Thrombosis

Audience at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice

DUBROVNIK, CROATIA—An updated scoring system can more accurately identify lymphoma patients who may require thromboprophylaxis, according to researchers.

The revised scoring system, ThroLy, proved more effective than other systems for predicting thromboembolic events in lymphoma patients.

Researchers found the updated ThroLy had a positive predictive value of 22% to 25%, a negative predictive value of 96%, sensitivity of 56% to 57%, and specificity of 85% to 87%.

Darko Antić, MD, PhD, of the University of Belgrade in Serbia, presented these findings at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Antić said he and his colleagues developed ThroLy because other systems used to predict venous thromboembolism (VTE) are not quite right for lymphoma. He noted that the Padua score is not designed for cancer patients, and the Khorana score is predominantly for solid tumor malignancies.

“It’s good . . . , but it’s not specific for lymphoma patients,” Dr. Antić said.

With this in mind, he and his colleagues developed ThroLy. They based the scoring system on variables used in the Padua and Khorana systems as well as variables that are specific to lymphoma patients.

In a past study*, the researchers found several variables that were independently associated with risk for VTE in lymphoma:

• Previous VTE
• Previous acute myocardial infarction/stroke
• Mediastinal involvement
• Body mass index > 30 kg/m²
• Reduced mobility
• Extranodal localization
• Development of neutropenia
• Hemoglobin level < 100g/L.

Previous VTE, previous acute myocardial infarction/stroke, obesity, and mediastinal involvement were all worth 2 points, and the other factors were worth a single point.

Patients with scores of 0 to 1 were considered low-risk, patients with scores of 2 to 3 were considered intermediate-risk, and patients with scores of 4 or greater were considered high-risk.

Prospective validation

To validate and refine ThroLy, Dr. Antić and his colleagues used it to assess 1723 lymphoma patients treated at 8 institutions in Austria, Croatia, France, Jordan, Macedonia, Spain, Switzerland, and the United States.

Patients had indolent non-Hodgkin lymphoma (n=467), aggressive non-Hodgkin lymphoma (n=647), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=235), and Hodgkin lymphoma (n=366). Most subjects (84%) were outpatients.

Nine percent of patients had thrombosis (n=142), with 7% having VTE (n=121).

ThroLy had a positive predictive value of 17%, compared to 11% with Khorana and 13% with Padua. The negative predictive value was 93%, 92%, and 95%, respectively.

The sensitivity was 51% with ThroLy, 42% with Khorana, and 70% with Padua. The specificity was 72%, 64%, and 52%, respectively.

“The positive predictive value was low [with ThroLy] but definitely higher than the positive predictive value of the other two [scoring systems],” Dr. Antić noted.

Updated models

To further improve ThroLy, the researchers updated the system, creating two new models.

Model 1 included the following variables:

• Type of lymphoma/clinical stage (aggressive/advanced)—1 point
• Previous VTE—5 points
• Reduced mobility—2 points
• Hemoglobin level < 100 g/L—1 point
• Presence of vascular devices—1 point.

Model 2 included all of the aforementioned variables as well as thrombophilic condition, which was worth 1 point.

With these models, patients were divided into two risk groups—low-risk (≤ 2 points) and high-risk (>2 points).

For Model 1, the positive predictive value was 22%, the negative predictive value was 96%, the sensitivity was 56%, and the specificity was 85%.

For Model 2, the positive predictive value was 25%, the negative predictive value was 96%, the sensitivity was 57%, and the specificity was 87%.

Dr. Antić said there were no major differences in model discrimination and calibration according to the country in which a patient was treated or whether patients were treated in inpatient or outpatient settings.

Dr. Antić did not report any conflicts of interest.

*Antić D et al. Am J Hematol. 2016 Oct;91(10):1014-9. doi: 10.1002/ajh.24466.

Audience at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice

DUBROVNIK, CROATIA—An updated scoring system can more accurately identify lymphoma patients who may require thromboprophylaxis, according to researchers.

The revised scoring system, ThroLy, proved more effective than other systems for predicting thromboembolic events in lymphoma patients.

Researchers found the updated ThroLy had a positive predictive value of 22% to 25%, a negative predictive value of 96%, sensitivity of 56% to 57%, and specificity of 85% to 87%.

Darko Antić, MD, PhD, of the University of Belgrade in Serbia, presented these findings at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Antić said he and his colleagues developed ThroLy because other systems used to predict venous thromboembolism (VTE) are not quite right for lymphoma. He noted that the Padua score is not designed for cancer patients, and the Khorana score is predominantly for solid tumor malignancies.

“It’s good . . . , but it’s not specific for lymphoma patients,” Dr. Antić said.

With this in mind, he and his colleagues developed ThroLy. They based the scoring system on variables used in the Padua and Khorana systems as well as variables that are specific to lymphoma patients.

In a past study*, the researchers found several variables that were independently associated with risk for VTE in lymphoma:

• Previous VTE
• Previous acute myocardial infarction/stroke
• Mediastinal involvement
• Body mass index > 30 kg/m²
• Reduced mobility
• Extranodal localization
• Development of neutropenia
• Hemoglobin level < 100g/L.

Previous VTE, previous acute myocardial infarction/stroke, obesity, and mediastinal involvement were all worth 2 points, and the other factors were worth a single point.

Patients with scores of 0 to 1 were considered low-risk, patients with scores of 2 to 3 were considered intermediate-risk, and patients with scores of 4 or greater were considered high-risk.

Prospective validation

To validate and refine ThroLy, Dr. Antić and his colleagues used it to assess 1723 lymphoma patients treated at 8 institutions in Austria, Croatia, France, Jordan, Macedonia, Spain, Switzerland, and the United States.

Patients had indolent non-Hodgkin lymphoma (n=467), aggressive non-Hodgkin lymphoma (n=647), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=235), and Hodgkin lymphoma (n=366). Most subjects (84%) were outpatients.

Nine percent of patients had thrombosis (n=142), with 7% having VTE (n=121).

ThroLy had a positive predictive value of 17%, compared to 11% with Khorana and 13% with Padua. The negative predictive value was 93%, 92%, and 95%, respectively.

The sensitivity was 51% with ThroLy, 42% with Khorana, and 70% with Padua. The specificity was 72%, 64%, and 52%, respectively.

“The positive predictive value was low [with ThroLy] but definitely higher than the positive predictive value of the other two [scoring systems],” Dr. Antić noted.

Updated models

To further improve ThroLy, the researchers updated the system, creating two new models.

Model 1 included the following variables:

• Type of lymphoma/clinical stage (aggressive/advanced)—1 point
• Previous VTE—5 points
• Reduced mobility—2 points
• Hemoglobin level < 100 g/L—1 point
• Presence of vascular devices—1 point.

Model 2 included all of the aforementioned variables as well as thrombophilic condition, which was worth 1 point.

With these models, patients were divided into two risk groups—low-risk (≤ 2 points) and high-risk (>2 points).

For Model 1, the positive predictive value was 22%, the negative predictive value was 96%, the sensitivity was 56%, and the specificity was 85%.

For Model 2, the positive predictive value was 25%, the negative predictive value was 96%, the sensitivity was 57%, and the specificity was 87%.

Dr. Antić said there were no major differences in model discrimination and calibration according to the country in which a patient was treated or whether patients were treated in inpatient or outpatient settings.

Dr. Antić did not report any conflicts of interest.

*Antić D et al. Am J Hematol. 2016 Oct;91(10):1014-9. doi: 10.1002/ajh.24466.

Audience at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice

DUBROVNIK, CROATIA—An updated scoring system can more accurately identify lymphoma patients who may require thromboprophylaxis, according to researchers.

The revised scoring system, ThroLy, proved more effective than other systems for predicting thromboembolic events in lymphoma patients.

Researchers found the updated ThroLy had a positive predictive value of 22% to 25%, a negative predictive value of 96%, sensitivity of 56% to 57%, and specificity of 85% to 87%.

Darko Antić, MD, PhD, of the University of Belgrade in Serbia, presented these findings at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Antić said he and his colleagues developed ThroLy because other systems used to predict venous thromboembolism (VTE) are not quite right for lymphoma. He noted that the Padua score is not designed for cancer patients, and the Khorana score is predominantly for solid tumor malignancies.

“It’s good . . . , but it’s not specific for lymphoma patients,” Dr. Antić said.

With this in mind, he and his colleagues developed ThroLy. They based the scoring system on variables used in the Padua and Khorana systems as well as variables that are specific to lymphoma patients.

In a past study*, the researchers found several variables that were independently associated with risk for VTE in lymphoma:

• Previous VTE
• Previous acute myocardial infarction/stroke
• Mediastinal involvement
• Body mass index > 30 kg/m²
• Reduced mobility
• Extranodal localization
• Development of neutropenia
• Hemoglobin level < 100g/L.

Previous VTE, previous acute myocardial infarction/stroke, obesity, and mediastinal involvement were all worth 2 points, and the other factors were worth a single point.

