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Fitusiran: Great ‘leap forward’ in hemophilia treatment
Fitusiran is a small interfering RNA molecule that blocks antithrombin production in liver cells. Instead of taking the traditional approach in hemophilia treatment of boosting the coagulation cascade by replacing what’s missing, the idea of fitusiran is to short circuit the body’s anticoagulation system by targeting antithrombin.
Patients in two trials presented at the meeting, ATLAS-A/B and ATLAS-INH, had about a 90% reduction in their annualized bleeding rates when treated with prophylactic fitusiran, with half or more having no bleeds that required treatment during the 9-month trials. The median annualized bleeding rate fell to 0, trial investigators reported at the meeting.
These findings held in both hemophilia A and B with and without inhibitors, which are antibodies formed against exogenous clotting factors, and on subanalysis of spontaneous and joint bleeding rates. Reduced bleeding was associated with substantial improvements in health-care related quality of life, particularly in the physical health domain.
A question about study design
An audience member at ASH noted that the trials didn’t compare fitusiran against prophylactic treatment, which is standard of care for hemophilia, but rather against episodic treatment – concentrated factors or bypassing agents in subjects with inhibitors – once subjects in the control groups started to bleed.
Still, the numbers reported in the studies “have never been achieved with standard prophylaxis in the past.” Furthermore, standard prophylaxis requires lifelong intravenous infusions, sometimes several a week, said lead ATLAS-A/B investigator Alok Srivastava, MD, a hematologist at the Christian Medical College in Vellore, India.
Fitusiran was dosed in the studies as a once-a-month 80 mg subcutaneous injection, so is much less bothersome. Also, it seems likely that some patients will only need dosing every other month. Maker Sanofi Genzyme is exploring lower and less frequent dosing to reduce thrombotic event risks that emerged in earlier studies, said Steven Pipe, MD, a pediatric hematologist at the University of Michigan, Ann Arbor, and the senior investigator on ATLAS-A/B, which assessed fitusiran in patients without inhibitors.
Serious thrombotic events occurred in two fitusiran patients in the trials, one of which led to discontinuation.
No pricing information
Overall, “I think [fitusiran] is a tremendous leap forward” with “the opportunity to transform the day-to-day lives of patients,” particularly those with hemophilia B, who have limited treatment options, Dr. Pipe said.
If approved for the U.S. market, fitusiran will go up against the monoclonal antibody emicizumab (Hemlibra), a subcutaneous injection dosed weekly to monthly that mimics the function of factor VIII, so it’s approved only for hemophilia A with or without inhibitors.
Several audience members at ASH noted that a major consideration for fitusiran, if approved, will be its cost. There’s no pricing information yet, but annual list price for emicizumab is reported to be in the $500,000 range.
For hemophilia A, “it will come to what proves to be the most efficacious and safe, with also consideration given to pricing,” Nigel Key, MD, a hematologist at the University of North Carolina at Chapel Hill, said in a comment.
Trial details
In ATLAS-A/B, 80 male patients were randomized to prophylactic fitusiran once monthly and 40 to continue with clotting factors as needed for bleeding. Just over 20% had hemophilia B, the rest hemophilia A. The mean age was 34 years, and subjects had a mean of about 12 bleeds in the 6 months leading up to the study.
Half of the fitusiran group had no treated bleeds during the study period versus only 5% in the control arm.
The five treatment emergent serious adverse events in the fitusiran arm included cholelithiasis in two subjects, plus cholecystitis, lower respiratory tract infection, and asthma in one each. Two fitusiran patients discontinued treatment because of cholecystitis and increased alanine aminotransferase.
ATLAS-INH had the same study design, and investigated patients with inhibitors; again, just over 20% had hemophilia B, the rest A. Mean age was 28 years, and patients had a mean of about 13 bleeds over the 6 months before the study. A total of 38 subjects were randomized to fitusiran, and 19 to bypassing agents as needed.
Almost 66% of fitusiran patients had no treated bleeds versus about 5% in the control arm.
There “was far less bleeding both for hemophilia A and B. It’s definitely a clinically meaningful and important” effect, said ATLAS-INH lead investigator Guy Young, MD, director of the hemostasis and thrombosis program at Children’s Hospital Los Angeles.
He said the improved quality of life with fitusiran noted in both trials was “not surprising. If you only have to dose once a month subcutaneously, and you are not bleeding, of course your quality of life is going to improve.”
Both fitusiran thrombotic events occurred in ATLAS-INH. One patient developed deep vein thrombosis, subclavian vein thrombosis, and superficial thrombophlebitis but stayed in the study. Another discontinued after developing suspected spinal vessel thrombosis. Serious adverse events among five other subjects included acute cholecystitis and hematuria.
Fitusiran was associated with liver enzyme elevations in both trials, but they were generally mild to moderate.
The studies were funded by fitusiran maker Sanofi Genzyme. Several investigators were employees. Dr. Pipe is a consultant, Dr. Srivastava is a researcher and adviser, and Dr. Young is a speaker and consultant for the company and disclosed honoraria from it. Dr. Key had no relevant disclosures.
Fitusiran is a small interfering RNA molecule that blocks antithrombin production in liver cells. Instead of taking the traditional approach in hemophilia treatment of boosting the coagulation cascade by replacing what’s missing, the idea of fitusiran is to short circuit the body’s anticoagulation system by targeting antithrombin.
Patients in two trials presented at the meeting, ATLAS-A/B and ATLAS-INH, had about a 90% reduction in their annualized bleeding rates when treated with prophylactic fitusiran, with half or more having no bleeds that required treatment during the 9-month trials. The median annualized bleeding rate fell to 0, trial investigators reported at the meeting.
These findings held in both hemophilia A and B with and without inhibitors, which are antibodies formed against exogenous clotting factors, and on subanalysis of spontaneous and joint bleeding rates. Reduced bleeding was associated with substantial improvements in health-care related quality of life, particularly in the physical health domain.
