleeding risk with oral anticoagulants in patients with GI cancer
MELBOURNE – The treatment of cancer-associated thrombosis may be complicated by increased bleeding risk in patients with gastrointestinal cancer, in whom direct oral anticoagulants may not be the ideal first choice, one expert reported at the International Society on Thrombosis and Haemostasis congress.
Agnes Y.Y. Lee, MD, medical director of the Thrombosis Program at Vancouver General Hospital and the University of British Columbia, spoke about the challenges and necessity of treating cancer-associated thrombosis, pointing out that about 20% of all cases of venous thromboembolism (VTE) are associated with cancer.
“In those with cancer, thrombosis can also interfere with cancer treatment, increases health care costs, and is extraordinarily burdensome to patients and their families,” she said. “Fortunately the most effective way to reduce this burden is to use anticoagulant therapy for prevention and treatment.”
While direct oral anticoagulants have been shown in several studies to be comparable to warfarin in treating most patients with thrombosis, Dr. Lee said there has been a question of how they compare in safety and efficacy to low-molecular-weight heparin in individuals with cancer.
Data from the Hokusai VTE Cancer trial, which compared oral edoxaban with subcutaneous dalteparin in patients with cancer, showed that the two treatments were comparable in time to first occurrence of thrombosis. However, the study did show a fourfold higher risk of bleeding with edoxaban, compared with that of dalteparin, among individuals with gastrointestinal cancers, a difference in bleeding rate that was not seen in patients with nongastrointestinal cancers, Dr. Lee said.
Dr. Lee pointed out that this study also showed a higher bleeding risk in patients with other bleeding risk factors, including those with primary or metastatic brain cancer.
“This study also showed that, when patients developed major bleeding, 60%-80% of them required hospitalization or an ICU stay, so major bleeding is a serious complication and certainly will increase the cost of therapy for these patients,” she said.
In the SELECT-D pilot study, which compared rivaroxaban with dalteparin in patients with cancer, there was a higher risk of bleeding for patients with esophageal or gastroesophageal cancers.
Bleeding risk is generally not well addressed in current guidelines on managing hemostasis in patients with malignancies, partly because it is difficult to quantify bleeding in these patients whose hemoglobin levels would be affected by their disease and their chemotherapy, Dr. Lee said in an interview.
“The bleeding events in cancer patients do get more complicated because there’s all this other noise in the background,” she said.
Commenting on her personal approach to treatment, Dr. Lee said she favors starting patients on low-molecular-weight heparin because it gives her time to understand patients, their disease, and their needs.
“A lot of patients arrive, and they can’t really tell me what their cancer is doing, they can’t really tell me what cancer therapy they’re going through,” she says. “And if they’re on a long list of drugs, then I have to talk to my pharmacist about whether there are drug-drug interactions.”
If patients were well managed on low-molecular-weight heparin without any bleeding, then Dr. Lee said she would consider switching them to direct oral anticoagulants.
Cochair of the session, Ingrid Pabinger, MD, from the Medical University of Vienna commented that vitamin K antagonists should not be forgotten because some patients are unable to afford low-molecular-weight heparin.
However Dr. Lee said these were last on the list for her because of the risk of drug-drug interactions, drug-food interactions, and the issues faced by patients experiencing vomiting or diarrhea with their chemotherapy.
Dr. Lee reported research funding, consultancies, and honoraria from the pharmaceutical sector.
MELBOURNE – The treatment of cancer-associated thrombosis may be complicated by increased bleeding risk in patients with gastrointestinal cancer, in whom direct oral anticoagulants may not be the ideal first choice, one expert reported at the International Society on Thrombosis and Haemostasis congress.
Agnes Y.Y. Lee, MD, medical director of the Thrombosis Program at Vancouver General Hospital and the University of British Columbia, spoke about the challenges and necessity of treating cancer-associated thrombosis, pointing out that about 20% of all cases of venous thromboembolism (VTE) are associated with cancer.
“In those with cancer, thrombosis can also interfere with cancer treatment, increases health care costs, and is extraordinarily burdensome to patients and their families,” she said. “Fortunately the most effective way to reduce this burden is to use anticoagulant therapy for prevention and treatment.”
While direct oral anticoagulants have been shown in several studies to be comparable to warfarin in treating most patients with thrombosis, Dr. Lee said there has been a question of how they compare in safety and efficacy to low-molecular-weight heparin in individuals with cancer.
Data from the Hokusai VTE Cancer trial, which compared oral edoxaban with subcutaneous dalteparin in patients with cancer, showed that the two treatments were comparable in time to first occurrence of thrombosis. However, the study did show a fourfold higher risk of bleeding with edoxaban, compared with that of dalteparin, among individuals with gastrointestinal cancers, a difference in bleeding rate that was not seen in patients with nongastrointestinal cancers, Dr. Lee said.
Dr. Lee pointed out that this study also showed a higher bleeding risk in patients with other bleeding risk factors, including those with primary or metastatic brain cancer.