Patients with scores of 0 to 1 were considered low-risk, patients with scores of 2 to 3 were considered intermediate-risk, and patients with scores of 4 or greater were considered high-risk.

Prospective validation

To validate and refine ThroLy, Dr. Antić and his colleagues used it to assess 1723 lymphoma patients treated at 8 institutions in Austria, Croatia, France, Jordan, Macedonia, Spain, Switzerland, and the United States.

Patients had indolent non-Hodgkin lymphoma (n=467), aggressive non-Hodgkin lymphoma (n=647), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=235), and Hodgkin lymphoma (n=366). Most subjects (84%) were outpatients.

Nine percent of patients had thrombosis (n=142), with 7% having VTE (n=121).

ThroLy had a positive predictive value of 17%, compared to 11% with Khorana and 13% with Padua. The negative predictive value was 93%, 92%, and 95%, respectively.

The sensitivity was 51% with ThroLy, 42% with Khorana, and 70% with Padua. The specificity was 72%, 64%, and 52%, respectively.

“The positive predictive value was low [with ThroLy] but definitely higher than the positive predictive value of the other two [scoring systems],” Dr. Antić noted.

Updated models

To further improve ThroLy, the researchers updated the system, creating two new models.

Model 1 included the following variables:

• Type of lymphoma/clinical stage (aggressive/advanced)—1 point
• Previous VTE—5 points
• Reduced mobility—2 points
• Hemoglobin level < 100 g/L—1 point
• Presence of vascular devices—1 point.

Model 2 included all of the aforementioned variables as well as thrombophilic condition, which was worth 1 point.

With these models, patients were divided into two risk groups—low-risk (≤ 2 points) and high-risk (>2 points).

For Model 1, the positive predictive value was 22%, the negative predictive value was 96%, the sensitivity was 56%, and the specificity was 85%.

For Model 2, the positive predictive value was 25%, the negative predictive value was 96%, the sensitivity was 57%, and the specificity was 87%.

Dr. Antić said there were no major differences in model discrimination and calibration according to the country in which a patient was treated or whether patients were treated in inpatient or outpatient settings.

Dr. Antić did not report any conflicts of interest.

*Antić D et al. Am J Hematol. 2016 Oct;91(10):1014-9. doi: 10.1002/ajh.24466.

Image by Kevin MacKenzie

Danish researchers conducted a large, 16-year study of patients with venous thromboembolism (VTE) and found a high recurrence risk in all types of VTE.

At 6 months of follow-up, patients with unprovoked and provoked VTE had similar risk of recurrence, lower than that for patients with cancer-related VTE.

But at a 10-year follow-up, patients with unprovoked VTE had a recurrence risk similar to cancer-related VTE.

Based on these findings, the investigators concluded that risk stratification for these patients needs to be optimized.

“Our findings indicate that we may need to rethink arbitrary categorization, considering the heterogeneity of patients with venous thromboembolism,” they wrote.

They published their findings in The American Journal of Medicine.

The investigators used data from 3 nationwide Danish registries to analyze the risk of recurrent VTE in 73,993 patients with incident VTE. They stratified the patients according to whether the VTE was unprovoked, provoked, or cancer-related.

Provoked VTE occurs in patients without cancer but with other contributing factors such as surgery or trauma, and unprovoked VTE occurs without well-known provoking risk factors. Investigators did not include non-melanoma skin cancer in the cancer-related VTE classification.

Median age of the study population was 62.3 years and 54.1% were women.

During a median follow-up of 3.7 years, 9,205 patients experienced a recurrent event.

At the 6-month follow-up, the recurrence rates per 100 person-years were 6.92 for provoked, 6.80 for unprovoked, and 9.06 for cancer-related VTE.

And at the 10-year follow-up, recurrence rates were 2.22 (provoked), 2.84 (unprovoked), and 3.70 (cancer-related). This corresponded to an 18% higher adjusted relative risk of recurrence for patients with unprovoked VTE than patients with provoked VTE.

The investigators observed that at 10 years, the recurrence risk following an unprovoked VTE resembled the risk of patients with cancer-related VTE.

They suggested the mechanism for this could be a “rebound thrombosis” caused by a discontinuation of oral anticoagulants after an unprovoked VTE.

The investigators noted that the findings persisted through various sensitivity analyses “conducted to challenge the robustness of our finding.”

Two areas of concern, they wrote, arise from these findings: how long to anticoagulate patients and which patients to treat.

"Optimal duration of anticoagulation is a pivotal and an ongoing scientific and clinical concern," explained lead investigator Ida Ehlers Albertsen, MD, of Aalborg University in Denmark.

"The emergence of the non-vitamin K antagonist oral anticoagulants has changed the landscape for prevention of thrombosis, and contemporary risk stratification approaches may need to be adjusted according to these effective and safer agents." 

Image by Kevin MacKenzie

Danish researchers conducted a large, 16-year study of patients with venous thromboembolism (VTE) and found a high recurrence risk in all types of VTE.

At 6 months of follow-up, patients with unprovoked and provoked VTE had similar risk of recurrence, lower than that for patients with cancer-related VTE.

But at a 10-year follow-up, patients with unprovoked VTE had a recurrence risk similar to cancer-related VTE.

Based on these findings, the investigators concluded that risk stratification for these patients needs to be optimized.

“Our findings indicate that we may need to rethink arbitrary categorization, considering the heterogeneity of patients with venous thromboembolism,” they wrote.

They published their findings in The American Journal of Medicine.

The investigators used data from 3 nationwide Danish registries to analyze the risk of recurrent VTE in 73,993 patients with incident VTE. They stratified the patients according to whether the VTE was unprovoked, provoked, or cancer-related.

Provoked VTE occurs in patients without cancer but with other contributing factors such as surgery or trauma, and unprovoked VTE occurs without well-known provoking risk factors. Investigators did not include non-melanoma skin cancer in the cancer-related VTE classification.

Median age of the study population was 62.3 years and 54.1% were women.

During a median follow-up of 3.7 years, 9,205 patients experienced a recurrent event.

At the 6-month follow-up, the recurrence rates per 100 person-years were 6.92 for provoked, 6.80 for unprovoked, and 9.06 for cancer-related VTE.

And at the 10-year follow-up, recurrence rates were 2.22 (provoked), 2.84 (unprovoked), and 3.70 (cancer-related). This corresponded to an 18% higher adjusted relative risk of recurrence for patients with unprovoked VTE than patients with provoked VTE.

The investigators observed that at 10 years, the recurrence risk following an unprovoked VTE resembled the risk of patients with cancer-related VTE.

They suggested the mechanism for this could be a “rebound thrombosis” caused by a discontinuation of oral anticoagulants after an unprovoked VTE.

The investigators noted that the findings persisted through various sensitivity analyses “conducted to challenge the robustness of our finding.”

Two areas of concern, they wrote, arise from these findings: how long to anticoagulate patients and which patients to treat.

"Optimal duration of anticoagulation is a pivotal and an ongoing scientific and clinical concern," explained lead investigator Ida Ehlers Albertsen, MD, of Aalborg University in Denmark.

"The emergence of the non-vitamin K antagonist oral anticoagulants has changed the landscape for prevention of thrombosis, and contemporary risk stratification approaches may need to be adjusted according to these effective and safer agents." 

Image by Kevin MacKenzie

Danish researchers conducted a large, 16-year study of patients with venous thromboembolism (VTE) and found a high recurrence risk in all types of VTE.

At 6 months of follow-up, patients with unprovoked and provoked VTE had similar risk of recurrence, lower than that for patients with cancer-related VTE.

But at a 10-year follow-up, patients with unprovoked VTE had a recurrence risk similar to cancer-related VTE.

Based on these findings, the investigators concluded that risk stratification for these patients needs to be optimized.

“Our findings indicate that we may need to rethink arbitrary categorization, considering the heterogeneity of patients with venous thromboembolism,” they wrote.

They published their findings in The American Journal of Medicine.

The investigators used data from 3 nationwide Danish registries to analyze the risk of recurrent VTE in 73,993 patients with incident VTE. They stratified the patients according to whether the VTE was unprovoked, provoked, or cancer-related.

Provoked VTE occurs in patients without cancer but with other contributing factors such as surgery or trauma, and unprovoked VTE occurs without well-known provoking risk factors. Investigators did not include non-melanoma skin cancer in the cancer-related VTE classification.

Median age of the study population was 62.3 years and 54.1% were women.

During a median follow-up of 3.7 years, 9,205 patients experienced a recurrent event.

At the 6-month follow-up, the recurrence rates per 100 person-years were 6.92 for provoked, 6.80 for unprovoked, and 9.06 for cancer-related VTE.

And at the 10-year follow-up, recurrence rates were 2.22 (provoked), 2.84 (unprovoked), and 3.70 (cancer-related). This corresponded to an 18% higher adjusted relative risk of recurrence for patients with unprovoked VTE than patients with provoked VTE.

