Thrombosis

Catalyst Biosciences

BOSTON—The activated factor VIIa variant marzeptacog alfa has demonstrated efficacy as prophylaxis for patients with hemophilia A or B who also have inhibitors, according to researchers.

Three patients have completed dosing with marzeptacog alfa in a phase 2/3 study.

None of these patients experienced bleeding during treatment, and none have developed antidrug antibodies or reported injection site reactions.

As for the other 2 patients enrolled in this study, 1 withdrew consent, and 1 died of an adverse event unrelated to marzeptacog alfa.

Howard Levy, chief medical officer of Catalyst Biosciences, Inc., presented these data at the 2018 Hemophilia Drug Development Summit.

The trial is sponsored by Catalyst Biosciences, the company developing marzeptacog alfa.

Results

The goal of this ongoing trial is to determine whether daily subcutaneous injections of marzeptacog alfa can eliminate or minimize spontaneous bleeding episodes. The primary endpoint is a reduction in annualized bleed rate (ABR) compared to each individual’s recorded historical ABR.

Thus far, the trial has enrolled 5 patients with hemophilia A or B and inhibitors. (Catalyst would not disclose how many patients have hemophilia A and how many have hemophilia B).

One patient with a historic ABR of 26.7 completed the trial with no bleeds after 50 days of treatment with marzeptacog alfa at 60 µg/kg.

This patient had previously experienced a bleed on day 46 when receiving marzeptacog alfa at 30 µg/kg, and the patient experienced another bleed 16 days after the end of dosing at 60 µg/kg.

A second patient with a historic ABR of 16.6 had no bleeds when receiving marzeptacog alfa at 30 µg/kg for 50 days.

And a third patient with a historic ABR of 15.9 had no bleeds when receiving marzeptacog alfa at 30 µg/kg for 44 days.

“The data from these 3 individuals support the efficacy of [marzeptacog alfa] to reduce annualized bleed rates after daily subcutaneous injections,” said Nassim Usman, PhD, chief executive officer of Catalyst Biosciences.

“Importantly, to date, we have not observed any injection site reactions nor any anti-drug antibodies after more than 200 subcutaneous doses of [marzeptacog alfa].”

A fourth patient with a historic ABR of 18.3 had a fatal hemorrhagic stroke on day 11 that was considered unrelated to marzeptacog alfa. The patient had previously treated hypertension that was going untreated at the time of death.

A fifth patient with a historic ABR of 12.2 withdrew consent.

Catalyst Biosciences

BOSTON—The activated factor VIIa variant marzeptacog alfa has demonstrated efficacy as prophylaxis for patients with hemophilia A or B who also have inhibitors, according to researchers.

Three patients have completed dosing with marzeptacog alfa in a phase 2/3 study.

None of these patients experienced bleeding during treatment, and none have developed antidrug antibodies or reported injection site reactions.

As for the other 2 patients enrolled in this study, 1 withdrew consent, and 1 died of an adverse event unrelated to marzeptacog alfa.

Howard Levy, chief medical officer of Catalyst Biosciences, Inc., presented these data at the 2018 Hemophilia Drug Development Summit.

The trial is sponsored by Catalyst Biosciences, the company developing marzeptacog alfa.

Results

The goal of this ongoing trial is to determine whether daily subcutaneous injections of marzeptacog alfa can eliminate or minimize spontaneous bleeding episodes. The primary endpoint is a reduction in annualized bleed rate (ABR) compared to each individual’s recorded historical ABR.

Thus far, the trial has enrolled 5 patients with hemophilia A or B and inhibitors. (Catalyst would not disclose how many patients have hemophilia A and how many have hemophilia B).

One patient with a historic ABR of 26.7 completed the trial with no bleeds after 50 days of treatment with marzeptacog alfa at 60 µg/kg.

This patient had previously experienced a bleed on day 46 when receiving marzeptacog alfa at 30 µg/kg, and the patient experienced another bleed 16 days after the end of dosing at 60 µg/kg.

A second patient with a historic ABR of 16.6 had no bleeds when receiving marzeptacog alfa at 30 µg/kg for 50 days.

And a third patient with a historic ABR of 15.9 had no bleeds when receiving marzeptacog alfa at 30 µg/kg for 44 days.

“The data from these 3 individuals support the efficacy of [marzeptacog alfa] to reduce annualized bleed rates after daily subcutaneous injections,” said Nassim Usman, PhD, chief executive officer of Catalyst Biosciences.

“Importantly, to date, we have not observed any injection site reactions nor any anti-drug antibodies after more than 200 subcutaneous doses of [marzeptacog alfa].”

A fourth patient with a historic ABR of 18.3 had a fatal hemorrhagic stroke on day 11 that was considered unrelated to marzeptacog alfa. The patient had previously treated hypertension that was going untreated at the time of death.

A fifth patient with a historic ABR of 12.2 withdrew consent.

Catalyst Biosciences

BOSTON—The activated factor VIIa variant marzeptacog alfa has demonstrated efficacy as prophylaxis for patients with hemophilia A or B who also have inhibitors, according to researchers.

Three patients have completed dosing with marzeptacog alfa in a phase 2/3 study.

None of these patients experienced bleeding during treatment, and none have developed antidrug antibodies or reported injection site reactions.

As for the other 2 patients enrolled in this study, 1 withdrew consent, and 1 died of an adverse event unrelated to marzeptacog alfa.

Howard Levy, chief medical officer of Catalyst Biosciences, Inc., presented these data at the 2018 Hemophilia Drug Development Summit.

The trial is sponsored by Catalyst Biosciences, the company developing marzeptacog alfa.

Results

The goal of this ongoing trial is to determine whether daily subcutaneous injections of marzeptacog alfa can eliminate or minimize spontaneous bleeding episodes. The primary endpoint is a reduction in annualized bleed rate (ABR) compared to each individual’s recorded historical ABR.

Thus far, the trial has enrolled 5 patients with hemophilia A or B and inhibitors. (Catalyst would not disclose how many patients have hemophilia A and how many have hemophilia B).

One patient with a historic ABR of 26.7 completed the trial with no bleeds after 50 days of treatment with marzeptacog alfa at 60 µg/kg.

This patient had previously experienced a bleed on day 46 when receiving marzeptacog alfa at 30 µg/kg, and the patient experienced another bleed 16 days after the end of dosing at 60 µg/kg.

A second patient with a historic ABR of 16.6 had no bleeds when receiving marzeptacog alfa at 30 µg/kg for 50 days.

And a third patient with a historic ABR of 15.9 had no bleeds when receiving marzeptacog alfa at 30 µg/kg for 44 days.

“The data from these 3 individuals support the efficacy of [marzeptacog alfa] to reduce annualized bleed rates after daily subcutaneous injections,” said Nassim Usman, PhD, chief executive officer of Catalyst Biosciences.

“Importantly, to date, we have not observed any injection site reactions nor any anti-drug antibodies after more than 200 subcutaneous doses of [marzeptacog alfa].”

A fourth patient with a historic ABR of 18.3 had a fatal hemorrhagic stroke on day 11 that was considered unrelated to marzeptacog alfa. The patient had previously treated hypertension that was going untreated at the time of death.

A fifth patient with a historic ABR of 12.2 withdrew consent.

NEW ORLEANS – Both the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio proved to be better predictors of the presence or absence of deep vein thrombosis than the ubiquitous D-dimer test in a retrospective study, Jason Mouabbi, MD, reported at the annual meeting of the American College of Physicians.

What’s more, both the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) can be readily calculated from the readout of a complete blood count (CBC) with differential. A CBC costs an average of $16, and everybody that comes through a hospital emergency department gets one. In contrast, the average charge for a D-dimer test is about $231 nationwide, and depending upon the specific test used the results can take up to a couple of hours to come back, noted Dr. Mouabbi of St. John Hospital and Medical Center in Detroit.

“The NLR and PLR ratios offer a new, powerful, affordable, simple, and readily available tool in the hands of clinicians to help them in the diagnosis of DVT,” he said. “The NLR can be useful to rule out DVT when it’s negative, whereas PLR can be useful in ruling DVT when positive.”