A question about study design
An audience member at ASH noted that the trials didn’t compare fitusiran against prophylactic treatment, which is standard of care for hemophilia, but rather against episodic treatment – concentrated factors or bypassing agents in subjects with inhibitors – once subjects in the control groups started to bleed.
Still, the numbers reported in the studies “have never been achieved with standard prophylaxis in the past.” Furthermore, standard prophylaxis requires lifelong intravenous infusions, sometimes several a week, said lead ATLAS-A/B investigator Alok Srivastava, MD, a hematologist at the Christian Medical College in Vellore, India.
Fitusiran was dosed in the studies as a once-a-month 80 mg subcutaneous injection, so is much less bothersome. Also, it seems likely that some patients will only need dosing every other month. Maker Sanofi Genzyme is exploring lower and less frequent dosing to reduce thrombotic event risks that emerged in earlier studies, said Steven Pipe, MD, a pediatric hematologist at the University of Michigan, Ann Arbor, and the senior investigator on ATLAS-A/B, which assessed fitusiran in patients without inhibitors.
Serious thrombotic events occurred in two fitusiran patients in the trials, one of which led to discontinuation.
No pricing information
Overall, “I think [fitusiran] is a tremendous leap forward” with “the opportunity to transform the day-to-day lives of patients,” particularly those with hemophilia B, who have limited treatment options, Dr. Pipe said.
If approved for the U.S. market, fitusiran will go up against the monoclonal antibody emicizumab (Hemlibra), a subcutaneous injection dosed weekly to monthly that mimics the function of factor VIII, so it’s approved only for hemophilia A with or without inhibitors.
Several audience members at ASH noted that a major consideration for fitusiran, if approved, will be its cost. There’s no pricing information yet, but annual list price for emicizumab is reported to be in the $500,000 range.
For hemophilia A, “it will come to what proves to be the most efficacious and safe, with also consideration given to pricing,” Nigel Key, MD, a hematologist at the University of North Carolina at Chapel Hill, said in a comment.
Trial details
In ATLAS-A/B, 80 male patients were randomized to prophylactic fitusiran once monthly and 40 to continue with clotting factors as needed for bleeding. Just over 20% had hemophilia B, the rest hemophilia A. The mean age was 34 years, and subjects had a mean of about 12 bleeds in the 6 months leading up to the study.
Half of the fitusiran group had no treated bleeds during the study period versus only 5% in the control arm.
The five treatment emergent serious adverse events in the fitusiran arm included cholelithiasis in two subjects, plus cholecystitis, lower respiratory tract infection, and asthma in one each. Two fitusiran patients discontinued treatment because of cholecystitis and increased alanine aminotransferase.
ATLAS-INH had the same study design, and investigated patients with inhibitors; again, just over 20% had hemophilia B, the rest A. Mean age was 28 years, and patients had a mean of about 13 bleeds over the 6 months before the study. A total of 38 subjects were randomized to fitusiran, and 19 to bypassing agents as needed.
Almost 66% of fitusiran patients had no treated bleeds versus about 5% in the control arm.
There “was far less bleeding both for hemophilia A and B. It’s definitely a clinically meaningful and important” effect, said ATLAS-INH lead investigator Guy Young, MD, director of the hemostasis and thrombosis program at Children’s Hospital Los Angeles.
He said the improved quality of life with fitusiran noted in both trials was “not surprising. If you only have to dose once a month subcutaneously, and you are not bleeding, of course your quality of life is going to improve.”
Both fitusiran thrombotic events occurred in ATLAS-INH. One patient developed deep vein thrombosis, subclavian vein thrombosis, and superficial thrombophlebitis but stayed in the study. Another discontinued after developing suspected spinal vessel thrombosis. Serious adverse events among five other subjects included acute cholecystitis and hematuria.
Fitusiran was associated with liver enzyme elevations in both trials, but they were generally mild to moderate.
The studies were funded by fitusiran maker Sanofi Genzyme. Several investigators were employees. Dr. Pipe is a consultant, Dr. Srivastava is a researcher and adviser, and Dr. Young is a speaker and consultant for the company and disclosed honoraria from it. Dr. Key had no relevant disclosures.
Fitusiran is a small interfering RNA molecule that blocks antithrombin production in liver cells. Instead of taking the traditional approach in hemophilia treatment of boosting the coagulation cascade by replacing what’s missing, the idea of fitusiran is to short circuit the body’s anticoagulation system by targeting antithrombin.
Patients in two trials presented at the meeting, ATLAS-A/B and ATLAS-INH, had about a 90% reduction in their annualized bleeding rates when treated with prophylactic fitusiran, with half or more having no bleeds that required treatment during the 9-month trials. The median annualized bleeding rate fell to 0, trial investigators reported at the meeting.
These findings held in both hemophilia A and B with and without inhibitors, which are antibodies formed against exogenous clotting factors, and on subanalysis of spontaneous and joint bleeding rates. Reduced bleeding was associated with substantial improvements in health-care related quality of life, particularly in the physical health domain.
A question about study design
An audience member at ASH noted that the trials didn’t compare fitusiran against prophylactic treatment, which is standard of care for hemophilia, but rather against episodic treatment – concentrated factors or bypassing agents in subjects with inhibitors – once subjects in the control groups started to bleed.
Still, the numbers reported in the studies “have never been achieved with standard prophylaxis in the past.” Furthermore, standard prophylaxis requires lifelong intravenous infusions, sometimes several a week, said lead ATLAS-A/B investigator Alok Srivastava, MD, a hematologist at the Christian Medical College in Vellore, India.