The investigators observed that at 10 years, the recurrence risk following an unprovoked VTE resembled the risk of patients with cancer-related VTE.

They suggested the mechanism for this could be a “rebound thrombosis” caused by a discontinuation of oral anticoagulants after an unprovoked VTE.

The investigators noted that the findings persisted through various sensitivity analyses “conducted to challenge the robustness of our finding.”

Two areas of concern, they wrote, arise from these findings: how long to anticoagulate patients and which patients to treat.

"Optimal duration of anticoagulation is a pivotal and an ongoing scientific and clinical concern," explained lead investigator Ida Ehlers Albertsen, MD, of Aalborg University in Denmark.

"The emergence of the non-vitamin K antagonist oral anticoagulants has changed the landscape for prevention of thrombosis, and contemporary risk stratification approaches may need to be adjusted according to these effective and safer agents." 

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) approved emicizumab-kxwh (Hemlibra) for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients, including newborns, with hemophilia A with or without factor VIII (FVIII) inhibitors.

Emicizumab is a humanized bispecific factor IXa- and factor X-directed antibody for patients with congenital FVIII deficiency.

It was first approved in 2017 for hemophilia A patients with FVIII inhibitors.

The current approval expands the indication to include patients without FVIII inhibitors and provides new dosing regimens.

The FDA based the current approval on the HAVEN 3 and HAVEN 4 trials.

HAVEN 3 (NCT02847637)

This multicenter trial randomized 89 patients with severe hemophilia A without FVIII inhibitors to receive emicizumab prophylaxis at one of 3 dose levels: 1.5 mg/kg once weekly (ARM A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C). Patients had previously received on-demand treatment with FVIII.

Before the start of the trial, investigators stratified patients by 24-week bleed rate—fewer than 9 bleeds and 9 or more bleeds.

Patients were treated with emicizumab for a minimum of 24 weeks.

Patients in Arm A experienced a 96% reduction in annualized bleed rate (ABR) compared to patients with no prophylaxis (ABR ratio=0.04; P<0.0001).

Patients in Arm B had a 97% reduction in ABR compared to patients with no prophylaxis (ABR ratio=0.03; P<0.0001).

The trial met all bleed-related secondary endpoints, such as all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds.

HAVEN 4 (NCT03020160)

This was a single-arm multicenter trial in 48 adult and adolescent males with hemophilia A with or without FVIII inhibitors. The patients had previously received on-demand or prophylactic treatment with FVIII or bypassing agents.

The study was conducted in two parts: a run-in of 7 patients to determine the pharmacokinetics after a single 6 mg/kg dose in four weeks. This was followed by the same dose once every four weeks for at least 24 weeks.

The second part was an expansion cohort of 41 patients who received emicizumab at 3 mg/kg once weekly for the first four weeks followed by 6 mg/kg once every four weeks for at least 24 weeks.

The ABR for treated bleeds was 2.4 (95% CI: 1.38, 4.28) and the median ABR was 0.0 (interquartile range: 0.00, 2.08).

The recommended loading dose is 3 mg/kg once weekly for the first four weeks for all prophylactic regimens.

Safety

The prescribing information for emicizumab includes a warning about thrombotic microangiopathy and thromboembolism.

These events were reported on average when a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab prophylaxis.

According to the warning box, patients should be monitored for these events if aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab dosing suspended.

The most common adverse reactions reported for emicizumab with an incidence ≥10% were injection site reactions (22%), headache (15%), and arthralgia (15%).

Emicizumab is manufactured by Genentech, Inc., a member of the Roche Group.

Additional data on emicizumab can be found in an earlier Roche media release. 

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) approved emicizumab-kxwh (Hemlibra) for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients, including newborns, with hemophilia A with or without factor VIII (FVIII) inhibitors.

Emicizumab is a humanized bispecific factor IXa- and factor X-directed antibody for patients with congenital FVIII deficiency.

It was first approved in 2017 for hemophilia A patients with FVIII inhibitors.

The current approval expands the indication to include patients without FVIII inhibitors and provides new dosing regimens.

The FDA based the current approval on the HAVEN 3 and HAVEN 4 trials.

HAVEN 3 (NCT02847637)

This multicenter trial randomized 89 patients with severe hemophilia A without FVIII inhibitors to receive emicizumab prophylaxis at one of 3 dose levels: 1.5 mg/kg once weekly (ARM A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C). Patients had previously received on-demand treatment with FVIII.

Before the start of the trial, investigators stratified patients by 24-week bleed rate—fewer than 9 bleeds and 9 or more bleeds.

Patients were treated with emicizumab for a minimum of 24 weeks.

Patients in Arm A experienced a 96% reduction in annualized bleed rate (ABR) compared to patients with no prophylaxis (ABR ratio=0.04; P<0.0001).

Patients in Arm B had a 97% reduction in ABR compared to patients with no prophylaxis (ABR ratio=0.03; P<0.0001).

The trial met all bleed-related secondary endpoints, such as all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds.

HAVEN 4 (NCT03020160)

This was a single-arm multicenter trial in 48 adult and adolescent males with hemophilia A with or without FVIII inhibitors. The patients had previously received on-demand or prophylactic treatment with FVIII or bypassing agents.

The study was conducted in two parts: a run-in of 7 patients to determine the pharmacokinetics after a single 6 mg/kg dose in four weeks. This was followed by the same dose once every four weeks for at least 24 weeks.

The second part was an expansion cohort of 41 patients who received emicizumab at 3 mg/kg once weekly for the first four weeks followed by 6 mg/kg once every four weeks for at least 24 weeks.

The ABR for treated bleeds was 2.4 (95% CI: 1.38, 4.28) and the median ABR was 0.0 (interquartile range: 0.00, 2.08).

The recommended loading dose is 3 mg/kg once weekly for the first four weeks for all prophylactic regimens.

Safety

The prescribing information for emicizumab includes a warning about thrombotic microangiopathy and thromboembolism.

These events were reported on average when a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab prophylaxis.

According to the warning box, patients should be monitored for these events if aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab dosing suspended.

The most common adverse reactions reported for emicizumab with an incidence ≥10% were injection site reactions (22%), headache (15%), and arthralgia (15%).

Emicizumab is manufactured by Genentech, Inc., a member of the Roche Group.

Additional data on emicizumab can be found in an earlier Roche media release. 

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) approved emicizumab-kxwh (Hemlibra) for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients, including newborns, with hemophilia A with or without factor VIII (FVIII) inhibitors.

Emicizumab is a humanized bispecific factor IXa- and factor X-directed antibody for patients with congenital FVIII deficiency.

It was first approved in 2017 for hemophilia A patients with FVIII inhibitors.

The current approval expands the indication to include patients without FVIII inhibitors and provides new dosing regimens.

The FDA based the current approval on the HAVEN 3 and HAVEN 4 trials.

HAVEN 3 (NCT02847637)

This multicenter trial randomized 89 patients with severe hemophilia A without FVIII inhibitors to receive emicizumab prophylaxis at one of 3 dose levels: 1.5 mg/kg once weekly (ARM A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C). Patients had previously received on-demand treatment with FVIII.

Before the start of the trial, investigators stratified patients by 24-week bleed rate—fewer than 9 bleeds and 9 or more bleeds.

Patients were treated with emicizumab for a minimum of 24 weeks.

Patients in Arm A experienced a 96% reduction in annualized bleed rate (ABR) compared to patients with no prophylaxis (ABR ratio=0.04; P<0.0001).

Patients in Arm B had a 97% reduction in ABR compared to patients with no prophylaxis (ABR ratio=0.03; P<0.0001).

The trial met all bleed-related secondary endpoints, such as all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds.

HAVEN 4 (NCT03020160)

This was a single-arm multicenter trial in 48 adult and adolescent males with hemophilia A with or without FVIII inhibitors. The patients had previously received on-demand or prophylactic treatment with FVIII or bypassing agents.

The study was conducted in two parts: a run-in of 7 patients to determine the pharmacokinetics after a single 6 mg/kg dose in four weeks. This was followed by the same dose once every four weeks for at least 24 weeks.

The second part was an expansion cohort of 41 patients who received emicizumab at 3 mg/kg once weekly for the first four weeks followed by 6 mg/kg once every four weeks for at least 24 weeks.

The ABR for treated bleeds was 2.4 (95% CI: 1.38, 4.28) and the median ABR was 0.0 (interquartile range: 0.00, 2.08).

The recommended loading dose is 3 mg/kg once weekly for the first four weeks for all prophylactic regimens.

Safety

The prescribing information for emicizumab includes a warning about thrombotic microangiopathy and thromboembolism.

These events were reported on average when a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab prophylaxis.

According to the warning box, patients should be monitored for these events if aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab dosing suspended.