Investigators in a variety of fields are looking at the NLR and PLR as emerging practical, easily obtainable biomarkers for systemic inflammation. And DVT is thought to be an inflammatory process, he explained.

Dr. Mouabbi presented a single-center retrospective study of 102 matched patients who presented with lower extremity swelling and had a CBC drawn, as well as a D-dimer test, on the same day they underwent a lower extremity Doppler ultrasound evaluation. In 51 patients, the ultrasound revealed the presence of DVT and anticoagulation was started. In the other 51 patients, the ultrasound exam was negative and they weren’t anticoagulated. Since the study purpose was to assess the implications of a primary elevation of NLR and/or PLR, patients with rheumatic diseases, inflammatory bowel disease, recent surgery, chronic renal or liver disease, inherited thrombophilia, infection, or other possible secondary causes of altered ratios were excluded from the study.

A positive NLR was considered 3.4 or higher, a positive PLR was a ratio of 230 or more, and a positive D-dimer level was 500 ng/mL or greater. The NLR and PLR collectively outperformed the D-dimer test in terms of sensitivity, specificity, positive predictive value, and negative predictive value.

In addition, 89% of the DVT group were classified as “double-positive,” meaning they were both NLR and PLR positive. That combination provided the best diagnostic value of all, since none of the controls were double-positive and only 2% were PLR positive.

While the results are encouraging, before NLR and PLR can supplant D-dimer in patients with suspected DVT in clinical practice a confirmatory prospective study should be carried out, according to Dr. Mouabbi. Ideally it should include the use of the Wells score, which is part of most diagnostic algorithms as a preliminary means of categorizing DVT probability as low, moderate, or high. However, the popularity of the Wells score has fallen off in the face of reports that the results are subjective and variable. Indeed, the Wells score was included in the electronic medical record of so few participants in Dr. Mouabbi’s study that he couldn’t evaluate its utility.

He reported having no financial conflicts regarding his study, which was conducted free of commercial support.

[email protected]

NEW ORLEANS – Both the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio proved to be better predictors of the presence or absence of deep vein thrombosis than the ubiquitous D-dimer test in a retrospective study, Jason Mouabbi, MD, reported at the annual meeting of the American College of Physicians.

What’s more, both the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) can be readily calculated from the readout of a complete blood count (CBC) with differential. A CBC costs an average of $16, and everybody that comes through a hospital emergency department gets one. In contrast, the average charge for a D-dimer test is about $231 nationwide, and depending upon the specific test used the results can take up to a couple of hours to come back, noted Dr. Mouabbi of St. John Hospital and Medical Center in Detroit.

“The NLR and PLR ratios offer a new, powerful, affordable, simple, and readily available tool in the hands of clinicians to help them in the diagnosis of DVT,” he said. “The NLR can be useful to rule out DVT when it’s negative, whereas PLR can be useful in ruling DVT when positive.”

Investigators in a variety of fields are looking at the NLR and PLR as emerging practical, easily obtainable biomarkers for systemic inflammation. And DVT is thought to be an inflammatory process, he explained.

Dr. Mouabbi presented a single-center retrospective study of 102 matched patients who presented with lower extremity swelling and had a CBC drawn, as well as a D-dimer test, on the same day they underwent a lower extremity Doppler ultrasound evaluation. In 51 patients, the ultrasound revealed the presence of DVT and anticoagulation was started. In the other 51 patients, the ultrasound exam was negative and they weren’t anticoagulated. Since the study purpose was to assess the implications of a primary elevation of NLR and/or PLR, patients with rheumatic diseases, inflammatory bowel disease, recent surgery, chronic renal or liver disease, inherited thrombophilia, infection, or other possible secondary causes of altered ratios were excluded from the study.

A positive NLR was considered 3.4 or higher, a positive PLR was a ratio of 230 or more, and a positive D-dimer level was 500 ng/mL or greater. The NLR and PLR collectively outperformed the D-dimer test in terms of sensitivity, specificity, positive predictive value, and negative predictive value.

In addition, 89% of the DVT group were classified as “double-positive,” meaning they were both NLR and PLR positive. That combination provided the best diagnostic value of all, since none of the controls were double-positive and only 2% were PLR positive.

While the results are encouraging, before NLR and PLR can supplant D-dimer in patients with suspected DVT in clinical practice a confirmatory prospective study should be carried out, according to Dr. Mouabbi. Ideally it should include the use of the Wells score, which is part of most diagnostic algorithms as a preliminary means of categorizing DVT probability as low, moderate, or high. However, the popularity of the Wells score has fallen off in the face of reports that the results are subjective and variable. Indeed, the Wells score was included in the electronic medical record of so few participants in Dr. Mouabbi’s study that he couldn’t evaluate its utility.

He reported having no financial conflicts regarding his study, which was conducted free of commercial support.

[email protected]

NEW ORLEANS – Both the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio proved to be better predictors of the presence or absence of deep vein thrombosis than the ubiquitous D-dimer test in a retrospective study, Jason Mouabbi, MD, reported at the annual meeting of the American College of Physicians.

What’s more, both the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) can be readily calculated from the readout of a complete blood count (CBC) with differential. A CBC costs an average of $16, and everybody that comes through a hospital emergency department gets one. In contrast, the average charge for a D-dimer test is about $231 nationwide, and depending upon the specific test used the results can take up to a couple of hours to come back, noted Dr. Mouabbi of St. John Hospital and Medical Center in Detroit.

“The NLR and PLR ratios offer a new, powerful, affordable, simple, and readily available tool in the hands of clinicians to help them in the diagnosis of DVT,” he said. “The NLR can be useful to rule out DVT when it’s negative, whereas PLR can be useful in ruling DVT when positive.”

Investigators in a variety of fields are looking at the NLR and PLR as emerging practical, easily obtainable biomarkers for systemic inflammation. And DVT is thought to be an inflammatory process, he explained.

Dr. Mouabbi presented a single-center retrospective study of 102 matched patients who presented with lower extremity swelling and had a CBC drawn, as well as a D-dimer test, on the same day they underwent a lower extremity Doppler ultrasound evaluation. In 51 patients, the ultrasound revealed the presence of DVT and anticoagulation was started. In the other 51 patients, the ultrasound exam was negative and they weren’t anticoagulated. Since the study purpose was to assess the implications of a primary elevation of NLR and/or PLR, patients with rheumatic diseases, inflammatory bowel disease, recent surgery, chronic renal or liver disease, inherited thrombophilia, infection, or other possible secondary causes of altered ratios were excluded from the study.

A positive NLR was considered 3.4 or higher, a positive PLR was a ratio of 230 or more, and a positive D-dimer level was 500 ng/mL or greater. The NLR and PLR collectively outperformed the D-dimer test in terms of sensitivity, specificity, positive predictive value, and negative predictive value.

In addition, 89% of the DVT group were classified as “double-positive,” meaning they were both NLR and PLR positive. That combination provided the best diagnostic value of all, since none of the controls were double-positive and only 2% were PLR positive.

While the results are encouraging, before NLR and PLR can supplant D-dimer in patients with suspected DVT in clinical practice a confirmatory prospective study should be carried out, according to Dr. Mouabbi. Ideally it should include the use of the Wells score, which is part of most diagnostic algorithms as a preliminary means of categorizing DVT probability as low, moderate, or high. However, the popularity of the Wells score has fallen off in the face of reports that the results are subjective and variable. Indeed, the Wells score was included in the electronic medical record of so few participants in Dr. Mouabbi’s study that he couldn’t evaluate its utility.

He reported having no financial conflicts regarding his study, which was conducted free of commercial support.

[email protected]

Photo courtesy of CDC

A new study suggests that certain patients with acute pulmonary embolism (PE) may be better off receiving outpatient treatment.

Researchers tested outpatient anticoagulant therapy in 200 PE patients with a low risk of mortality.

At 90 days of follow-up, there were no deaths or recurrences of venous thromboembolism (VTE), but 1 patient experienced major bleeding after a traumatic injury.

A majority of patients said they were satisfied with outpatient care.