Fitusiran was dosed in the studies as a once-a-month 80 mg subcutaneous injection, so is much less bothersome. Also, it seems likely that some patients will only need dosing every other month. Maker Sanofi Genzyme is exploring lower and less frequent dosing to reduce thrombotic event risks that emerged in earlier studies, said Steven Pipe, MD, a pediatric hematologist at the University of Michigan, Ann Arbor, and the senior investigator on ATLAS-A/B, which assessed fitusiran in patients without inhibitors.
Serious thrombotic events occurred in two fitusiran patients in the trials, one of which led to discontinuation.
No pricing information
Overall, “I think [fitusiran] is a tremendous leap forward” with “the opportunity to transform the day-to-day lives of patients,” particularly those with hemophilia B, who have limited treatment options, Dr. Pipe said.
If approved for the U.S. market, fitusiran will go up against the monoclonal antibody emicizumab (Hemlibra), a subcutaneous injection dosed weekly to monthly that mimics the function of factor VIII, so it’s approved only for hemophilia A with or without inhibitors.
Several audience members at ASH noted that a major consideration for fitusiran, if approved, will be its cost. There’s no pricing information yet, but annual list price for emicizumab is reported to be in the $500,000 range.
For hemophilia A, “it will come to what proves to be the most efficacious and safe, with also consideration given to pricing,” Nigel Key, MD, a hematologist at the University of North Carolina at Chapel Hill, said in a comment.
Trial details
In ATLAS-A/B, 80 male patients were randomized to prophylactic fitusiran once monthly and 40 to continue with clotting factors as needed for bleeding. Just over 20% had hemophilia B, the rest hemophilia A. The mean age was 34 years, and subjects had a mean of about 12 bleeds in the 6 months leading up to the study.
Half of the fitusiran group had no treated bleeds during the study period versus only 5% in the control arm.
The five treatment emergent serious adverse events in the fitusiran arm included cholelithiasis in two subjects, plus cholecystitis, lower respiratory tract infection, and asthma in one each. Two fitusiran patients discontinued treatment because of cholecystitis and increased alanine aminotransferase.
ATLAS-INH had the same study design, and investigated patients with inhibitors; again, just over 20% had hemophilia B, the rest A. Mean age was 28 years, and patients had a mean of about 13 bleeds over the 6 months before the study. A total of 38 subjects were randomized to fitusiran, and 19 to bypassing agents as needed.
Almost 66% of fitusiran patients had no treated bleeds versus about 5% in the control arm.
There “was far less bleeding both for hemophilia A and B. It’s definitely a clinically meaningful and important” effect, said ATLAS-INH lead investigator Guy Young, MD, director of the hemostasis and thrombosis program at Children’s Hospital Los Angeles.
He said the improved quality of life with fitusiran noted in both trials was “not surprising. If you only have to dose once a month subcutaneously, and you are not bleeding, of course your quality of life is going to improve.”
Both fitusiran thrombotic events occurred in ATLAS-INH. One patient developed deep vein thrombosis, subclavian vein thrombosis, and superficial thrombophlebitis but stayed in the study. Another discontinued after developing suspected spinal vessel thrombosis. Serious adverse events among five other subjects included acute cholecystitis and hematuria.
Fitusiran was associated with liver enzyme elevations in both trials, but they were generally mild to moderate.
The studies were funded by fitusiran maker Sanofi Genzyme. Several investigators were employees. Dr. Pipe is a consultant, Dr. Srivastava is a researcher and adviser, and Dr. Young is a speaker and consultant for the company and disclosed honoraria from it. Dr. Key had no relevant disclosures.
FROM ASH 2021
FDA approves new interferon for polycythemia vera
, according to an agency press release.
Besremi has a longer half-life than do other pegylated interferon-alfas, allowing for dosing every 2 weeks instead of weekly. If red blood cell counts remain normal for a year, patients have the option of switching to once-monthly dosing. As with similar products, Besremi is self-administered as a subcutaneous injection.
It’s the first interferon approved in the United States specifically for polycythemia vera. Besremi is also approved for upfront therapy, unlike FDA’s first approval for the condition, the oral JAK inhibitor ruxolitinib (Jakafi), which is indicated only after hydroxyurea failure.
Taiwan-based maker PharmaEssentia said in another press release that it will roll Besremi out to the U.S. market in the coming weeks.
“As we begin working closely with the community to integrate this important treatment into clinical practice, we also continue to expand our scientific efforts to unlock the full potential of our pioneering molecule,” said Ko-Chung Lin, PhD, the company’s CEO.
As for unlocking the full potential, Besremi is under investigation for other interferon indications, including myelofibrosis, leukemia, and chronic hepatitis.
The FDA’s approval was based on results in 51 adults treated for an average of 5 years; 31 (61%) had a complete hematologic response, defined as a hematocrit below 45% with no phlebotomy for at least 2 months, plus normal platelet and white cell counts, normal spleen size, and no blood clots.
“Noninferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months,” investigators noted in an earlier report (Lancet Haematol. 2020 Mar;7[3]:e196-e208).
Besremi carries the same boxed warning as those of peginterferon alfa-2b (Pegintron) and peginterferon alfa-2a (Pegasys), which notes the risk of life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Related contraindications include severe depression and other psychiatric problems; liver impairment; serious or untreated autoimmune disease, and immunosuppression following organ transplant.
Influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain were the most common adverse events in studies, occurring in over 40% of subjects. Urinary tract infections, transient ischemic attacks, and depression were the most frequent serious complications, occurring in over 4%.
Labeling also notes the risk for fetal harm and the need for effective contraception.
Besremi was approved in Europe in 2019 and is approved in Taiwan and South Korea.
Polycythemia vera is a rare condition thought to be caused by acquired bone marrow stem cell mutations that trigger an overproduction of red blood cells. Patients are at increased risk of blood clots and emboli, and subsequent heart attacks, strokes, and other problems. There’s also the risk of transformation to secondary myelofibrosis or leukemia.
, according to an agency press release.