The most common adverse reactions reported for emicizumab with an incidence ≥10% were injection site reactions (22%), headache (15%), and arthralgia (15%).

Emicizumab is manufactured by Genentech, Inc., a member of the Roche Group.

Additional data on emicizumab can be found in an earlier Roche media release. 

Women who use combined oral contraceptives (COC) without hormone-free or low-dose hormone intervals have a slightly elevated, but not statistically significant, risk of venous thromboembolism (VTE), compared with women who use cyclic COCs, according to research published in JAMA Internal Medicine.

areeya_ann/Thinkstock

Jie Li, PhD, from the Center for Drug Evaluation and Research, and colleagues performed a retrospective cohort study of 733,007 women aged 18-50 years in the Sentinel Distributed Database from 2007 to 2015 who received low-dose extended and continuous cycle (210,691 women; mean age, 30 years) COCs or cyclic COCs (522,316 women; mean age, 29 years). Continuous cycle COCs were defined as an 84/7 cycle or a 365/0 cycle, while cyclic COCs were 21/7 cycles.

The researchers noted some baseline differences between the two groups, with gynecologic conditions occurring in 40% of the noncyclic group, compared with 32% in the cyclic group; cardiovascular and metabolic conditions occurring in 7% of noncyclic women, compared with 5% of cyclic women; inflammatory disease occurring in 3% of noncyclic women, compared with 2% of cyclic women; and a slightly higher rate of health care services use in the noncyclic group, compared with the cyclic group.

Dr. Li and associates found 228 cases of VTE in the noncyclic group and 297 cases in the cyclic group, with an incidence rate of 1.54 (95% confidence interval, 1.34-1.74) per 1,000 person-years for noncyclic users and 0.83 (95% CI, 0.74-0.93) per 1,000 person-years for cyclic users (crude hazard ratio, 1.84; 95% CI, 1.53-2.21).

However, propensity score matching lowered the incidence rate to 1.44 (95% CI, 1.24-1.64) per 1,000 person-years for the noncyclic group and raised it to 1.09 (95% CI, 0.92-1.27) per 1,000 person-years for the cyclic group, for an adjusted hazard ratio of 1.32 (95% CI, 1.07-1.64), which does not show “strong evidence” of VTE risk based on a small absolute risk difference of 0.27 cases per 1,000 persons, the researchers said. They added that there might be residual or unmeasured confounding, perhaps for potential concurrent medication use or incompletely measured covariates.

“Accordingly, we do not recommend selective prescribing of COCs based on the cyclic and continuous/extended type,” Dr. Li and colleagues wrote. “Clinicians should prescribe COCs based on patients’ individual risk factors and preferences.”

The Sentinel Initiative is funded by a contract from the Department of Health and Human Services. The authors reported no relevant conflicts of interest.

SOURCE: Li J et al. JAMA Intern Med. 2018 Oct 1. doi: 10.1001/jamainternmed.2018.4251.

Women who use combined oral contraceptives (COC) without hormone-free or low-dose hormone intervals have a slightly elevated, but not statistically significant, risk of venous thromboembolism (VTE), compared with women who use cyclic COCs, according to research published in JAMA Internal Medicine.

areeya_ann/Thinkstock

Jie Li, PhD, from the Center for Drug Evaluation and Research, and colleagues performed a retrospective cohort study of 733,007 women aged 18-50 years in the Sentinel Distributed Database from 2007 to 2015 who received low-dose extended and continuous cycle (210,691 women; mean age, 30 years) COCs or cyclic COCs (522,316 women; mean age, 29 years). Continuous cycle COCs were defined as an 84/7 cycle or a 365/0 cycle, while cyclic COCs were 21/7 cycles.

The researchers noted some baseline differences between the two groups, with gynecologic conditions occurring in 40% of the noncyclic group, compared with 32% in the cyclic group; cardiovascular and metabolic conditions occurring in 7% of noncyclic women, compared with 5% of cyclic women; inflammatory disease occurring in 3% of noncyclic women, compared with 2% of cyclic women; and a slightly higher rate of health care services use in the noncyclic group, compared with the cyclic group.

Dr. Li and associates found 228 cases of VTE in the noncyclic group and 297 cases in the cyclic group, with an incidence rate of 1.54 (95% confidence interval, 1.34-1.74) per 1,000 person-years for noncyclic users and 0.83 (95% CI, 0.74-0.93) per 1,000 person-years for cyclic users (crude hazard ratio, 1.84; 95% CI, 1.53-2.21).

However, propensity score matching lowered the incidence rate to 1.44 (95% CI, 1.24-1.64) per 1,000 person-years for the noncyclic group and raised it to 1.09 (95% CI, 0.92-1.27) per 1,000 person-years for the cyclic group, for an adjusted hazard ratio of 1.32 (95% CI, 1.07-1.64), which does not show “strong evidence” of VTE risk based on a small absolute risk difference of 0.27 cases per 1,000 persons, the researchers said. They added that there might be residual or unmeasured confounding, perhaps for potential concurrent medication use or incompletely measured covariates.

“Accordingly, we do not recommend selective prescribing of COCs based on the cyclic and continuous/extended type,” Dr. Li and colleagues wrote. “Clinicians should prescribe COCs based on patients’ individual risk factors and preferences.”

The Sentinel Initiative is funded by a contract from the Department of Health and Human Services. The authors reported no relevant conflicts of interest.

SOURCE: Li J et al. JAMA Intern Med. 2018 Oct 1. doi: 10.1001/jamainternmed.2018.4251.

Women who use combined oral contraceptives (COC) without hormone-free or low-dose hormone intervals have a slightly elevated, but not statistically significant, risk of venous thromboembolism (VTE), compared with women who use cyclic COCs, according to research published in JAMA Internal Medicine.

areeya_ann/Thinkstock

Jie Li, PhD, from the Center for Drug Evaluation and Research, and colleagues performed a retrospective cohort study of 733,007 women aged 18-50 years in the Sentinel Distributed Database from 2007 to 2015 who received low-dose extended and continuous cycle (210,691 women; mean age, 30 years) COCs or cyclic COCs (522,316 women; mean age, 29 years). Continuous cycle COCs were defined as an 84/7 cycle or a 365/0 cycle, while cyclic COCs were 21/7 cycles.

The researchers noted some baseline differences between the two groups, with gynecologic conditions occurring in 40% of the noncyclic group, compared with 32% in the cyclic group; cardiovascular and metabolic conditions occurring in 7% of noncyclic women, compared with 5% of cyclic women; inflammatory disease occurring in 3% of noncyclic women, compared with 2% of cyclic women; and a slightly higher rate of health care services use in the noncyclic group, compared with the cyclic group.

Dr. Li and associates found 228 cases of VTE in the noncyclic group and 297 cases in the cyclic group, with an incidence rate of 1.54 (95% confidence interval, 1.34-1.74) per 1,000 person-years for noncyclic users and 0.83 (95% CI, 0.74-0.93) per 1,000 person-years for cyclic users (crude hazard ratio, 1.84; 95% CI, 1.53-2.21).

However, propensity score matching lowered the incidence rate to 1.44 (95% CI, 1.24-1.64) per 1,000 person-years for the noncyclic group and raised it to 1.09 (95% CI, 0.92-1.27) per 1,000 person-years for the cyclic group, for an adjusted hazard ratio of 1.32 (95% CI, 1.07-1.64), which does not show “strong evidence” of VTE risk based on a small absolute risk difference of 0.27 cases per 1,000 persons, the researchers said. They added that there might be residual or unmeasured confounding, perhaps for potential concurrent medication use or incompletely measured covariates.

“Accordingly, we do not recommend selective prescribing of COCs based on the cyclic and continuous/extended type,” Dr. Li and colleagues wrote. “Clinicians should prescribe COCs based on patients’ individual risk factors and preferences.”

The Sentinel Initiative is funded by a contract from the Department of Health and Human Services. The authors reported no relevant conflicts of interest.

SOURCE: Li J et al. JAMA Intern Med. 2018 Oct 1. doi: 10.1001/jamainternmed.2018.4251.

SAN DIEGO – In patients with atrial fibrillation and stable coronary artery disease, a randomized trial of oral anticoagulation alone versus an anticoagulant plus a single antiplatelet agent failed to establish noninferiority of the single-agent approach. The trial could not demonstrate its primary endpoint of all-cause death, myocardial infarction, stroke, or systemic embolism.

But a secondary endpoint that included major bleeding did demonstrate equivalence, leading the researchers to suggest that oral anticoagulation (OAC) alone may be sufficient in most patients.

“Combined OAC and single antiplatelet therapy is unlikely to provide net clinical benefit over OAC alone. Thus, OAC alone might be reasonable for AF [atrial fibrillation] patients beyond 1 year after coronary stenting,” Yukiko Nakano, MD, of Kyoto (Japan) University Graduate School of Medicine, said during a press conference at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation. The report was simultaneously published Sept. 24 in Circulation (doi: 10.1161/CIRCULATIONAHA.118.036768).