Joseph Bledsoe, MD, of Intermountain Medical Center in Salt Lake City, Utah, and his colleagues reported these results in CHEST.

The researchers tracked patients who were treated for acute PE in 5 Intermountain Healthcare emergency departments (EDs) from 2013 to 2016.

The patients had to have a low risk of mortality according to the Pulmonary Embolism Severity Index score (<86), echocardiography (no signs of right heart strain), and whole-leg compression ultrasound.

Patients could not have deep vein thrombosis proximal to the popliteal vein, hypoxia, hypotension, hepatic failure, or renal failure. They had to be eligible for therapeutic anticoagulation and not have any condition requiring hospitalization.

With these criteria, the researchers selected 200 patients. They were observed in the ED or hospital for 12 to 24 hours and then discharged with anticoagulant therapy.

Patients received rivaroxaban (n=149), enoxaparin transitioned to warfarin (n=26), apixaban (n=24), or enoxaparin alone (n=1).

Results

The study’s primary outcome was the 90-day composite rate of all-cause mortality, recurrent symptomatic VTE, and major bleeding.

There were no deaths and no cases of recurrent VTE. One patient did experience major bleeding at day 61 due to a traumatic thigh injury.

Within 7 days of study enrollment, there were 19 patients (9.5%) who returned to the ED and 2 patients (1%) who were admitted to the hospital. One patient with pulmonary infarct was admitted for pain control (day 2), and another was admitted for an elective coronary intervention (day 7) due to a positive cardiac stress test.

Within 30 days, 32 patients (16%) returned to the ED, and 5 (3%) were admitted to the hospital for events unrelated to their PE.

The study also showed that patients were largely satisfied with outpatient care. Of the 146 patients who completed a satisfaction survey at 90 days, 89% said they would choose outpatient management if they had another PE in the future.

“We found a large subset of patients with blood clots who’d do well at home; in fact, who probably did better at home,” Dr Bledsoe said. “When patients are sent home versus staying in the hospital, they’re at lower risk of getting another infection. It’s a lot less expensive, too.”

Currently, the standard of care in the US for acute PE is hospitalization for all patients. That’s recommended, in part, because their overall mortality rate is 17%.

However, the lower mortality rate among some appropriately risk-stratified patients suggests that at-home care, which has become the norm in some European countries, leads to better outcomes for those patients overall and less chance of a hospital-introduced infection, according to Dr Bledsoe.

“Our findings show that, if you appropriately risk-stratify patients, there are a lot of people with blood clots who are safe to go home,” he said.

Dr Bledsoe added that similar research should be conducted outside of the Intermountain Healthcare system to confirm the results of this study, and a larger group of patients should be studied.

Photo courtesy of CDC

A new study suggests that certain patients with acute pulmonary embolism (PE) may be better off receiving outpatient treatment.

Researchers tested outpatient anticoagulant therapy in 200 PE patients with a low risk of mortality.

At 90 days of follow-up, there were no deaths or recurrences of venous thromboembolism (VTE), but 1 patient experienced major bleeding after a traumatic injury.

A majority of patients said they were satisfied with outpatient care.

Joseph Bledsoe, MD, of Intermountain Medical Center in Salt Lake City, Utah, and his colleagues reported these results in CHEST.

The researchers tracked patients who were treated for acute PE in 5 Intermountain Healthcare emergency departments (EDs) from 2013 to 2016.

The patients had to have a low risk of mortality according to the Pulmonary Embolism Severity Index score (<86), echocardiography (no signs of right heart strain), and whole-leg compression ultrasound.

Patients could not have deep vein thrombosis proximal to the popliteal vein, hypoxia, hypotension, hepatic failure, or renal failure. They had to be eligible for therapeutic anticoagulation and not have any condition requiring hospitalization.

With these criteria, the researchers selected 200 patients. They were observed in the ED or hospital for 12 to 24 hours and then discharged with anticoagulant therapy.

Patients received rivaroxaban (n=149), enoxaparin transitioned to warfarin (n=26), apixaban (n=24), or enoxaparin alone (n=1).

Results

The study’s primary outcome was the 90-day composite rate of all-cause mortality, recurrent symptomatic VTE, and major bleeding.

There were no deaths and no cases of recurrent VTE. One patient did experience major bleeding at day 61 due to a traumatic thigh injury.

Within 7 days of study enrollment, there were 19 patients (9.5%) who returned to the ED and 2 patients (1%) who were admitted to the hospital. One patient with pulmonary infarct was admitted for pain control (day 2), and another was admitted for an elective coronary intervention (day 7) due to a positive cardiac stress test.

Within 30 days, 32 patients (16%) returned to the ED, and 5 (3%) were admitted to the hospital for events unrelated to their PE.

The study also showed that patients were largely satisfied with outpatient care. Of the 146 patients who completed a satisfaction survey at 90 days, 89% said they would choose outpatient management if they had another PE in the future.

“We found a large subset of patients with blood clots who’d do well at home; in fact, who probably did better at home,” Dr Bledsoe said. “When patients are sent home versus staying in the hospital, they’re at lower risk of getting another infection. It’s a lot less expensive, too.”

Currently, the standard of care in the US for acute PE is hospitalization for all patients. That’s recommended, in part, because their overall mortality rate is 17%.

However, the lower mortality rate among some appropriately risk-stratified patients suggests that at-home care, which has become the norm in some European countries, leads to better outcomes for those patients overall and less chance of a hospital-introduced infection, according to Dr Bledsoe.

“Our findings show that, if you appropriately risk-stratify patients, there are a lot of people with blood clots who are safe to go home,” he said.

Dr Bledsoe added that similar research should be conducted outside of the Intermountain Healthcare system to confirm the results of this study, and a larger group of patients should be studied.

Photo courtesy of CDC

A new study suggests that certain patients with acute pulmonary embolism (PE) may be better off receiving outpatient treatment.

Researchers tested outpatient anticoagulant therapy in 200 PE patients with a low risk of mortality.

At 90 days of follow-up, there were no deaths or recurrences of venous thromboembolism (VTE), but 1 patient experienced major bleeding after a traumatic injury.

A majority of patients said they were satisfied with outpatient care.

Joseph Bledsoe, MD, of Intermountain Medical Center in Salt Lake City, Utah, and his colleagues reported these results in CHEST.

The researchers tracked patients who were treated for acute PE in 5 Intermountain Healthcare emergency departments (EDs) from 2013 to 2016.

The patients had to have a low risk of mortality according to the Pulmonary Embolism Severity Index score (<86), echocardiography (no signs of right heart strain), and whole-leg compression ultrasound.

Patients could not have deep vein thrombosis proximal to the popliteal vein, hypoxia, hypotension, hepatic failure, or renal failure. They had to be eligible for therapeutic anticoagulation and not have any condition requiring hospitalization.

With these criteria, the researchers selected 200 patients. They were observed in the ED or hospital for 12 to 24 hours and then discharged with anticoagulant therapy.

Patients received rivaroxaban (n=149), enoxaparin transitioned to warfarin (n=26), apixaban (n=24), or enoxaparin alone (n=1).

Results

The study’s primary outcome was the 90-day composite rate of all-cause mortality, recurrent symptomatic VTE, and major bleeding.

There were no deaths and no cases of recurrent VTE. One patient did experience major bleeding at day 61 due to a traumatic thigh injury.

Within 7 days of study enrollment, there were 19 patients (9.5%) who returned to the ED and 2 patients (1%) who were admitted to the hospital. One patient with pulmonary infarct was admitted for pain control (day 2), and another was admitted for an elective coronary intervention (day 7) due to a positive cardiac stress test.

Within 30 days, 32 patients (16%) returned to the ED, and 5 (3%) were admitted to the hospital for events unrelated to their PE.

The study also showed that patients were largely satisfied with outpatient care. Of the 146 patients who completed a satisfaction survey at 90 days, 89% said they would choose outpatient management if they had another PE in the future.

“We found a large subset of patients with blood clots who’d do well at home; in fact, who probably did better at home,” Dr Bledsoe said. “When patients are sent home versus staying in the hospital, they’re at lower risk of getting another infection. It’s a lot less expensive, too.”