Besremi has a longer half-life than do other pegylated interferon-alfas, allowing for dosing every 2 weeks instead of weekly. If red blood cell counts remain normal for a year, patients have the option of switching to once-monthly dosing. As with similar products, Besremi is self-administered as a subcutaneous injection.
It’s the first interferon approved in the United States specifically for polycythemia vera. Besremi is also approved for upfront therapy, unlike FDA’s first approval for the condition, the oral JAK inhibitor ruxolitinib (Jakafi), which is indicated only after hydroxyurea failure.
Taiwan-based maker PharmaEssentia said in another press release that it will roll Besremi out to the U.S. market in the coming weeks.
“As we begin working closely with the community to integrate this important treatment into clinical practice, we also continue to expand our scientific efforts to unlock the full potential of our pioneering molecule,” said Ko-Chung Lin, PhD, the company’s CEO.
As for unlocking the full potential, Besremi is under investigation for other interferon indications, including myelofibrosis, leukemia, and chronic hepatitis.
The FDA’s approval was based on results in 51 adults treated for an average of 5 years; 31 (61%) had a complete hematologic response, defined as a hematocrit below 45% with no phlebotomy for at least 2 months, plus normal platelet and white cell counts, normal spleen size, and no blood clots.
“Noninferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months,” investigators noted in an earlier report (Lancet Haematol. 2020 Mar;7[3]:e196-e208).
Besremi carries the same boxed warning as those of peginterferon alfa-2b (Pegintron) and peginterferon alfa-2a (Pegasys), which notes the risk of life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Related contraindications include severe depression and other psychiatric problems; liver impairment; serious or untreated autoimmune disease, and immunosuppression following organ transplant.
Influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain were the most common adverse events in studies, occurring in over 40% of subjects. Urinary tract infections, transient ischemic attacks, and depression were the most frequent serious complications, occurring in over 4%.
Labeling also notes the risk for fetal harm and the need for effective contraception.
Besremi was approved in Europe in 2019 and is approved in Taiwan and South Korea.
Polycythemia vera is a rare condition thought to be caused by acquired bone marrow stem cell mutations that trigger an overproduction of red blood cells. Patients are at increased risk of blood clots and emboli, and subsequent heart attacks, strokes, and other problems. There’s also the risk of transformation to secondary myelofibrosis or leukemia.
, according to an agency press release.
Besremi has a longer half-life than do other pegylated interferon-alfas, allowing for dosing every 2 weeks instead of weekly. If red blood cell counts remain normal for a year, patients have the option of switching to once-monthly dosing. As with similar products, Besremi is self-administered as a subcutaneous injection.
It’s the first interferon approved in the United States specifically for polycythemia vera. Besremi is also approved for upfront therapy, unlike FDA’s first approval for the condition, the oral JAK inhibitor ruxolitinib (Jakafi), which is indicated only after hydroxyurea failure.
Taiwan-based maker PharmaEssentia said in another press release that it will roll Besremi out to the U.S. market in the coming weeks.
“As we begin working closely with the community to integrate this important treatment into clinical practice, we also continue to expand our scientific efforts to unlock the full potential of our pioneering molecule,” said Ko-Chung Lin, PhD, the company’s CEO.
As for unlocking the full potential, Besremi is under investigation for other interferon indications, including myelofibrosis, leukemia, and chronic hepatitis.
The FDA’s approval was based on results in 51 adults treated for an average of 5 years; 31 (61%) had a complete hematologic response, defined as a hematocrit below 45% with no phlebotomy for at least 2 months, plus normal platelet and white cell counts, normal spleen size, and no blood clots.
“Noninferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months,” investigators noted in an earlier report (Lancet Haematol. 2020 Mar;7[3]:e196-e208).
Besremi carries the same boxed warning as those of peginterferon alfa-2b (Pegintron) and peginterferon alfa-2a (Pegasys), which notes the risk of life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Related contraindications include severe depression and other psychiatric problems; liver impairment; serious or untreated autoimmune disease, and immunosuppression following organ transplant.
Influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain were the most common adverse events in studies, occurring in over 40% of subjects. Urinary tract infections, transient ischemic attacks, and depression were the most frequent serious complications, occurring in over 4%.
Labeling also notes the risk for fetal harm and the need for effective contraception.
Besremi was approved in Europe in 2019 and is approved in Taiwan and South Korea.
Polycythemia vera is a rare condition thought to be caused by acquired bone marrow stem cell mutations that trigger an overproduction of red blood cells. Patients are at increased risk of blood clots and emboli, and subsequent heart attacks, strokes, and other problems. There’s also the risk of transformation to secondary myelofibrosis or leukemia.
Data from Spain yield new insights on a rare hemophilia
The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).
The report was published online in Blood Advances.
These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.
“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”
The Spanish AHA registry data
The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.
The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.
A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.
“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).
Women and those with high inhibitor levels were less likely to achieve CR, they said.
Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”
The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).
Additional insights
“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”
Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.
The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”
Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.
“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.
Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.
They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.
Still, the findings add value, they said.
“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”
“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”
Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.
“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”
The data are especially useful with respect to use of immunosuppressive regimens, he said.
“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”
“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”
The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.
The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).
The report was published online in Blood Advances.
These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.
“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”
The Spanish AHA registry data
The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.
The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.
A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.
“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).
Women and those with high inhibitor levels were less likely to achieve CR, they said.
Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”
The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).
Additional insights
“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”
Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.
The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”
Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.
“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.
Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.
They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.
Still, the findings add value, they said.
“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”
“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”
Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.
“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”
The data are especially useful with respect to use of immunosuppressive regimens, he said.
“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”
“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”
The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.
The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).
The report was published online in Blood Advances.
These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.
“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”
The Spanish AHA registry data
The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.
The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.
A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.
“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).
Women and those with high inhibitor levels were less likely to achieve CR, they said.
Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”
The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).