Jim Kling/MDedge News

The study was stopped prematurely because of insufficient recruitment, which may have contributed to the failed primary endpoint. It’s a shortcoming that befalls many such studies, perhaps because cardiologists tend to be set in their ways when it comes to treatment of patients after a stent implant. “Cardiologists just think they know the answer, and they don’t want to expose their patients (to a clinical trial). They say, ‘I have my patients on whatever regimen. It seems to be working, and they’re not bleeding, so I don’t want to change it.’ This study suggests that we probably can stop one of the two (antiplatelet drugs) and get by with a single agent, and in this case they got by with no agent (in the monotherapy arm),” said C. Michael Gibson, MD, chief of clinical research in the division of cardiology at Beth Israel Deaconess Medical Center, Boston, who was a discussant at the press conference.

The study recruited 696 patients who were receiving OAC plus single antiplatelet therapy (SAPT) 1 year after receiving a stent. They were randomized 1:1 to continue combined therapy or to stop SAPT and then followed for a median of 2.5 years. A total of 74% of patients who received OAC alone were taking warfarin, while 26% were taking a direct oral anticoagulant. The SAPT group took aspirin or clopidogrel.

Overall, 15.7% of OAC patients experienced the primary endpoint, compared with 13.6% of the combined group (noninferiority P = .20). None of the individual components of the primary endpoint were statistically significantly different between the groups. International Society on Thrombosis and Haemostasis major bleeding and Thrombolysis in Myocardial Infarction major bleeding trended in favor of OAC alone. The secondary endpoint (primary endpoint plus major bleeding) achieved noninferiority, occurring in 19.5% of the OAC group and 19.4% of the combined therapy group (noninferiority P = .016; superiority P = .96).

Daiichi-Sankyo funded the trial. Dr. Nakano had no conflicts of interest. Dr. Gibson reported numerous financial ties to pharmaceutical companies, including Daiichi-Sankyo.

SAN DIEGO – In patients with atrial fibrillation and stable coronary artery disease, a randomized trial of oral anticoagulation alone versus an anticoagulant plus a single antiplatelet agent failed to establish noninferiority of the single-agent approach. The trial could not demonstrate its primary endpoint of all-cause death, myocardial infarction, stroke, or systemic embolism.

But a secondary endpoint that included major bleeding did demonstrate equivalence, leading the researchers to suggest that oral anticoagulation (OAC) alone may be sufficient in most patients.

“Combined OAC and single antiplatelet therapy is unlikely to provide net clinical benefit over OAC alone. Thus, OAC alone might be reasonable for AF [atrial fibrillation] patients beyond 1 year after coronary stenting,” Yukiko Nakano, MD, of Kyoto (Japan) University Graduate School of Medicine, said during a press conference at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation. The report was simultaneously published Sept. 24 in Circulation (doi: 10.1161/CIRCULATIONAHA.118.036768).

Jim Kling/MDedge News

The study was stopped prematurely because of insufficient recruitment, which may have contributed to the failed primary endpoint. It’s a shortcoming that befalls many such studies, perhaps because cardiologists tend to be set in their ways when it comes to treatment of patients after a stent implant. “Cardiologists just think they know the answer, and they don’t want to expose their patients (to a clinical trial). They say, ‘I have my patients on whatever regimen. It seems to be working, and they’re not bleeding, so I don’t want to change it.’ This study suggests that we probably can stop one of the two (antiplatelet drugs) and get by with a single agent, and in this case they got by with no agent (in the monotherapy arm),” said C. Michael Gibson, MD, chief of clinical research in the division of cardiology at Beth Israel Deaconess Medical Center, Boston, who was a discussant at the press conference.

The study recruited 696 patients who were receiving OAC plus single antiplatelet therapy (SAPT) 1 year after receiving a stent. They were randomized 1:1 to continue combined therapy or to stop SAPT and then followed for a median of 2.5 years. A total of 74% of patients who received OAC alone were taking warfarin, while 26% were taking a direct oral anticoagulant. The SAPT group took aspirin or clopidogrel.

Overall, 15.7% of OAC patients experienced the primary endpoint, compared with 13.6% of the combined group (noninferiority P = .20). None of the individual components of the primary endpoint were statistically significantly different between the groups. International Society on Thrombosis and Haemostasis major bleeding and Thrombolysis in Myocardial Infarction major bleeding trended in favor of OAC alone. The secondary endpoint (primary endpoint plus major bleeding) achieved noninferiority, occurring in 19.5% of the OAC group and 19.4% of the combined therapy group (noninferiority P = .016; superiority P = .96).

Daiichi-Sankyo funded the trial. Dr. Nakano had no conflicts of interest. Dr. Gibson reported numerous financial ties to pharmaceutical companies, including Daiichi-Sankyo.

SAN DIEGO – In patients with atrial fibrillation and stable coronary artery disease, a randomized trial of oral anticoagulation alone versus an anticoagulant plus a single antiplatelet agent failed to establish noninferiority of the single-agent approach. The trial could not demonstrate its primary endpoint of all-cause death, myocardial infarction, stroke, or systemic embolism.

But a secondary endpoint that included major bleeding did demonstrate equivalence, leading the researchers to suggest that oral anticoagulation (OAC) alone may be sufficient in most patients.

“Combined OAC and single antiplatelet therapy is unlikely to provide net clinical benefit over OAC alone. Thus, OAC alone might be reasonable for AF [atrial fibrillation] patients beyond 1 year after coronary stenting,” Yukiko Nakano, MD, of Kyoto (Japan) University Graduate School of Medicine, said during a press conference at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation. The report was simultaneously published Sept. 24 in Circulation (doi: 10.1161/CIRCULATIONAHA.118.036768).

Jim Kling/MDedge News

The study was stopped prematurely because of insufficient recruitment, which may have contributed to the failed primary endpoint. It’s a shortcoming that befalls many such studies, perhaps because cardiologists tend to be set in their ways when it comes to treatment of patients after a stent implant. “Cardiologists just think they know the answer, and they don’t want to expose their patients (to a clinical trial). They say, ‘I have my patients on whatever regimen. It seems to be working, and they’re not bleeding, so I don’t want to change it.’ This study suggests that we probably can stop one of the two (antiplatelet drugs) and get by with a single agent, and in this case they got by with no agent (in the monotherapy arm),” said C. Michael Gibson, MD, chief of clinical research in the division of cardiology at Beth Israel Deaconess Medical Center, Boston, who was a discussant at the press conference.

The study recruited 696 patients who were receiving OAC plus single antiplatelet therapy (SAPT) 1 year after receiving a stent. They were randomized 1:1 to continue combined therapy or to stop SAPT and then followed for a median of 2.5 years. A total of 74% of patients who received OAC alone were taking warfarin, while 26% were taking a direct oral anticoagulant. The SAPT group took aspirin or clopidogrel.

Overall, 15.7% of OAC patients experienced the primary endpoint, compared with 13.6% of the combined group (noninferiority P = .20). None of the individual components of the primary endpoint were statistically significantly different between the groups. International Society on Thrombosis and Haemostasis major bleeding and Thrombolysis in Myocardial Infarction major bleeding trended in favor of OAC alone. The secondary endpoint (primary endpoint plus major bleeding) achieved noninferiority, occurring in 19.5% of the OAC group and 19.4% of the combined therapy group (noninferiority P = .016; superiority P = .96).

Daiichi-Sankyo funded the trial. Dr. Nakano had no conflicts of interest. Dr. Gibson reported numerous financial ties to pharmaceutical companies, including Daiichi-Sankyo.

Universitair Medisch Centrum

Immediate compression therapy provides a “clear benefit” for patients with deep vein thrombosis (DVT), according to the senior author of a study published in Blood.

In this prospective study, patients who started compression therapy within the first 24 hours of DVT diagnosis were 20% less likely to develop residual vein occlusion (RVO) than patients who did not start compression therapy in the acute phase.

Furthermore, patients who did not develop RVO were 8% less likely to have post-thrombotic syndrome (PTS) than patients with RVO.

“We found little reason for those treating DVT not to use compression therapy as a prevention measure against future complications,” said study author Arina J. ten Cate-Hoek, MD, PhD, of Maastricht University in the Netherlands.

“Although the use of compression stockings after DVT is routine across much of Europe, it is less common in the United States, where guidelines emphasize compression primarily for patients who complain of ongoing symptoms.”

Dr. ten Cate-Hoek and her colleagues studied 592 adults with DVT who were treated in 10 centers across the Netherlands.

All patients were treated with anticoagulants, largely vitamin K antagonists (80.6%) but also direct oral anticoagulants (3.0%), investigational anticoagulants (11.1%), and low-molecular-weight heparin (4.4%).

Within 24 hours of DVT diagnosis, most patients received compression therapy (pressure 35 mmHg) with either multilayer compression bandaging (62.3%) or compression hosiery (25.5%). A minority of patients did not receive compression in the acute phase (12.2%).