Currently, the standard of care in the US for acute PE is hospitalization for all patients. That’s recommended, in part, because their overall mortality rate is 17%.

However, the lower mortality rate among some appropriately risk-stratified patients suggests that at-home care, which has become the norm in some European countries, leads to better outcomes for those patients overall and less chance of a hospital-introduced infection, according to Dr Bledsoe.

“Our findings show that, if you appropriately risk-stratify patients, there are a lot of people with blood clots who are safe to go home,” he said.

Dr Bledsoe added that similar research should be conducted outside of the Intermountain Healthcare system to confirm the results of this study, and a larger group of patients should be studied.

Photo courtesy of Janssen

The Bruton tyrosine kinase inhibitor ibrutinib has been linked to a 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.

Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Joseph Mock, MD, of the University of Virginia Health System in Charlottesville, and his colleagues.

Their report was published in Clinical Lymphoma, Myeloma & Leukemia.

Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting, but the authors suggested this rate could be higher in everyday clinical practice.

“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria,” the researchers wrote. “These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice.”

The researchers conducted a review of patients treated within the University of Virginia Health System between January 2012 and May 2016.

The team identified 70 patients, with an average age of 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%), mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström’s macroglobulinemia (1%).

Bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis.

However, major bleeding, defined as grade 3 or higher, occurred in 19% of patients (n=13). Seven of these patients were taking combined antiplatelet and anticoagulant therapy, 4 were taking antiplatelet agents alone, 1 was taking an anticoagulant agent alone, and 1 was taking only ibrutinib.

Univariate analysis showed that the factors associated with an increased risk of major bleeding were antiplatelet or anticoagulant medication, the combination of the 2 medications, interacting medications, anemia (hemoglobin less than 12 g/dL), and an elevated international normalized ratio (INR, > 1.5).

In a multivariate analysis, only the following factors were associated with an increased risk of major bleeding:

• Concomitant antiplatelet and anticoagulant use—hazard ratio=20.0 (95% CI, 2.1-200.0; P=0.0005) vs no antiplatelet/anticoagulant therapy
• Elevated INR—hazard ratio=4.6 (95% CI, 1.1-19.6; P=0.0409).

The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.

Overall, the team said their findings confirm “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.”

They noted that this study was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive.”

Photo courtesy of Janssen

The Bruton tyrosine kinase inhibitor ibrutinib has been linked to a 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.

Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Joseph Mock, MD, of the University of Virginia Health System in Charlottesville, and his colleagues.

Their report was published in Clinical Lymphoma, Myeloma & Leukemia.

Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting, but the authors suggested this rate could be higher in everyday clinical practice.

“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria,” the researchers wrote. “These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice.”

The researchers conducted a review of patients treated within the University of Virginia Health System between January 2012 and May 2016.

The team identified 70 patients, with an average age of 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%), mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström’s macroglobulinemia (1%).

Bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis.

However, major bleeding, defined as grade 3 or higher, occurred in 19% of patients (n=13). Seven of these patients were taking combined antiplatelet and anticoagulant therapy, 4 were taking antiplatelet agents alone, 1 was taking an anticoagulant agent alone, and 1 was taking only ibrutinib.

Univariate analysis showed that the factors associated with an increased risk of major bleeding were antiplatelet or anticoagulant medication, the combination of the 2 medications, interacting medications, anemia (hemoglobin less than 12 g/dL), and an elevated international normalized ratio (INR, > 1.5).

In a multivariate analysis, only the following factors were associated with an increased risk of major bleeding:

• Concomitant antiplatelet and anticoagulant use—hazard ratio=20.0 (95% CI, 2.1-200.0; P=0.0005) vs no antiplatelet/anticoagulant therapy
• Elevated INR—hazard ratio=4.6 (95% CI, 1.1-19.6; P=0.0409).

The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.

Overall, the team said their findings confirm “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.”

They noted that this study was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive.”

Photo courtesy of Janssen

The Bruton tyrosine kinase inhibitor ibrutinib has been linked to a 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.

Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Joseph Mock, MD, of the University of Virginia Health System in Charlottesville, and his colleagues.

Their report was published in Clinical Lymphoma, Myeloma & Leukemia.

Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting, but the authors suggested this rate could be higher in everyday clinical practice.

“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria,” the researchers wrote. “These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice.”

The researchers conducted a review of patients treated within the University of Virginia Health System between January 2012 and May 2016.

The team identified 70 patients, with an average age of 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%), mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström’s macroglobulinemia (1%).

Bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis.

However, major bleeding, defined as grade 3 or higher, occurred in 19% of patients (n=13). Seven of these patients were taking combined antiplatelet and anticoagulant therapy, 4 were taking antiplatelet agents alone, 1 was taking an anticoagulant agent alone, and 1 was taking only ibrutinib.

Univariate analysis showed that the factors associated with an increased risk of major bleeding were antiplatelet or anticoagulant medication, the combination of the 2 medications, interacting medications, anemia (hemoglobin less than 12 g/dL), and an elevated international normalized ratio (INR, > 1.5).

In a multivariate analysis, only the following factors were associated with an increased risk of major bleeding:

• Concomitant antiplatelet and anticoagulant use—hazard ratio=20.0 (95% CI, 2.1-200.0; P=0.0005) vs no antiplatelet/anticoagulant therapy
• Elevated INR—hazard ratio=4.6 (95% CI, 1.1-19.6; P=0.0409).

The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.

Overall, the team said their findings confirm “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.”

They noted that this study was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive.”

Photo from Business Wire

Health Canada has approved emicizumab (Hemlibra®) for use as routine prophylaxis to prevent or reduce bleeding episodes in hemophilia A patients with factor VIII inhibitors.

Emicizumab is a bispecific factor IXa- and factor X-directed antibody. It bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII that is needed for effective blood clotting.

Emicizumab is given as a once-weekly subcutaneous injection.

“Preventing bleeds in patients with hemophilia A can be extremely challenging, usually requiring patients to self-infuse medications multiple times a week, or even daily,” said Jayson Stoffman, MD, of the University of Manitoba in Winnipeg.

“The development of inhibitors adds a significant challenge, with more demanding treatments that are often less effective. Hemlibra offers these patients the chance to effectively reduce the frequency of their bleeds with a once-weekly injection at home. This could significantly improve the quality of life for inhibitor patients, and particularly children and their families.”

Trial results

The Health Canada approval of emicizumab is based on data from a pair of phase 3 trials—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was an 87% reduction in treated bleeds with emicizumab compared to no prophylaxis (P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (P<0.0001).

The proportion of patients with 0 treated bleeds was 62.9% among emicizumab recipients and 5.6% among patients who did not receive prophylaxis.

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 µ/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

There was 1 death, but it was considered unrelated to emicizumab. The patient had developed TMA but died of rectal hemorrhage.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds/treated joint bleeds. None of the patients had treated target joint bleeds.

A subset of 23 patients received emicizumab for at least 12 weeks (median treatment duration of 38.1 weeks; range, 12.7 to 41.6 weeks).

Of these 23 patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds/treated joint bleeds.

There were 40 patients who had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo from Business Wire

Health Canada has approved emicizumab (Hemlibra®) for use as routine prophylaxis to prevent or reduce bleeding episodes in hemophilia A patients with factor VIII inhibitors.

Emicizumab is a bispecific factor IXa- and factor X-directed antibody. It bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII that is needed for effective blood clotting.

Emicizumab is given as a once-weekly subcutaneous injection.

“Preventing bleeds in patients with hemophilia A can be extremely challenging, usually requiring patients to self-infuse medications multiple times a week, or even daily,” said Jayson Stoffman, MD, of the University of Manitoba in Winnipeg.

“The development of inhibitors adds a significant challenge, with more demanding treatments that are often less effective. Hemlibra offers these patients the chance to effectively reduce the frequency of their bleeds with a once-weekly injection at home. This could significantly improve the quality of life for inhibitor patients, and particularly children and their families.”

Trial results

The Health Canada approval of emicizumab is based on data from a pair of phase 3 trials—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was an 87% reduction in treated bleeds with emicizumab compared to no prophylaxis (P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (P<0.0001).