Additional insights
“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”
Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.
The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”
Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.
“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.
Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.
They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.
Still, the findings add value, they said.
“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”
“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”
Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.
“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”
The data are especially useful with respect to use of immunosuppressive regimens, he said.
“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”
“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”
The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.
FROM BLOOD ADVANCES
Rivaroxaban’s single daily dose may lead to higher bleeding risk than other DOACs
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
FROM ANNALS OF INTERNAL MEDICINE
No added risk of hepatic cancer in patients with hemophilia after successful HCV treatment
Research has shown that hepatitis C virus infections in patients with hemophilia lead to the development of hepatocellular carcinoma (HCC) at a relatively younger age than that in patients without hemophilia. However, according to Yosuke Inukai of Nagoya (Japan) University and colleagues.
The researchers assessed 699 patients who achieved SVR after HCV antiviral treatment: 78 patients with hemophilia (H group) and 621 patients without hemophilia (NH group). They examined patient characteristics, clinical outcomes, and the cumulative incidence of HCC after SVR, according to a report published online in Annals of Hepatology.
No added risk
Patients in the H-group were significantly younger and had a lower hepatic fibrosis score, compared with the NH group. Over a follow-up period of 7 years, there were no differences seen in the incidence of liver-related disease or overall death between the two groups. HCC was diagnosed in 4 patients in the H group and 36 patients in the NH group after SVR.
Multivariate analysis showed that male sex, patient age, and the presence of cirrhosis were significant risk factors for HCC incidence. However, after propensity-score matching that adjusted for the risk factors of HCC between the two groups, there was no significant difference seen in the cumulative incidence of HCC between the two groups.
Need for vigilance
The lack of a significant difference in the cumulative incidence of HCC after SVR or the long-term prognosis in patients with and without hemophilia, suggests that SVR could reduce the rates of liver carcinogenesis and liver disease–related mortality in both groups of patients, the researchers stated.
However: “Although there were no differences in overall survival, deaths from liver failure and bleeding events were observed in patients with hemophilia during the study period. Since the age in the H group at the time of starting antiviral treatment was 16 years younger than that in the NH group, careful observation is needed in patients with hemophilia even after eradication of HCV,” the researchers concluded.
The authors reported that they had no conflicts of interest.
Research has shown that hepatitis C virus infections in patients with hemophilia lead to the development of hepatocellular carcinoma (HCC) at a relatively younger age than that in patients without hemophilia. However, according to Yosuke Inukai of Nagoya (Japan) University and colleagues.
The researchers assessed 699 patients who achieved SVR after HCV antiviral treatment: 78 patients with hemophilia (H group) and 621 patients without hemophilia (NH group). They examined patient characteristics, clinical outcomes, and the cumulative incidence of HCC after SVR, according to a report published online in Annals of Hepatology.
No added risk
Patients in the H-group were significantly younger and had a lower hepatic fibrosis score, compared with the NH group. Over a follow-up period of 7 years, there were no differences seen in the incidence of liver-related disease or overall death between the two groups. HCC was diagnosed in 4 patients in the H group and 36 patients in the NH group after SVR.
Multivariate analysis showed that male sex, patient age, and the presence of cirrhosis were significant risk factors for HCC incidence. However, after propensity-score matching that adjusted for the risk factors of HCC between the two groups, there was no significant difference seen in the cumulative incidence of HCC between the two groups.
Need for vigilance
The lack of a significant difference in the cumulative incidence of HCC after SVR or the long-term prognosis in patients with and without hemophilia, suggests that SVR could reduce the rates of liver carcinogenesis and liver disease–related mortality in both groups of patients, the researchers stated.
However: “Although there were no differences in overall survival, deaths from liver failure and bleeding events were observed in patients with hemophilia during the study period. Since the age in the H group at the time of starting antiviral treatment was 16 years younger than that in the NH group, careful observation is needed in patients with hemophilia even after eradication of HCV,” the researchers concluded.
The authors reported that they had no conflicts of interest.
Research has shown that hepatitis C virus infections in patients with hemophilia lead to the development of hepatocellular carcinoma (HCC) at a relatively younger age than that in patients without hemophilia. However, according to Yosuke Inukai of Nagoya (Japan) University and colleagues.
The researchers assessed 699 patients who achieved SVR after HCV antiviral treatment: 78 patients with hemophilia (H group) and 621 patients without hemophilia (NH group). They examined patient characteristics, clinical outcomes, and the cumulative incidence of HCC after SVR, according to a report published online in Annals of Hepatology.
No added risk
Patients in the H-group were significantly younger and had a lower hepatic fibrosis score, compared with the NH group. Over a follow-up period of 7 years, there were no differences seen in the incidence of liver-related disease or overall death between the two groups. HCC was diagnosed in 4 patients in the H group and 36 patients in the NH group after SVR.
Multivariate analysis showed that male sex, patient age, and the presence of cirrhosis were significant risk factors for HCC incidence. However, after propensity-score matching that adjusted for the risk factors of HCC between the two groups, there was no significant difference seen in the cumulative incidence of HCC between the two groups.
Need for vigilance
The lack of a significant difference in the cumulative incidence of HCC after SVR or the long-term prognosis in patients with and without hemophilia, suggests that SVR could reduce the rates of liver carcinogenesis and liver disease–related mortality in both groups of patients, the researchers stated.
However: “Although there were no differences in overall survival, deaths from liver failure and bleeding events were observed in patients with hemophilia during the study period. Since the age in the H group at the time of starting antiviral treatment was 16 years younger than that in the NH group, careful observation is needed in patients with hemophilia even after eradication of HCV,” the researchers concluded.
The authors reported that they had no conflicts of interest.
FROM ANNALS OF HEPATOLOGY
Intracranial hemorrhaging a high risk for patients with hemophilia, especially neonates
The observed rates of intracranial hemorrhaging (ICH) in patients with hemophilia were higher compared to the general populations among all age groups examined, according to a meta-analysis of studies reported online ahead of print in Blood.