The average time from DVT diagnosis to RVO assessment was 5.3 months.

The incidence of RVO was significantly lower in patients who received immediate compression than in those who did not—46.3% and 66.7%, respectively (odds ratio [OR], 0.46; P=0.005).

In addition, PTS was more common among patients with RVO.

At 6 months, the incidence of PTS was 55.7% among patients with RVO and 44.3% among patients without RVO (OR, 0.66; P=0.029). At 24 months, the incidence of PTS was 54.0% and 46.0%, respectively (OR, 0.65; P=0.013).

The researchers said there was no significant association between RVO and recurrent DVT or pulmonary embolism.

Among the 30 patients with DVT recurrence, 60% had RVO and 40% did not (OR, 0.82; P=0.263).

Among the 19 patients who had recurrent pulmonary embolism, 52.6% had RVO and 47.7% did not (OR, 0.95; P=0.805).

Dr. ten Cate-Hoek noted that compression therapy is thought to improve blood flow by reducing the diameter of veins so that blood is pushed through them more forcefully, which helps to clear clot material.

“I think we can infer from our findings that this improved blood flow certainly helps prevent complications like residual vein occlusion and post-thrombotic syndrome after DVT,” she said.

“Given these outcomes, and that compression stockings are fairly easy to self-administer, relatively inexpensive, and minimally intrusive, compression therapy offers a clear benefit for all patients with DVT.”

Universitair Medisch Centrum

Immediate compression therapy provides a “clear benefit” for patients with deep vein thrombosis (DVT), according to the senior author of a study published in Blood.

In this prospective study, patients who started compression therapy within the first 24 hours of DVT diagnosis were 20% less likely to develop residual vein occlusion (RVO) than patients who did not start compression therapy in the acute phase.

Furthermore, patients who did not develop RVO were 8% less likely to have post-thrombotic syndrome (PTS) than patients with RVO.

“We found little reason for those treating DVT not to use compression therapy as a prevention measure against future complications,” said study author Arina J. ten Cate-Hoek, MD, PhD, of Maastricht University in the Netherlands.

“Although the use of compression stockings after DVT is routine across much of Europe, it is less common in the United States, where guidelines emphasize compression primarily for patients who complain of ongoing symptoms.”

Dr. ten Cate-Hoek and her colleagues studied 592 adults with DVT who were treated in 10 centers across the Netherlands.

All patients were treated with anticoagulants, largely vitamin K antagonists (80.6%) but also direct oral anticoagulants (3.0%), investigational anticoagulants (11.1%), and low-molecular-weight heparin (4.4%).

Within 24 hours of DVT diagnosis, most patients received compression therapy (pressure 35 mmHg) with either multilayer compression bandaging (62.3%) or compression hosiery (25.5%). A minority of patients did not receive compression in the acute phase (12.2%).

The average time from DVT diagnosis to RVO assessment was 5.3 months.

The incidence of RVO was significantly lower in patients who received immediate compression than in those who did not—46.3% and 66.7%, respectively (odds ratio [OR], 0.46; P=0.005).

In addition, PTS was more common among patients with RVO.

At 6 months, the incidence of PTS was 55.7% among patients with RVO and 44.3% among patients without RVO (OR, 0.66; P=0.029). At 24 months, the incidence of PTS was 54.0% and 46.0%, respectively (OR, 0.65; P=0.013).

The researchers said there was no significant association between RVO and recurrent DVT or pulmonary embolism.

Among the 30 patients with DVT recurrence, 60% had RVO and 40% did not (OR, 0.82; P=0.263).

Among the 19 patients who had recurrent pulmonary embolism, 52.6% had RVO and 47.7% did not (OR, 0.95; P=0.805).

Dr. ten Cate-Hoek noted that compression therapy is thought to improve blood flow by reducing the diameter of veins so that blood is pushed through them more forcefully, which helps to clear clot material.

“I think we can infer from our findings that this improved blood flow certainly helps prevent complications like residual vein occlusion and post-thrombotic syndrome after DVT,” she said.

“Given these outcomes, and that compression stockings are fairly easy to self-administer, relatively inexpensive, and minimally intrusive, compression therapy offers a clear benefit for all patients with DVT.”

Universitair Medisch Centrum

Immediate compression therapy provides a “clear benefit” for patients with deep vein thrombosis (DVT), according to the senior author of a study published in Blood.

In this prospective study, patients who started compression therapy within the first 24 hours of DVT diagnosis were 20% less likely to develop residual vein occlusion (RVO) than patients who did not start compression therapy in the acute phase.

Furthermore, patients who did not develop RVO were 8% less likely to have post-thrombotic syndrome (PTS) than patients with RVO.

“We found little reason for those treating DVT not to use compression therapy as a prevention measure against future complications,” said study author Arina J. ten Cate-Hoek, MD, PhD, of Maastricht University in the Netherlands.

“Although the use of compression stockings after DVT is routine across much of Europe, it is less common in the United States, where guidelines emphasize compression primarily for patients who complain of ongoing symptoms.”

Dr. ten Cate-Hoek and her colleagues studied 592 adults with DVT who were treated in 10 centers across the Netherlands.

All patients were treated with anticoagulants, largely vitamin K antagonists (80.6%) but also direct oral anticoagulants (3.0%), investigational anticoagulants (11.1%), and low-molecular-weight heparin (4.4%).

Within 24 hours of DVT diagnosis, most patients received compression therapy (pressure 35 mmHg) with either multilayer compression bandaging (62.3%) or compression hosiery (25.5%). A minority of patients did not receive compression in the acute phase (12.2%).

The average time from DVT diagnosis to RVO assessment was 5.3 months.

The incidence of RVO was significantly lower in patients who received immediate compression than in those who did not—46.3% and 66.7%, respectively (odds ratio [OR], 0.46; P=0.005).

In addition, PTS was more common among patients with RVO.

At 6 months, the incidence of PTS was 55.7% among patients with RVO and 44.3% among patients without RVO (OR, 0.66; P=0.029). At 24 months, the incidence of PTS was 54.0% and 46.0%, respectively (OR, 0.65; P=0.013).

The researchers said there was no significant association between RVO and recurrent DVT or pulmonary embolism.

Among the 30 patients with DVT recurrence, 60% had RVO and 40% did not (OR, 0.82; P=0.263).

Among the 19 patients who had recurrent pulmonary embolism, 52.6% had RVO and 47.7% did not (OR, 0.95; P=0.805).

Dr. ten Cate-Hoek noted that compression therapy is thought to improve blood flow by reducing the diameter of veins so that blood is pushed through them more forcefully, which helps to clear clot material.

“I think we can infer from our findings that this improved blood flow certainly helps prevent complications like residual vein occlusion and post-thrombotic syndrome after DVT,” she said.

“Given these outcomes, and that compression stockings are fairly easy to self-administer, relatively inexpensive, and minimally intrusive, compression therapy offers a clear benefit for all patients with DVT.”

Synthetic cannabinoids laced with superwarfarin were behind a recent outbreak of severe coagulopathy in Illinois.

In most cases, vitamin K replacement therapy alleviated symptoms, but four patients died after developing intracranial bleeding, said Amar H. Kelkar, MD, of the University of Illinois at Peoria.

Experts continue to look for how and why superwarfarin ended up in synthetic cannabinoids, whose street names include spice and K2, wrote Dr. Kelkar and his associates. Their report is in the New England Journal of Medicine.

Starting in March 2018, more than 150 patients across Illinois presented to hospitals with bleeding diathesis that involved persistent coagulopathy, the investigators explained. Early inquiries revealed that patients had consumed synthetic cannabinoids. Serum tests identified vitamin K antagonists, including brodifacoum, bromadiolone, and difenacoum. During arrests of suspected distributors, police confiscated synthetic cannabinoids that also tested positive for brodifacoum.

To help characterize the outbreak, the investigators reviewed admissions to Saint Francis Medical Center in Peoria, Ill., between March 28 and April 21, 2018. They identified 34 cases in which patients with vitamin K–dependent factor coagulopathy reported recent exposure to synthetic cannabinoids.

Fifteen of these patients underwent confirmatory anticoagulant testing, which universally confirmed superwarfarin poisoning. Brodifacoum was detected in all patients, difenacoum in five patients, bromadiolone in two patients, and warfarin in one patient.

Common presenting symptoms included gross hematuria (56% of patients) and abdominal pain (47%). Computed tomography identified renal abnormalities in 12 patients.

All patients received oral vitamin K₁ (phytonadione). Red cell transfusions, fresh-frozen plasma infusions, and 4-factor prothrombin complex concentrate, or a combination of these treatments, were also used in some patients.

Among the four confirmed deaths in this outbreak, one occurred in a patient in this case series. The patient, a 37-year-old woman presenting to the emergency department with markedly reduced consciousness, was reported by her friends to have recently used synthetic cannabinoids and methamphetamine. She had no personal or family history of coagulopathy.