The proportion of patients with 0 treated bleeds was 62.9% among emicizumab recipients and 5.6% among patients who did not receive prophylaxis.

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 µ/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

There was 1 death, but it was considered unrelated to emicizumab. The patient had developed TMA but died of rectal hemorrhage.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds/treated joint bleeds. None of the patients had treated target joint bleeds.

A subset of 23 patients received emicizumab for at least 12 weeks (median treatment duration of 38.1 weeks; range, 12.7 to 41.6 weeks).

Of these 23 patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds/treated joint bleeds.

There were 40 patients who had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo from Business Wire

Health Canada has approved emicizumab (Hemlibra®) for use as routine prophylaxis to prevent or reduce bleeding episodes in hemophilia A patients with factor VIII inhibitors.

Emicizumab is a bispecific factor IXa- and factor X-directed antibody. It bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII that is needed for effective blood clotting.

Emicizumab is given as a once-weekly subcutaneous injection.

“Preventing bleeds in patients with hemophilia A can be extremely challenging, usually requiring patients to self-infuse medications multiple times a week, or even daily,” said Jayson Stoffman, MD, of the University of Manitoba in Winnipeg.

“The development of inhibitors adds a significant challenge, with more demanding treatments that are often less effective. Hemlibra offers these patients the chance to effectively reduce the frequency of their bleeds with a once-weekly injection at home. This could significantly improve the quality of life for inhibitor patients, and particularly children and their families.”

Trial results

The Health Canada approval of emicizumab is based on data from a pair of phase 3 trials—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was an 87% reduction in treated bleeds with emicizumab compared to no prophylaxis (P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (P<0.0001).

The proportion of patients with 0 treated bleeds was 62.9% among emicizumab recipients and 5.6% among patients who did not receive prophylaxis.

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 µ/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

There was 1 death, but it was considered unrelated to emicizumab. The patient had developed TMA but died of rectal hemorrhage.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds/treated joint bleeds. None of the patients had treated target joint bleeds.

A subset of 23 patients received emicizumab for at least 12 weeks (median treatment duration of 38.1 weeks; range, 12.7 to 41.6 weeks).

Of these 23 patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds/treated joint bleeds.

There were 40 patients who had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Lab mouse

Researchers say they have discovered how hypoxia increases the risk of thrombosis.

The team noted that the cellular response to hypoxia is mediated by hypoxia-inducible factor 1 (HIF1).

The researchers were able to show that HIF1 downregulates expression of protein S (PS), a natural anticoagulant, which increases the risk of thrombosis.

“Our earlier work found that PS inhibits a key clotting protein, factor IXa,” said Rinku Majumder, PhD, of LSU Health Sciences Center in New Orleans, Louisiana.

“We knew that PS deficiency could occur in hypoxia but not why. With this study, our group identified the gene regulatory mechanism by which oxygen concentration controls PS production.”

Dr Majumder and her colleagues described this discovery in a letter published in Blood.

Because PS is primarily produced in the liver, the researchers cultured human hepatocarcinoma cells in normoxic and hypoxic conditions and then measured levels of PS.

The team found that increasing hypoxia reduced PS levels and increased stability of the HIF1α subunit of HIF1. The researchers said this inverse relationship between HIF1α and PS levels suggests HIF1 might regulate PS expression, and this theory was confirmed via experiments with mice.

Dr Majumder and her colleagues pointed out that an oxygen-dependent signaling system degrades HIF1α, and oxygen deficiency prevents HIF1α degradation. The HIF1α P564A mutant (HIF1α dPA) is resistant to degradation, which results in elevated HIF1 even in normoxic conditions.

The researchers conducted experiments with knockout mice expressing HIF1α dPA in the liver, HIF1α liver-specific knockout mice, and control mice.

When compared to PS levels in liver samples from control mice (100%), PS levels were elevated in liver samples from the HIF1α liver-specific knockout mice (220%) and reduced in samples from the HIF1α dPA mice (50%).

PS messenger RNA was 2-fold higher in HIF1α knockout mice than in controls. In HIF1α dPA mice, PS messenger RNA was 0.3-fold that of controls.

PS levels in plasma from HIF1α knockout mice were double the levels of controls, while PS levels in plasma from HIF1α dPA mice were half that of controls.

Plasma from HIF1α knockout mice produced 5-fold less thrombin and plasma from HIF1α dPA mice produced 1.5-fold more thrombin than control plasma.

Subsequent experiments confirmed that the variations in thrombin generation were due to changes in plasma PS levels, the researchers said.

The team concluded that stabilization of HIF1 in the liver, which is a normal response to hypoxia, is associated with reduced PS expression. This results in lower plasma PS levels and an increased risk of thrombosis.

Lab mouse

Researchers say they have discovered how hypoxia increases the risk of thrombosis.

The team noted that the cellular response to hypoxia is mediated by hypoxia-inducible factor 1 (HIF1).

The researchers were able to show that HIF1 downregulates expression of protein S (PS), a natural anticoagulant, which increases the risk of thrombosis.

“Our earlier work found that PS inhibits a key clotting protein, factor IXa,” said Rinku Majumder, PhD, of LSU Health Sciences Center in New Orleans, Louisiana.

“We knew that PS deficiency could occur in hypoxia but not why. With this study, our group identified the gene regulatory mechanism by which oxygen concentration controls PS production.”

Dr Majumder and her colleagues described this discovery in a letter published in Blood.

Because PS is primarily produced in the liver, the researchers cultured human hepatocarcinoma cells in normoxic and hypoxic conditions and then measured levels of PS.

The team found that increasing hypoxia reduced PS levels and increased stability of the HIF1α subunit of HIF1. The researchers said this inverse relationship between HIF1α and PS levels suggests HIF1 might regulate PS expression, and this theory was confirmed via experiments with mice.

Dr Majumder and her colleagues pointed out that an oxygen-dependent signaling system degrades HIF1α, and oxygen deficiency prevents HIF1α degradation. The HIF1α P564A mutant (HIF1α dPA) is resistant to degradation, which results in elevated HIF1 even in normoxic conditions.

The researchers conducted experiments with knockout mice expressing HIF1α dPA in the liver, HIF1α liver-specific knockout mice, and control mice.

When compared to PS levels in liver samples from control mice (100%), PS levels were elevated in liver samples from the HIF1α liver-specific knockout mice (220%) and reduced in samples from the HIF1α dPA mice (50%).

PS messenger RNA was 2-fold higher in HIF1α knockout mice than in controls. In HIF1α dPA mice, PS messenger RNA was 0.3-fold that of controls.

PS levels in plasma from HIF1α knockout mice were double the levels of controls, while PS levels in plasma from HIF1α dPA mice were half that of controls.

Plasma from HIF1α knockout mice produced 5-fold less thrombin and plasma from HIF1α dPA mice produced 1.5-fold more thrombin than control plasma.

Subsequent experiments confirmed that the variations in thrombin generation were due to changes in plasma PS levels, the researchers said.

The team concluded that stabilization of HIF1 in the liver, which is a normal response to hypoxia, is associated with reduced PS expression. This results in lower plasma PS levels and an increased risk of thrombosis.

Lab mouse

Researchers say they have discovered how hypoxia increases the risk of thrombosis.

The team noted that the cellular response to hypoxia is mediated by hypoxia-inducible factor 1 (HIF1).

The researchers were able to show that HIF1 downregulates expression of protein S (PS), a natural anticoagulant, which increases the risk of thrombosis.

“Our earlier work found that PS inhibits a key clotting protein, factor IXa,” said Rinku Majumder, PhD, of LSU Health Sciences Center in New Orleans, Louisiana.

“We knew that PS deficiency could occur in hypoxia but not why. With this study, our group identified the gene regulatory mechanism by which oxygen concentration controls PS production.”

Dr Majumder and her colleagues described this discovery in a letter published in Blood.

Because PS is primarily produced in the liver, the researchers cultured human hepatocarcinoma cells in normoxic and hypoxic conditions and then measured levels of PS.