As previously reported, the risk seemed higher in the group of infants and toddlers, and neonates with hemophilia showed a 33-fold higher risk of ICH than newborns in the general population, in the current study.
The researchers performed a literature review and assessed 45 studies that represented 54,470 patients, 809,151 person-years and 5,326 live births of patients with hemophilia. Pooled ICH incidence and mortality were calculated for three age groups: persons of all ages with hemophilia; children and young adults below 25 years of age with hemophilia; and neonates with hemophilia.
Overall results
Among the persons of all ages, the pooled ICH incidence and mortality rates were 2.3 (95% confidence interval, 1.2-4.8) and 0.8 (95% CI, 0.5-1.2) per 1,000 person-years, respectively, according to the authors. They found that in children and young adults, the pooled ICH incidence and mortality rates were 7.4 (95% CI, 4.9-11.1) and 0.5 (95% CI, 0.3-0.9) per 1,000 person-years, respectively. In neonates, the pooled cumulative ICH incidence was 2.1% (95% CI, 1.5-2.8) per 100 live births and the pooled ICH cumulative mortality was 0.2% (95% CI, 0.0-1.2) per 100 live births.
Overall, the occurrence of ICH was classified as spontaneous in 35%-58% of cases.
Neonates at risk
The observed ICH rates in hemophilia were higher compared to the general populations among the age groups assessed. Neonates showed the highest risk of ICH, which is confirmed by other studies in severe hemophilia demonstrating that neonates were at 11.2 times higher risk for ICH compared with 1- to 12-month-old children, and is also strongly increased compared to neonates in the general populations, the researchers stated.
A previous large study of term infants reported 361 intracranial bleeding episodes per 583,340 live births (0.062% per 100 live births), and comparing this to the current pooled estimate of 2.1% per 100 live births, neonates with hemophilia showed a 33-fold higher risk of ICH than newborns in the general population, according to the researchers.
Monitoring and follow-up
“Our findings suggest that adequate follow-up and monitoring of patients is warranted among all ages, especially in the presence of risk factors. Prophylaxis seems to halve ICH risk in children and adults with severe hemophilia, which supports existing recommendations encouraging early initiation of prophylactic treatment,” the authors advised.
Accurate capture of the true frequency of ICH is challenged by considerable clinical heterogeneity, limiting the precision and generalizability of the pooled estimates, leading to the likelihood that ICH and mortality were underdiagnosed in this analysis, according to the authors.
“We found high ICH incidence and mortality rates in patients with hemophilia. Our findings suggest that ICH is still an important problem in hemophilia requiring adequate counseling of patients of all ages,” the researchers concluded.
This work was supported by a grant from Sobi. Some of the authors reported research, consulting or lecturing fees from a variety of pharmaceutical companies, including Sobi.
The observed rates of intracranial hemorrhaging (ICH) in patients with hemophilia were higher compared to the general populations among all age groups examined, according to a meta-analysis of studies reported online ahead of print in Blood.
As previously reported, the risk seemed higher in the group of infants and toddlers, and neonates with hemophilia showed a 33-fold higher risk of ICH than newborns in the general population, in the current study.
The researchers performed a literature review and assessed 45 studies that represented 54,470 patients, 809,151 person-years and 5,326 live births of patients with hemophilia. Pooled ICH incidence and mortality were calculated for three age groups: persons of all ages with hemophilia; children and young adults below 25 years of age with hemophilia; and neonates with hemophilia.
Overall results
Among the persons of all ages, the pooled ICH incidence and mortality rates were 2.3 (95% confidence interval, 1.2-4.8) and 0.8 (95% CI, 0.5-1.2) per 1,000 person-years, respectively, according to the authors. They found that in children and young adults, the pooled ICH incidence and mortality rates were 7.4 (95% CI, 4.9-11.1) and 0.5 (95% CI, 0.3-0.9) per 1,000 person-years, respectively. In neonates, the pooled cumulative ICH incidence was 2.1% (95% CI, 1.5-2.8) per 100 live births and the pooled ICH cumulative mortality was 0.2% (95% CI, 0.0-1.2) per 100 live births.
Overall, the occurrence of ICH was classified as spontaneous in 35%-58% of cases.
Neonates at risk
The observed ICH rates in hemophilia were higher compared to the general populations among the age groups assessed. Neonates showed the highest risk of ICH, which is confirmed by other studies in severe hemophilia demonstrating that neonates were at 11.2 times higher risk for ICH compared with 1- to 12-month-old children, and is also strongly increased compared to neonates in the general populations, the researchers stated.
A previous large study of term infants reported 361 intracranial bleeding episodes per 583,340 live births (0.062% per 100 live births), and comparing this to the current pooled estimate of 2.1% per 100 live births, neonates with hemophilia showed a 33-fold higher risk of ICH than newborns in the general population, according to the researchers.
Monitoring and follow-up
“Our findings suggest that adequate follow-up and monitoring of patients is warranted among all ages, especially in the presence of risk factors. Prophylaxis seems to halve ICH risk in children and adults with severe hemophilia, which supports existing recommendations encouraging early initiation of prophylactic treatment,” the authors advised.
Accurate capture of the true frequency of ICH is challenged by considerable clinical heterogeneity, limiting the precision and generalizability of the pooled estimates, leading to the likelihood that ICH and mortality were underdiagnosed in this analysis, according to the authors.
“We found high ICH incidence and mortality rates in patients with hemophilia. Our findings suggest that ICH is still an important problem in hemophilia requiring adequate counseling of patients of all ages,” the researchers concluded.
This work was supported by a grant from Sobi. Some of the authors reported research, consulting or lecturing fees from a variety of pharmaceutical companies, including Sobi.