“This study also showed that, when patients developed major bleeding, 60%-80% of them required hospitalization or an ICU stay, so major bleeding is a serious complication and certainly will increase the cost of therapy for these patients,” she said.
In the SELECT-D pilot study, which compared rivaroxaban with dalteparin in patients with cancer, there was a higher risk of bleeding for patients with esophageal or gastroesophageal cancers.
Bleeding risk is generally not well addressed in current guidelines on managing hemostasis in patients with malignancies, partly because it is difficult to quantify bleeding in these patients whose hemoglobin levels would be affected by their disease and their chemotherapy, Dr. Lee said in an interview.
“The bleeding events in cancer patients do get more complicated because there’s all this other noise in the background,” she said.
Commenting on her personal approach to treatment, Dr. Lee said she favors starting patients on low-molecular-weight heparin because it gives her time to understand patients, their disease, and their needs.
“A lot of patients arrive, and they can’t really tell me what their cancer is doing, they can’t really tell me what cancer therapy they’re going through,” she says. “And if they’re on a long list of drugs, then I have to talk to my pharmacist about whether there are drug-drug interactions.”
If patients were well managed on low-molecular-weight heparin without any bleeding, then Dr. Lee said she would consider switching them to direct oral anticoagulants.
Cochair of the session, Ingrid Pabinger, MD, from the Medical University of Vienna commented that vitamin K antagonists should not be forgotten because some patients are unable to afford low-molecular-weight heparin.
However Dr. Lee said these were last on the list for her because of the risk of drug-drug interactions, drug-food interactions, and the issues faced by patients experiencing vomiting or diarrhea with their chemotherapy.
Dr. Lee reported research funding, consultancies, and honoraria from the pharmaceutical sector.
MELBOURNE – The treatment of cancer-associated thrombosis may be complicated by increased bleeding risk in patients with gastrointestinal cancer, in whom direct oral anticoagulants may not be the ideal first choice, one expert reported at the International Society on Thrombosis and Haemostasis congress.
Agnes Y.Y. Lee, MD, medical director of the Thrombosis Program at Vancouver General Hospital and the University of British Columbia, spoke about the challenges and necessity of treating cancer-associated thrombosis, pointing out that about 20% of all cases of venous thromboembolism (VTE) are associated with cancer.
“In those with cancer, thrombosis can also interfere with cancer treatment, increases health care costs, and is extraordinarily burdensome to patients and their families,” she said. “Fortunately the most effective way to reduce this burden is to use anticoagulant therapy for prevention and treatment.”
While direct oral anticoagulants have been shown in several studies to be comparable to warfarin in treating most patients with thrombosis, Dr. Lee said there has been a question of how they compare in safety and efficacy to low-molecular-weight heparin in individuals with cancer.
Data from the Hokusai VTE Cancer trial, which compared oral edoxaban with subcutaneous dalteparin in patients with cancer, showed that the two treatments were comparable in time to first occurrence of thrombosis. However, the study did show a fourfold higher risk of bleeding with edoxaban, compared with that of dalteparin, among individuals with gastrointestinal cancers, a difference in bleeding rate that was not seen in patients with nongastrointestinal cancers, Dr. Lee said.
Dr. Lee pointed out that this study also showed a higher bleeding risk in patients with other bleeding risk factors, including those with primary or metastatic brain cancer.
“This study also showed that, when patients developed major bleeding, 60%-80% of them required hospitalization or an ICU stay, so major bleeding is a serious complication and certainly will increase the cost of therapy for these patients,” she said.
In the SELECT-D pilot study, which compared rivaroxaban with dalteparin in patients with cancer, there was a higher risk of bleeding for patients with esophageal or gastroesophageal cancers.
Bleeding risk is generally not well addressed in current guidelines on managing hemostasis in patients with malignancies, partly because it is difficult to quantify bleeding in these patients whose hemoglobin levels would be affected by their disease and their chemotherapy, Dr. Lee said in an interview.
“The bleeding events in cancer patients do get more complicated because there’s all this other noise in the background,” she said.
Commenting on her personal approach to treatment, Dr. Lee said she favors starting patients on low-molecular-weight heparin because it gives her time to understand patients, their disease, and their needs.
“A lot of patients arrive, and they can’t really tell me what their cancer is doing, they can’t really tell me what cancer therapy they’re going through,” she says. “And if they’re on a long list of drugs, then I have to talk to my pharmacist about whether there are drug-drug interactions.”
If patients were well managed on low-molecular-weight heparin without any bleeding, then Dr. Lee said she would consider switching them to direct oral anticoagulants.
Cochair of the session, Ingrid Pabinger, MD, from the Medical University of Vienna commented that vitamin K antagonists should not be forgotten because some patients are unable to afford low-molecular-weight heparin.
However Dr. Lee said these were last on the list for her because of the risk of drug-drug interactions, drug-food interactions, and the issues faced by patients experiencing vomiting or diarrhea with their chemotherapy.
Dr. Lee reported research funding, consultancies, and honoraria from the pharmaceutical sector.
EXPERT ANALYSIS FROM 2019 ISTH CONGRESS