The team found that increasing hypoxia reduced PS levels and increased stability of the HIF1α subunit of HIF1. The researchers said this inverse relationship between HIF1α and PS levels suggests HIF1 might regulate PS expression, and this theory was confirmed via experiments with mice.

Dr Majumder and her colleagues pointed out that an oxygen-dependent signaling system degrades HIF1α, and oxygen deficiency prevents HIF1α degradation. The HIF1α P564A mutant (HIF1α dPA) is resistant to degradation, which results in elevated HIF1 even in normoxic conditions.

The researchers conducted experiments with knockout mice expressing HIF1α dPA in the liver, HIF1α liver-specific knockout mice, and control mice.

When compared to PS levels in liver samples from control mice (100%), PS levels were elevated in liver samples from the HIF1α liver-specific knockout mice (220%) and reduced in samples from the HIF1α dPA mice (50%).

PS messenger RNA was 2-fold higher in HIF1α knockout mice than in controls. In HIF1α dPA mice, PS messenger RNA was 0.3-fold that of controls.

PS levels in plasma from HIF1α knockout mice were double the levels of controls, while PS levels in plasma from HIF1α dPA mice were half that of controls.

Plasma from HIF1α knockout mice produced 5-fold less thrombin and plasma from HIF1α dPA mice produced 1.5-fold more thrombin than control plasma.

Subsequent experiments confirmed that the variations in thrombin generation were due to changes in plasma PS levels, the researchers said.

The team concluded that stabilization of HIF1 in the liver, which is a normal response to hypoxia, is associated with reduced PS expression. This results in lower plasma PS levels and an increased risk of thrombosis.

Clinical question: What is the prevalence of pulmonary embolism (PE) in patients presenting to the ED with syncope?

Clinical question: What is the prevalence of pulmonary embolism (PE) in patients presenting to the ED with syncope?

Clinical question: What is the prevalence of pulmonary embolism (PE) in patients presenting to the ED with syncope?

Image by Tom Ellenberger

New research suggests the Fanconi anemia (FA) pathway plays a key role in repairing double-strand breaks (DSBs) created by CRISPR-Cas9 genome editing.

Researchers said they found that Cas9-induced single-strand template repair requires the FA pathway, and the protein FANCD2 localizes to Cas9-induced DSBs.

The team said this research provides insight into why CRISPR-Cas9 does not produce equal success in all cells.

Furthermore, the work might help researchers boost the efficiency with which cells insert new DNA into the genome and generally tweak CRISPR-Cas9 editing to get the desired outcome.

“If you want to treat sickle cell anemia, your chances of success are inextricably tied to the efficiency with which you can replace the mutated sickle cell gene with the correct one,” said study author Chris Richardson, PhD, formerly of the University of California, Berkeley, but now at Spotlight Therapeutics in Hayward, California.

“If you harvest a million cells from a patient and you have a 10% insertion rate, that is not as good as if you have 30% to 40%. Being able to manipulate those cells to increase the frequency of this process, called homology-directed repair, is exciting.”

Dr Richardson and his colleagues described this work in Nature Genetics.

CRISPR relies on DNA repair

The researchers noted that CRISPR-Cas9 creates targeted DSBs, and it’s up to the cell to repair the DNA.

This can happen in 2 ways. Enzymes can stitch the dangling ends back together, which often results in one or more bases being added or deleted, disrupting the function of the gene.

Alternatively, other enzymes can patch the break with a single strand of DNA that matches the DNA sequence upstream and downstream of the cut. A complementary DNA strand is created to complete the double-strand repair.

The former method, called non-homologous end-joining, appears to be the most common outcome after CRISPR cutting.

The latter method, homology-directed repair, happens more frequently in some cells than others and requires the presence of DNA that can be used to patch the break. Researchers often supply a single-stranded piece of DNA and hope the cell uses it to replace the faulty sequence with the new one.

Both processes are a bit mysterious, however, and no one knows why some cells readily patch in DNA while others do so infrequently.

“The enthusiasm for using CRISPR-Cas9 for medical or synthetic biology applications is great, but no one really knows what happens after you put it into cells,” Dr Richardson said. “It goes and creates these breaks, and you count on the cells to fix them, but people don’t really understand how that process works.”

To find out which DNA repair enzymes are critical to homology-directed repair after CRISPR cutting, Dr Richardson and his colleagues used a technique called CRISPR interference. They knocked out, one at a time, more than 2000 genes known or suspected to be involved in DNA repair.

The researchers were surprised to find that many of the genes that proved important—homology-directed repair dropped dramatically when they were silenced—were involved in the FA pathway.

FA pathway

The FA pathway was largely understood to repair DNA interstrand crosslinks, where a nucleotide on one strand of DNA bonds tightly with a nucleotide on the adjacent strand, interfering with DNA replication and often killing the cell.

“Based on our work, we believe that the Fanconi anemia pathway plays a major role in fixing other types of lesions as well, but is best understood as the pathway that repairs double-strand breaks,” Dr Richardson said. “After Cas9 editing, the Fanconi anemia pathway is required if you want to insert new DNA.”

The importance of the FA pathway in repairing DSBs casts doubt on some planned CRISPR treatments for Fanconi anemia itself.

Without an active FA pathway, cells may not be able to replace their mutated genes with normal genes after Cas9 makes a cut. In fact, the activity level of the FA pathway may affect how efficiently CRISPR can insert DNA in a specific cell.

The researchers concluded that, while end-joining is the default repair mechanism after a DSB, the FA pathway competes with it, and that higher activity results in more homology-directed repair and less end-joining.

Dr Richardson and his colleagues also found that 1 of the 21 proteins in the FA pathway, FANCD2, always homes in on the site of the DSB created by CRISPR-Cas9. This suggests FANCD2 plays an important role in regulating the insertion of new DNA at the cut site.

The researchers therefore believe FANCD2 could be tweaked to boost the frequency with which a cell inserts DNA via homology-directed repair.

“Also, since FANCD2 localizes to the site of Cas9 breaks, you can use FANCD2 to map where Cas9 is cutting in any cell type,” Dr Richardson said. “If you edit a population of cells and you want to know where the on- and off-target cuts are, you can just map where FANCD2 was found in the genome and you can find the cuts.”

Image by Tom Ellenberger

New research suggests the Fanconi anemia (FA) pathway plays a key role in repairing double-strand breaks (DSBs) created by CRISPR-Cas9 genome editing.

Researchers said they found that Cas9-induced single-strand template repair requires the FA pathway, and the protein FANCD2 localizes to Cas9-induced DSBs.

The team said this research provides insight into why CRISPR-Cas9 does not produce equal success in all cells.

Furthermore, the work might help researchers boost the efficiency with which cells insert new DNA into the genome and generally tweak CRISPR-Cas9 editing to get the desired outcome.

“If you want to treat sickle cell anemia, your chances of success are inextricably tied to the efficiency with which you can replace the mutated sickle cell gene with the correct one,” said study author Chris Richardson, PhD, formerly of the University of California, Berkeley, but now at Spotlight Therapeutics in Hayward, California.

“If you harvest a million cells from a patient and you have a 10% insertion rate, that is not as good as if you have 30% to 40%. Being able to manipulate those cells to increase the frequency of this process, called homology-directed repair, is exciting.”

Dr Richardson and his colleagues described this work in Nature Genetics.

CRISPR relies on DNA repair

The researchers noted that CRISPR-Cas9 creates targeted DSBs, and it’s up to the cell to repair the DNA.

This can happen in 2 ways. Enzymes can stitch the dangling ends back together, which often results in one or more bases being added or deleted, disrupting the function of the gene.

Alternatively, other enzymes can patch the break with a single strand of DNA that matches the DNA sequence upstream and downstream of the cut. A complementary DNA strand is created to complete the double-strand repair.

The former method, called non-homologous end-joining, appears to be the most common outcome after CRISPR cutting.

The latter method, homology-directed repair, happens more frequently in some cells than others and requires the presence of DNA that can be used to patch the break. Researchers often supply a single-stranded piece of DNA and hope the cell uses it to replace the faulty sequence with the new one.

Both processes are a bit mysterious, however, and no one knows why some cells readily patch in DNA while others do so infrequently.