The observed rates of intracranial hemorrhaging (ICH) in patients with hemophilia were higher compared to the general populations among all age groups examined, according to a meta-analysis of studies reported online ahead of print in Blood.
As previously reported, the risk seemed higher in the group of infants and toddlers, and neonates with hemophilia showed a 33-fold higher risk of ICH than newborns in the general population, in the current study.
The researchers performed a literature review and assessed 45 studies that represented 54,470 patients, 809,151 person-years and 5,326 live births of patients with hemophilia. Pooled ICH incidence and mortality were calculated for three age groups: persons of all ages with hemophilia; children and young adults below 25 years of age with hemophilia; and neonates with hemophilia.
Overall results
Among the persons of all ages, the pooled ICH incidence and mortality rates were 2.3 (95% confidence interval, 1.2-4.8) and 0.8 (95% CI, 0.5-1.2) per 1,000 person-years, respectively, according to the authors. They found that in children and young adults, the pooled ICH incidence and mortality rates were 7.4 (95% CI, 4.9-11.1) and 0.5 (95% CI, 0.3-0.9) per 1,000 person-years, respectively. In neonates, the pooled cumulative ICH incidence was 2.1% (95% CI, 1.5-2.8) per 100 live births and the pooled ICH cumulative mortality was 0.2% (95% CI, 0.0-1.2) per 100 live births.
Overall, the occurrence of ICH was classified as spontaneous in 35%-58% of cases.
Neonates at risk
The observed ICH rates in hemophilia were higher compared to the general populations among the age groups assessed. Neonates showed the highest risk of ICH, which is confirmed by other studies in severe hemophilia demonstrating that neonates were at 11.2 times higher risk for ICH compared with 1- to 12-month-old children, and is also strongly increased compared to neonates in the general populations, the researchers stated.
A previous large study of term infants reported 361 intracranial bleeding episodes per 583,340 live births (0.062% per 100 live births), and comparing this to the current pooled estimate of 2.1% per 100 live births, neonates with hemophilia showed a 33-fold higher risk of ICH than newborns in the general population, according to the researchers.
Monitoring and follow-up
“Our findings suggest that adequate follow-up and monitoring of patients is warranted among all ages, especially in the presence of risk factors. Prophylaxis seems to halve ICH risk in children and adults with severe hemophilia, which supports existing recommendations encouraging early initiation of prophylactic treatment,” the authors advised.
Accurate capture of the true frequency of ICH is challenged by considerable clinical heterogeneity, limiting the precision and generalizability of the pooled estimates, leading to the likelihood that ICH and mortality were underdiagnosed in this analysis, according to the authors.
“We found high ICH incidence and mortality rates in patients with hemophilia. Our findings suggest that ICH is still an important problem in hemophilia requiring adequate counseling of patients of all ages,” the researchers concluded.
This work was supported by a grant from Sobi. Some of the authors reported research, consulting or lecturing fees from a variety of pharmaceutical companies, including Sobi.
FROM BLOOD
New gene variant found for hereditary bleeding disorder
Clinical symptoms in a 19-year-old Vietnamese woman who experienced several life-threatening bleeding events, including ovarian hemorrhage, led to the discovery of a novel gene variant causing her bleeding disorder.
Blood analysis of the patients showed decreased fibrinogen level with “markedly elevated fibrinogen/fibrin degradation products and D-dimer levels.” Attempts to treat the patient with hemostatic surgery, administration of several medications, including nafamostat mesylate, tranexamic acid, and unfractionated heparin, produced no correction of her coagulation abnormalities, and the patient experienced repeated hemorrhagic events, according to researchers from the Tokyo Saiseikai Central Hospital, Japan, and colleagues.
However, the researchers found that treatment with recombinant human thrombomodulin (rhTM) remarkably improved the patient’s pathophysiology, according to the results of a case study reported in Blood Advances.
Genetic analysis
Upon screening and sequencing of the patient’s thrombomodulin gene, a previously unreported homozygous variation, c.793T>A (p.Cys265Ser) was discovered. Under normal circumstances, the Cys265 residue forms one of three disulfide bonds in the epidermal growth factor (EGF)-like domain 1 of thrombomoduliin (TM), according to the researchers.
However, transient expression analysis of the patient’s mutation using COS-1 cells demonstrated markedly reduced expression of TM-Cys265Ser on the plasma membrane relative to wild-type TM. The TM-Cys265Ser mutant was intracellularly degraded, probably due to EGF-like domain 1 misfolding, according to the researchers and the reduced expression of TM on the endothelial cell membrane may be responsible for the disseminated intravascular coagulation-like symptoms observed in the patient, the speculated.
“The clinical symptoms of the patient in this study were characterized by recurrent hemorrhage, indicating that TM-C265S mainly causes hyperfibrinolysis rather than hypercoagulation. The C265S mutation may disrupt the timely and delicate balance between coagulation and fibrinolysis,” the researchers suggested.
The authors reported that they had no conflicts of interest.
Clinical symptoms in a 19-year-old Vietnamese woman who experienced several life-threatening bleeding events, including ovarian hemorrhage, led to the discovery of a novel gene variant causing her bleeding disorder.
Blood analysis of the patients showed decreased fibrinogen level with “markedly elevated fibrinogen/fibrin degradation products and D-dimer levels.” Attempts to treat the patient with hemostatic surgery, administration of several medications, including nafamostat mesylate, tranexamic acid, and unfractionated heparin, produced no correction of her coagulation abnormalities, and the patient experienced repeated hemorrhagic events, according to researchers from the Tokyo Saiseikai Central Hospital, Japan, and colleagues.
However, the researchers found that treatment with recombinant human thrombomodulin (rhTM) remarkably improved the patient’s pathophysiology, according to the results of a case study reported in Blood Advances.