Computed tomography of the head without contrast material revealed severe acute intraparenchymal hemorrhage of the right basal nuclei and insula with intraventricular extension, a 10-mm left-sided midline shift, and herniation.

She met criteria for brain death 15 hours after hospital admission despite treatment with 10 mg of intravenous vitamin K₁, four units of fresh frozen plasma, and 2,300 units of Kcentra.

Treating these patients after hospital discharge was difficult because of a lack of consensus guidelines and access to follow-up care, Dr. Kelkar and his associates noted. Some patients were quoted $24,000 to $34,000 per month for oral vitamin K1 therapy, which also made caring for them difficult and highlighted the need for confirmatory laboratory testing of suspected cases of superwarfarin poisoning.

Dr. Kelkar reported having no conflicts of interest. Two coinvestigators reported relationships outside the submitted work with Shire, CSL Behring, HEMA Biologics, and other companies.

SOURCE: Kelkar AH et al. N Engl J Med. 2018;379:1216-23.

Synthetic cannabinoids laced with superwarfarin were behind a recent outbreak of severe coagulopathy in Illinois.

In most cases, vitamin K replacement therapy alleviated symptoms, but four patients died after developing intracranial bleeding, said Amar H. Kelkar, MD, of the University of Illinois at Peoria.

Experts continue to look for how and why superwarfarin ended up in synthetic cannabinoids, whose street names include spice and K2, wrote Dr. Kelkar and his associates. Their report is in the New England Journal of Medicine.

Starting in March 2018, more than 150 patients across Illinois presented to hospitals with bleeding diathesis that involved persistent coagulopathy, the investigators explained. Early inquiries revealed that patients had consumed synthetic cannabinoids. Serum tests identified vitamin K antagonists, including brodifacoum, bromadiolone, and difenacoum. During arrests of suspected distributors, police confiscated synthetic cannabinoids that also tested positive for brodifacoum.

To help characterize the outbreak, the investigators reviewed admissions to Saint Francis Medical Center in Peoria, Ill., between March 28 and April 21, 2018. They identified 34 cases in which patients with vitamin K–dependent factor coagulopathy reported recent exposure to synthetic cannabinoids.

Fifteen of these patients underwent confirmatory anticoagulant testing, which universally confirmed superwarfarin poisoning. Brodifacoum was detected in all patients, difenacoum in five patients, bromadiolone in two patients, and warfarin in one patient.

Common presenting symptoms included gross hematuria (56% of patients) and abdominal pain (47%). Computed tomography identified renal abnormalities in 12 patients.

All patients received oral vitamin K₁ (phytonadione). Red cell transfusions, fresh-frozen plasma infusions, and 4-factor prothrombin complex concentrate, or a combination of these treatments, were also used in some patients.

Among the four confirmed deaths in this outbreak, one occurred in a patient in this case series. The patient, a 37-year-old woman presenting to the emergency department with markedly reduced consciousness, was reported by her friends to have recently used synthetic cannabinoids and methamphetamine. She had no personal or family history of coagulopathy.

Computed tomography of the head without contrast material revealed severe acute intraparenchymal hemorrhage of the right basal nuclei and insula with intraventricular extension, a 10-mm left-sided midline shift, and herniation.

She met criteria for brain death 15 hours after hospital admission despite treatment with 10 mg of intravenous vitamin K₁, four units of fresh frozen plasma, and 2,300 units of Kcentra.

Treating these patients after hospital discharge was difficult because of a lack of consensus guidelines and access to follow-up care, Dr. Kelkar and his associates noted. Some patients were quoted $24,000 to $34,000 per month for oral vitamin K1 therapy, which also made caring for them difficult and highlighted the need for confirmatory laboratory testing of suspected cases of superwarfarin poisoning.

Dr. Kelkar reported having no conflicts of interest. Two coinvestigators reported relationships outside the submitted work with Shire, CSL Behring, HEMA Biologics, and other companies.

SOURCE: Kelkar AH et al. N Engl J Med. 2018;379:1216-23.

Synthetic cannabinoids laced with superwarfarin were behind a recent outbreak of severe coagulopathy in Illinois.

In most cases, vitamin K replacement therapy alleviated symptoms, but four patients died after developing intracranial bleeding, said Amar H. Kelkar, MD, of the University of Illinois at Peoria.

Experts continue to look for how and why superwarfarin ended up in synthetic cannabinoids, whose street names include spice and K2, wrote Dr. Kelkar and his associates. Their report is in the New England Journal of Medicine.

Starting in March 2018, more than 150 patients across Illinois presented to hospitals with bleeding diathesis that involved persistent coagulopathy, the investigators explained. Early inquiries revealed that patients had consumed synthetic cannabinoids. Serum tests identified vitamin K antagonists, including brodifacoum, bromadiolone, and difenacoum. During arrests of suspected distributors, police confiscated synthetic cannabinoids that also tested positive for brodifacoum.

To help characterize the outbreak, the investigators reviewed admissions to Saint Francis Medical Center in Peoria, Ill., between March 28 and April 21, 2018. They identified 34 cases in which patients with vitamin K–dependent factor coagulopathy reported recent exposure to synthetic cannabinoids.

Fifteen of these patients underwent confirmatory anticoagulant testing, which universally confirmed superwarfarin poisoning. Brodifacoum was detected in all patients, difenacoum in five patients, bromadiolone in two patients, and warfarin in one patient.

Common presenting symptoms included gross hematuria (56% of patients) and abdominal pain (47%). Computed tomography identified renal abnormalities in 12 patients.

All patients received oral vitamin K₁ (phytonadione). Red cell transfusions, fresh-frozen plasma infusions, and 4-factor prothrombin complex concentrate, or a combination of these treatments, were also used in some patients.

Among the four confirmed deaths in this outbreak, one occurred in a patient in this case series. The patient, a 37-year-old woman presenting to the emergency department with markedly reduced consciousness, was reported by her friends to have recently used synthetic cannabinoids and methamphetamine. She had no personal or family history of coagulopathy.

Computed tomography of the head without contrast material revealed severe acute intraparenchymal hemorrhage of the right basal nuclei and insula with intraventricular extension, a 10-mm left-sided midline shift, and herniation.

She met criteria for brain death 15 hours after hospital admission despite treatment with 10 mg of intravenous vitamin K₁, four units of fresh frozen plasma, and 2,300 units of Kcentra.

Treating these patients after hospital discharge was difficult because of a lack of consensus guidelines and access to follow-up care, Dr. Kelkar and his associates noted. Some patients were quoted $24,000 to $34,000 per month for oral vitamin K1 therapy, which also made caring for them difficult and highlighted the need for confirmatory laboratory testing of suspected cases of superwarfarin poisoning.

Dr. Kelkar reported having no conflicts of interest. Two coinvestigators reported relationships outside the submitted work with Shire, CSL Behring, HEMA Biologics, and other companies.

SOURCE: Kelkar AH et al. N Engl J Med. 2018;379:1216-23.

Anticoagulation thresholds based on CHA₂DS₂-VASc risk score varied from population to population, researchers reported in the Annals of Internal Medicine.

After accounting for differing rates of stroke in published studies, the benefit of warfarin anticoagulation varied nearly fourfold, said Sachin J. Shah, MD, of the University of California San Francisco and his associates. They called for guidelines that “better reflect the uncertainty in current thresholds of stroke risk score for recommending anticoagulation.”

Oral anticoagulation markedly reduces risk of ischemic stroke in patients with atrial fibrillation but increases the risk of major bleeding, including intracranial hemorrhage, which often is fatal. Therefore, when deciding whether to recommend oral anticoagulation, physicians must estimate clinical net benefit by quantifying the difference between reduction in stroke risk and increase in major bleeding risk, weighted by the severity of each outcome.

Guidelines on nonvalvular atrial fibrillation from the European Society of Cardiology and joint guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society (AHA/ACC/HRS) recommend oral anticoagulation when CHA₂DS₂-VASc (congestive heart failure, hypertension, age, diabetes, stroke, and vascular disease) risk score is 2 or greater. These guidelines implicitly assume that a particular CHA₂DS₂-VASc score denotes the same amount of risk across populations, even though a recent meta-analysis found otherwise, as the researchers noted.

To further test this assumption, they applied an existing Markov model to data from more than 33,000 members of the ATRIA-CVRN cohort. All patients had nonvalvular atrial fibrillation, were members of Kaiser Permanente Northern California, and were diagnosed during 1996-1997. About 81% had a CHA₂DS₂-VASc score of at least 2. For each patient, the researchers produced four estimates of the net clinical benefit of oral anticoagulation based on ischemic stroke rates from ATRIA, the Swedish AF cohort study, the SPORTIF study, and the Danish National Patient Registry.