“The enthusiasm for using CRISPR-Cas9 for medical or synthetic biology applications is great, but no one really knows what happens after you put it into cells,” Dr Richardson said. “It goes and creates these breaks, and you count on the cells to fix them, but people don’t really understand how that process works.”

To find out which DNA repair enzymes are critical to homology-directed repair after CRISPR cutting, Dr Richardson and his colleagues used a technique called CRISPR interference. They knocked out, one at a time, more than 2000 genes known or suspected to be involved in DNA repair.

The researchers were surprised to find that many of the genes that proved important—homology-directed repair dropped dramatically when they were silenced—were involved in the FA pathway.

FA pathway

The FA pathway was largely understood to repair DNA interstrand crosslinks, where a nucleotide on one strand of DNA bonds tightly with a nucleotide on the adjacent strand, interfering with DNA replication and often killing the cell.

“Based on our work, we believe that the Fanconi anemia pathway plays a major role in fixing other types of lesions as well, but is best understood as the pathway that repairs double-strand breaks,” Dr Richardson said. “After Cas9 editing, the Fanconi anemia pathway is required if you want to insert new DNA.”

The importance of the FA pathway in repairing DSBs casts doubt on some planned CRISPR treatments for Fanconi anemia itself.

Without an active FA pathway, cells may not be able to replace their mutated genes with normal genes after Cas9 makes a cut. In fact, the activity level of the FA pathway may affect how efficiently CRISPR can insert DNA in a specific cell.

The researchers concluded that, while end-joining is the default repair mechanism after a DSB, the FA pathway competes with it, and that higher activity results in more homology-directed repair and less end-joining.

Dr Richardson and his colleagues also found that 1 of the 21 proteins in the FA pathway, FANCD2, always homes in on the site of the DSB created by CRISPR-Cas9. This suggests FANCD2 plays an important role in regulating the insertion of new DNA at the cut site.

The researchers therefore believe FANCD2 could be tweaked to boost the frequency with which a cell inserts DNA via homology-directed repair.

“Also, since FANCD2 localizes to the site of Cas9 breaks, you can use FANCD2 to map where Cas9 is cutting in any cell type,” Dr Richardson said. “If you edit a population of cells and you want to know where the on- and off-target cuts are, you can just map where FANCD2 was found in the genome and you can find the cuts.”

Image by Tom Ellenberger

New research suggests the Fanconi anemia (FA) pathway plays a key role in repairing double-strand breaks (DSBs) created by CRISPR-Cas9 genome editing.

Researchers said they found that Cas9-induced single-strand template repair requires the FA pathway, and the protein FANCD2 localizes to Cas9-induced DSBs.

The team said this research provides insight into why CRISPR-Cas9 does not produce equal success in all cells.

Furthermore, the work might help researchers boost the efficiency with which cells insert new DNA into the genome and generally tweak CRISPR-Cas9 editing to get the desired outcome.

“If you want to treat sickle cell anemia, your chances of success are inextricably tied to the efficiency with which you can replace the mutated sickle cell gene with the correct one,” said study author Chris Richardson, PhD, formerly of the University of California, Berkeley, but now at Spotlight Therapeutics in Hayward, California.

“If you harvest a million cells from a patient and you have a 10% insertion rate, that is not as good as if you have 30% to 40%. Being able to manipulate those cells to increase the frequency of this process, called homology-directed repair, is exciting.”

Dr Richardson and his colleagues described this work in Nature Genetics.

CRISPR relies on DNA repair

The researchers noted that CRISPR-Cas9 creates targeted DSBs, and it’s up to the cell to repair the DNA.

This can happen in 2 ways. Enzymes can stitch the dangling ends back together, which often results in one or more bases being added or deleted, disrupting the function of the gene.

Alternatively, other enzymes can patch the break with a single strand of DNA that matches the DNA sequence upstream and downstream of the cut. A complementary DNA strand is created to complete the double-strand repair.

The former method, called non-homologous end-joining, appears to be the most common outcome after CRISPR cutting.

The latter method, homology-directed repair, happens more frequently in some cells than others and requires the presence of DNA that can be used to patch the break. Researchers often supply a single-stranded piece of DNA and hope the cell uses it to replace the faulty sequence with the new one.

Both processes are a bit mysterious, however, and no one knows why some cells readily patch in DNA while others do so infrequently.

“The enthusiasm for using CRISPR-Cas9 for medical or synthetic biology applications is great, but no one really knows what happens after you put it into cells,” Dr Richardson said. “It goes and creates these breaks, and you count on the cells to fix them, but people don’t really understand how that process works.”

To find out which DNA repair enzymes are critical to homology-directed repair after CRISPR cutting, Dr Richardson and his colleagues used a technique called CRISPR interference. They knocked out, one at a time, more than 2000 genes known or suspected to be involved in DNA repair.

The researchers were surprised to find that many of the genes that proved important—homology-directed repair dropped dramatically when they were silenced—were involved in the FA pathway.

FA pathway

The FA pathway was largely understood to repair DNA interstrand crosslinks, where a nucleotide on one strand of DNA bonds tightly with a nucleotide on the adjacent strand, interfering with DNA replication and often killing the cell.

“Based on our work, we believe that the Fanconi anemia pathway plays a major role in fixing other types of lesions as well, but is best understood as the pathway that repairs double-strand breaks,” Dr Richardson said. “After Cas9 editing, the Fanconi anemia pathway is required if you want to insert new DNA.”

The importance of the FA pathway in repairing DSBs casts doubt on some planned CRISPR treatments for Fanconi anemia itself.

Without an active FA pathway, cells may not be able to replace their mutated genes with normal genes after Cas9 makes a cut. In fact, the activity level of the FA pathway may affect how efficiently CRISPR can insert DNA in a specific cell.

The researchers concluded that, while end-joining is the default repair mechanism after a DSB, the FA pathway competes with it, and that higher activity results in more homology-directed repair and less end-joining.

Dr Richardson and his colleagues also found that 1 of the 21 proteins in the FA pathway, FANCD2, always homes in on the site of the DSB created by CRISPR-Cas9. This suggests FANCD2 plays an important role in regulating the insertion of new DNA at the cut site.

The researchers therefore believe FANCD2 could be tweaked to boost the frequency with which a cell inserts DNA via homology-directed repair.

“Also, since FANCD2 localizes to the site of Cas9 breaks, you can use FANCD2 to map where Cas9 is cutting in any cell type,” Dr Richardson said. “If you edit a population of cells and you want to know where the on- and off-target cuts are, you can just map where FANCD2 was found in the genome and you can find the cuts.”

Image by Andre E.X. Brown

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has reiterated its negative opinion of betrixaban.

Once again, the CHMP has concluded that it cannot recommend approval of betrixaban for the prevention of venous thromboembolism (VTE) in adults hospitalized for an acute medical illness with risk factors for VTE, including VTE-related death.

The CHMP previously issued a negative opinion of betrixaban in March, but Portola Pharmaceuticals, Inc., requested a re-examination of that opinion.

The CHMP agreed to re-examine the opinion and confirmed the refusal of the marketing authorization on July 26.

The marketing authorization application for betrixaban was supported by data from the phase 3 APEX study. In this trial, researchers compared oral betrixaban to injectable enoxaparin for the prevention of VTE in patients with acute medical illnesses.

The CHMP said APEX did not satisfactorily show betrixaban’s effectiveness when used for preventing VTE in patients admitted to the hospital for recent medical illness.

In addition, patients treated with betrixaban had more episodes of bleeding than patients who received enoxaparin.

The CHMP said the excess bleeding was an important concern because betrixaban was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and betrixaban’s long persistence in the body could complicate management of bleeding.

Overall, the CHMP said the benefits of betrixaban did not outweigh its risks.

Portola said this decision will not affect patients currently enrolled in clinical trials of betrixaban.

The company also said it will continue working with regulatory authorities in countries outside the European Union to potentially bring betrixaban to patients as quickly as possible.

“We are disappointed by the committee’s assessment given both the unmet need and the clinically meaningful outcomes of the APEX trial in reducing VTE and VTE-related deaths in a vulnerable patient population,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development for Portola.

“We remain confident in the potential public health impact of betrixaban and will maintain focus on the US commercial launch as we continue to work toward our goal of expanding patient access to betrixaban around the world.”

Betrixaban was approved in the US in June 2017 under the trade name Bevyxxa.

Image by Andre E.X. Brown

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has reiterated its negative opinion of betrixaban.

Once again, the CHMP has concluded that it cannot recommend approval of betrixaban for the prevention of venous thromboembolism (VTE) in adults hospitalized for an acute medical illness with risk factors for VTE, including VTE-related death.

The CHMP previously issued a negative opinion of betrixaban in March, but Portola Pharmaceuticals, Inc., requested a re-examination of that opinion.

The CHMP agreed to re-examine the opinion and confirmed the refusal of the marketing authorization on July 26.

The marketing authorization application for betrixaban was supported by data from the phase 3 APEX study. In this trial, researchers compared oral betrixaban to injectable enoxaparin for the prevention of VTE in patients with acute medical illnesses.

The CHMP said APEX did not satisfactorily show betrixaban’s effectiveness when used for preventing VTE in patients admitted to the hospital for recent medical illness.

In addition, patients treated with betrixaban had more episodes of bleeding than patients who received enoxaparin.

The CHMP said the excess bleeding was an important concern because betrixaban was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and betrixaban’s long persistence in the body could complicate management of bleeding.

Overall, the CHMP said the benefits of betrixaban did not outweigh its risks.

Portola said this decision will not affect patients currently enrolled in clinical trials of betrixaban.

The company also said it will continue working with regulatory authorities in countries outside the European Union to potentially bring betrixaban to patients as quickly as possible.

“We are disappointed by the committee’s assessment given both the unmet need and the clinically meaningful outcomes of the APEX trial in reducing VTE and VTE-related deaths in a vulnerable patient population,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development for Portola.

“We remain confident in the potential public health impact of betrixaban and will maintain focus on the US commercial launch as we continue to work toward our goal of expanding patient access to betrixaban around the world.”

Betrixaban was approved in the US in June 2017 under the trade name Bevyxxa.

Image by Andre E.X. Brown

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has reiterated its negative opinion of betrixaban.

Once again, the CHMP has concluded that it cannot recommend approval of betrixaban for the prevention of venous thromboembolism (VTE) in adults hospitalized for an acute medical illness with risk factors for VTE, including VTE-related death.

The CHMP previously issued a negative opinion of betrixaban in March, but Portola Pharmaceuticals, Inc., requested a re-examination of that opinion.

The CHMP agreed to re-examine the opinion and confirmed the refusal of the marketing authorization on July 26.

The marketing authorization application for betrixaban was supported by data from the phase 3 APEX study. In this trial, researchers compared oral betrixaban to injectable enoxaparin for the prevention of VTE in patients with acute medical illnesses.

The CHMP said APEX did not satisfactorily show betrixaban’s effectiveness when used for preventing VTE in patients admitted to the hospital for recent medical illness.

In addition, patients treated with betrixaban had more episodes of bleeding than patients who received enoxaparin.

The CHMP said the excess bleeding was an important concern because betrixaban was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and betrixaban’s long persistence in the body could complicate management of bleeding.

Overall, the CHMP said the benefits of betrixaban did not outweigh its risks.

Portola said this decision will not affect patients currently enrolled in clinical trials of betrixaban.

The company also said it will continue working with regulatory authorities in countries outside the European Union to potentially bring betrixaban to patients as quickly as possible.

“We are disappointed by the committee’s assessment given both the unmet need and the clinically meaningful outcomes of the APEX trial in reducing VTE and VTE-related deaths in a vulnerable patient population,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development for Portola.

“We remain confident in the potential public health impact of betrixaban and will maintain focus on the US commercial launch as we continue to work toward our goal of expanding patient access to betrixaban around the world.”

Betrixaban was approved in the US in June 2017 under the trade name Bevyxxa.

Photo courtesy of the CDC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a new indication for rivaroxaban (Xarelto) 2.5 mg tablets.

The recommendation is for rivaroxaban co-administered with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischemic events.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Rivaroxaban is already EC-approved for use in combination with ASA alone or ASA plus clopidogrel or ticlopidine for the prevention of atherothrombotic events in adults with acute coronary syndrome and elevated cardiac biomarkers.

The CHMP’s positive opinion for rivaroxaban in coronary artery disease and symptomatic peripheral artery disease is based on data from the COMPASS study. Results from this study were presented at ESC Congress 2017 and published simultaneously in NEJM.

COMPASS enrolled 27,395 patients with stable atherosclerotic vascular disease. They were randomized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily), or aspirin alone (100 mg once daily).

The study’s primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. This outcome occurred in 4.1% of patients in the rivaroxaban-aspirin arm, 4.9% of those in the rivaroxaban-alone arm, and 5.4% of those in the aspirin-alone arm.

There was a significant difference in the primary outcome between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) but not between the rivaroxaban-alone arm and the aspirin-alone arm (P=0.12).

The incidence of major bleeding was 3.1% in the rivaroxaban-aspirin arm, 2.8% in the rivaroxaban-alone arm, and 1.9% in the aspirin-alone arm.

There was a significant difference in major bleeding between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) as well as between the rivaroxaban-alone arm and the aspirin-alone arm (P<0.001).

Photo courtesy of the CDC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a new indication for rivaroxaban (Xarelto) 2.5 mg tablets.

The recommendation is for rivaroxaban co-administered with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischemic events.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Rivaroxaban is already EC-approved for use in combination with ASA alone or ASA plus clopidogrel or ticlopidine for the prevention of atherothrombotic events in adults with acute coronary syndrome and elevated cardiac biomarkers.

The CHMP’s positive opinion for rivaroxaban in coronary artery disease and symptomatic peripheral artery disease is based on data from the COMPASS study. Results from this study were presented at ESC Congress 2017 and published simultaneously in NEJM.

COMPASS enrolled 27,395 patients with stable atherosclerotic vascular disease. They were randomized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily), or aspirin alone (100 mg once daily).

The study’s primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. This outcome occurred in 4.1% of patients in the rivaroxaban-aspirin arm, 4.9% of those in the rivaroxaban-alone arm, and 5.4% of those in the aspirin-alone arm.

There was a significant difference in the primary outcome between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) but not between the rivaroxaban-alone arm and the aspirin-alone arm (P=0.12).

The incidence of major bleeding was 3.1% in the rivaroxaban-aspirin arm, 2.8% in the rivaroxaban-alone arm, and 1.9% in the aspirin-alone arm.

There was a significant difference in major bleeding between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) as well as between the rivaroxaban-alone arm and the aspirin-alone arm (P<0.001).

Photo courtesy of the CDC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a new indication for rivaroxaban (Xarelto) 2.5 mg tablets.

The recommendation is for rivaroxaban co-administered with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischemic events.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Rivaroxaban is already EC-approved for use in combination with ASA alone or ASA plus clopidogrel or ticlopidine for the prevention of atherothrombotic events in adults with acute coronary syndrome and elevated cardiac biomarkers.

The CHMP’s positive opinion for rivaroxaban in coronary artery disease and symptomatic peripheral artery disease is based on data from the COMPASS study. Results from this study were presented at ESC Congress 2017 and published simultaneously in NEJM.

COMPASS enrolled 27,395 patients with stable atherosclerotic vascular disease. They were randomized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily), or aspirin alone (100 mg once daily).

The study’s primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. This outcome occurred in 4.1% of patients in the rivaroxaban-aspirin arm, 4.9% of those in the rivaroxaban-alone arm, and 5.4% of those in the aspirin-alone arm.

There was a significant difference in the primary outcome between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) but not between the rivaroxaban-alone arm and the aspirin-alone arm (P=0.12).

The incidence of major bleeding was 3.1% in the rivaroxaban-aspirin arm, 2.8% in the rivaroxaban-alone arm, and 1.9% in the aspirin-alone arm.

There was a significant difference in major bleeding between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) as well as between the rivaroxaban-alone arm and the aspirin-alone arm (P<0.001).