Optimal anticoagulation thresholds were a CHA₂DS₂-VASc score of 3 or more using stroke rates from ATRIA, 2 or more based on Swedish AF rates, 1 or more based on SPORTIF rates, and 0 or more using rates from the Danish National Patient Registry. Oral anticoagulation thresholds were lower but still varied widely after accounting for the lower rates of intracranial hemorrhage associated with non–vitamin K antagonist therapy.

Therefore, current guidelines based on CHA₂DS₂-VASc score may need revising “in favor of more accurate, individualized assessments of risk for both ischemic stroke and major bleeding,” the investigators wrote. “Until such time, guidelines should better reflect the uncertainty of the current approach in which a patient’s CHA₂DS₂-VASc score is used as the primary basis for recommending oral anticoagulation.”

The study had no primary funding source. Dr. Shah reported having no conflicts of interest. Three coinvestigators disclosed research support from relevant pharmaceutical or device companies.

SOURCE: Shah SJ et al. Ann Intern Med. 2018 Sep 25. doi: 10.7326/M17-2762  

Anticoagulation thresholds based on CHA₂DS₂-VASc risk score varied from population to population, researchers reported in the Annals of Internal Medicine.

After accounting for differing rates of stroke in published studies, the benefit of warfarin anticoagulation varied nearly fourfold, said Sachin J. Shah, MD, of the University of California San Francisco and his associates. They called for guidelines that “better reflect the uncertainty in current thresholds of stroke risk score for recommending anticoagulation.”

Oral anticoagulation markedly reduces risk of ischemic stroke in patients with atrial fibrillation but increases the risk of major bleeding, including intracranial hemorrhage, which often is fatal. Therefore, when deciding whether to recommend oral anticoagulation, physicians must estimate clinical net benefit by quantifying the difference between reduction in stroke risk and increase in major bleeding risk, weighted by the severity of each outcome.

Guidelines on nonvalvular atrial fibrillation from the European Society of Cardiology and joint guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society (AHA/ACC/HRS) recommend oral anticoagulation when CHA₂DS₂-VASc (congestive heart failure, hypertension, age, diabetes, stroke, and vascular disease) risk score is 2 or greater. These guidelines implicitly assume that a particular CHA₂DS₂-VASc score denotes the same amount of risk across populations, even though a recent meta-analysis found otherwise, as the researchers noted.

To further test this assumption, they applied an existing Markov model to data from more than 33,000 members of the ATRIA-CVRN cohort. All patients had nonvalvular atrial fibrillation, were members of Kaiser Permanente Northern California, and were diagnosed during 1996-1997. About 81% had a CHA₂DS₂-VASc score of at least 2. For each patient, the researchers produced four estimates of the net clinical benefit of oral anticoagulation based on ischemic stroke rates from ATRIA, the Swedish AF cohort study, the SPORTIF study, and the Danish National Patient Registry.

Optimal anticoagulation thresholds were a CHA₂DS₂-VASc score of 3 or more using stroke rates from ATRIA, 2 or more based on Swedish AF rates, 1 or more based on SPORTIF rates, and 0 or more using rates from the Danish National Patient Registry. Oral anticoagulation thresholds were lower but still varied widely after accounting for the lower rates of intracranial hemorrhage associated with non–vitamin K antagonist therapy.

Therefore, current guidelines based on CHA₂DS₂-VASc score may need revising “in favor of more accurate, individualized assessments of risk for both ischemic stroke and major bleeding,” the investigators wrote. “Until such time, guidelines should better reflect the uncertainty of the current approach in which a patient’s CHA₂DS₂-VASc score is used as the primary basis for recommending oral anticoagulation.”

The study had no primary funding source. Dr. Shah reported having no conflicts of interest. Three coinvestigators disclosed research support from relevant pharmaceutical or device companies.

SOURCE: Shah SJ et al. Ann Intern Med. 2018 Sep 25. doi: 10.7326/M17-2762  

Anticoagulation thresholds based on CHA₂DS₂-VASc risk score varied from population to population, researchers reported in the Annals of Internal Medicine.

After accounting for differing rates of stroke in published studies, the benefit of warfarin anticoagulation varied nearly fourfold, said Sachin J. Shah, MD, of the University of California San Francisco and his associates. They called for guidelines that “better reflect the uncertainty in current thresholds of stroke risk score for recommending anticoagulation.”

Oral anticoagulation markedly reduces risk of ischemic stroke in patients with atrial fibrillation but increases the risk of major bleeding, including intracranial hemorrhage, which often is fatal. Therefore, when deciding whether to recommend oral anticoagulation, physicians must estimate clinical net benefit by quantifying the difference between reduction in stroke risk and increase in major bleeding risk, weighted by the severity of each outcome.

Guidelines on nonvalvular atrial fibrillation from the European Society of Cardiology and joint guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society (AHA/ACC/HRS) recommend oral anticoagulation when CHA₂DS₂-VASc (congestive heart failure, hypertension, age, diabetes, stroke, and vascular disease) risk score is 2 or greater. These guidelines implicitly assume that a particular CHA₂DS₂-VASc score denotes the same amount of risk across populations, even though a recent meta-analysis found otherwise, as the researchers noted.

To further test this assumption, they applied an existing Markov model to data from more than 33,000 members of the ATRIA-CVRN cohort. All patients had nonvalvular atrial fibrillation, were members of Kaiser Permanente Northern California, and were diagnosed during 1996-1997. About 81% had a CHA₂DS₂-VASc score of at least 2. For each patient, the researchers produced four estimates of the net clinical benefit of oral anticoagulation based on ischemic stroke rates from ATRIA, the Swedish AF cohort study, the SPORTIF study, and the Danish National Patient Registry.

Optimal anticoagulation thresholds were a CHA₂DS₂-VASc score of 3 or more using stroke rates from ATRIA, 2 or more based on Swedish AF rates, 1 or more based on SPORTIF rates, and 0 or more using rates from the Danish National Patient Registry. Oral anticoagulation thresholds were lower but still varied widely after accounting for the lower rates of intracranial hemorrhage associated with non–vitamin K antagonist therapy.

Therefore, current guidelines based on CHA₂DS₂-VASc score may need revising “in favor of more accurate, individualized assessments of risk for both ischemic stroke and major bleeding,” the investigators wrote. “Until such time, guidelines should better reflect the uncertainty of the current approach in which a patient’s CHA₂DS₂-VASc score is used as the primary basis for recommending oral anticoagulation.”

The study had no primary funding source. Dr. Shah reported having no conflicts of interest. Three coinvestigators disclosed research support from relevant pharmaceutical or device companies.

SOURCE: Shah SJ et al. Ann Intern Med. 2018 Sep 25. doi: 10.7326/M17-2762  

Photo from Bayer

The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.

Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.

As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.

The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated Jivi for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.

Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.

As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.

The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated Jivi for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.

Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.

As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.

The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated Jivi for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for damoctocog alfa pegol, a recombinant human factor VIII therapy.

Bayer is seeking European marketing authorization for damoctocog alfa pegol (formerly BAY94-9027) for the treatment and prophylaxis of bleeding in previously treated patients age 12 and older with hemophilia A.

The CHMP’s recommendation for damoctocog alfa pegol, which is approved in the U.S. under the name Jivi, will be reviewed by the European Commission (EC).

The EC typically makes a decision about marketing authorization within 67 days of the CHMP’s opinion. The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

The CHMP’s recommendation for damoctocog alfa pegol is supported by the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for damoctocog alfa pegol used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated damoctocog alfa pegol for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received damoctocog alfa pegol for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Damoctocog alfa pegol provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for damoctocog alfa pegol, a recombinant human factor VIII therapy.

Bayer is seeking European marketing authorization for damoctocog alfa pegol (formerly BAY94-9027) for the treatment and prophylaxis of bleeding in previously treated patients age 12 and older with hemophilia A.

The CHMP’s recommendation for damoctocog alfa pegol, which is approved in the U.S. under the name Jivi, will be reviewed by the European Commission (EC).

The EC typically makes a decision about marketing authorization within 67 days of the CHMP’s opinion. The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

The CHMP’s recommendation for damoctocog alfa pegol is supported by the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for damoctocog alfa pegol used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated damoctocog alfa pegol for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received damoctocog alfa pegol for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Damoctocog alfa pegol provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for damoctocog alfa pegol, a recombinant human factor VIII therapy.

Bayer is seeking European marketing authorization for damoctocog alfa pegol (formerly BAY94-9027) for the treatment and prophylaxis of bleeding in previously treated patients age 12 and older with hemophilia A.

The CHMP’s recommendation for damoctocog alfa pegol, which is approved in the U.S. under the name Jivi, will be reviewed by the European Commission (EC).

The EC typically makes a decision about marketing authorization within 67 days of the CHMP’s opinion. The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

The CHMP’s recommendation for damoctocog alfa pegol is supported by the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for damoctocog alfa pegol used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated damoctocog alfa pegol for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received damoctocog alfa pegol for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Damoctocog alfa pegol provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.