Genetic analysis
Upon screening and sequencing of the patient’s thrombomodulin gene, a previously unreported homozygous variation, c.793T>A (p.Cys265Ser) was discovered. Under normal circumstances, the Cys265 residue forms one of three disulfide bonds in the epidermal growth factor (EGF)-like domain 1 of thrombomoduliin (TM), according to the researchers.
However, transient expression analysis of the patient’s mutation using COS-1 cells demonstrated markedly reduced expression of TM-Cys265Ser on the plasma membrane relative to wild-type TM. The TM-Cys265Ser mutant was intracellularly degraded, probably due to EGF-like domain 1 misfolding, according to the researchers and the reduced expression of TM on the endothelial cell membrane may be responsible for the disseminated intravascular coagulation-like symptoms observed in the patient, the speculated.
“The clinical symptoms of the patient in this study were characterized by recurrent hemorrhage, indicating that TM-C265S mainly causes hyperfibrinolysis rather than hypercoagulation. The C265S mutation may disrupt the timely and delicate balance between coagulation and fibrinolysis,” the researchers suggested.
The authors reported that they had no conflicts of interest.
Clinical symptoms in a 19-year-old Vietnamese woman who experienced several life-threatening bleeding events, including ovarian hemorrhage, led to the discovery of a novel gene variant causing her bleeding disorder.
Blood analysis of the patients showed decreased fibrinogen level with “markedly elevated fibrinogen/fibrin degradation products and D-dimer levels.” Attempts to treat the patient with hemostatic surgery, administration of several medications, including nafamostat mesylate, tranexamic acid, and unfractionated heparin, produced no correction of her coagulation abnormalities, and the patient experienced repeated hemorrhagic events, according to researchers from the Tokyo Saiseikai Central Hospital, Japan, and colleagues.
However, the researchers found that treatment with recombinant human thrombomodulin (rhTM) remarkably improved the patient’s pathophysiology, according to the results of a case study reported in Blood Advances.
Genetic analysis
Upon screening and sequencing of the patient’s thrombomodulin gene, a previously unreported homozygous variation, c.793T>A (p.Cys265Ser) was discovered. Under normal circumstances, the Cys265 residue forms one of three disulfide bonds in the epidermal growth factor (EGF)-like domain 1 of thrombomoduliin (TM), according to the researchers.
However, transient expression analysis of the patient’s mutation using COS-1 cells demonstrated markedly reduced expression of TM-Cys265Ser on the plasma membrane relative to wild-type TM. The TM-Cys265Ser mutant was intracellularly degraded, probably due to EGF-like domain 1 misfolding, according to the researchers and the reduced expression of TM on the endothelial cell membrane may be responsible for the disseminated intravascular coagulation-like symptoms observed in the patient, the speculated.
“The clinical symptoms of the patient in this study were characterized by recurrent hemorrhage, indicating that TM-C265S mainly causes hyperfibrinolysis rather than hypercoagulation. The C265S mutation may disrupt the timely and delicate balance between coagulation and fibrinolysis,” the researchers suggested.
The authors reported that they had no conflicts of interest.
FROM BLOOD ADVANCES
Infusion shown effective for acquired von Willebrand disease
Acquired von Willebrand disease (aVWD) is a rare and serious condition associated with lymphoproliferative disorders, malignancy, autoimmune disorders, and cardiovascular disease. It is most commonly caused by monoclonal gammopathy of undetermined significance (MGUS), which acts to clear von Willebrand factor from the patient’s bloodstream. However, a continuous-infusion of plasma-derived von Willebrand factor (VWF) concentrate provided adequate hemostasis in aVWD resulting from MGUS, according to Kathryn E. Dane, PharmD, of Johns Hopkins University, Baltimore, and colleagues.
The infusion rapidly achieved target ristocetin cofactor activity with or without intravenous immunoglobulin in three patients, as detailed in the report published online in Blood Advances.
The three consecutive patients with aVWD were treated with plasma-derived VWF concentrate administered for periprocedural optimization (patient 1, an 85-year old woman) or to treat bleeding episodes (patient 2, an 88-year-old man; and patient 3, a 53-year-old woman). Factor VIII activity was measured via a 1-stage clotting test and von Willebrand factor activity was measured with a ristocetin cofactor assay.
Promising results
All three patients demonstrated increased VWF ristocetin cofactor and factor VIII activities within hours of initiation of the continuous infusion concentrate, according to the report.
“We hypothesize that the efficacy of CI VWF concentrate in aVWD may be related to continuous provision of VWF, allowing binding and neutralization of anti-VWF IgG antibodies, and providing adequate circulating unbound VWF for appropriate hemostatic efficacy,” the researchers concluded.
The authors reported that they had no competing financial interests.
Acquired von Willebrand disease (aVWD) is a rare and serious condition associated with lymphoproliferative disorders, malignancy, autoimmune disorders, and cardiovascular disease. It is most commonly caused by monoclonal gammopathy of undetermined significance (MGUS), which acts to clear von Willebrand factor from the patient’s bloodstream. However, a continuous-infusion of plasma-derived von Willebrand factor (VWF) concentrate provided adequate hemostasis in aVWD resulting from MGUS, according to Kathryn E. Dane, PharmD, of Johns Hopkins University, Baltimore, and colleagues.
The infusion rapidly achieved target ristocetin cofactor activity with or without intravenous immunoglobulin in three patients, as detailed in the report published online in Blood Advances.
The three consecutive patients with aVWD were treated with plasma-derived VWF concentrate administered for periprocedural optimization (patient 1, an 85-year old woman) or to treat bleeding episodes (patient 2, an 88-year-old man; and patient 3, a 53-year-old woman). Factor VIII activity was measured via a 1-stage clotting test and von Willebrand factor activity was measured with a ristocetin cofactor assay.
Promising results
All three patients demonstrated increased VWF ristocetin cofactor and factor VIII activities within hours of initiation of the continuous infusion concentrate, according to the report.
“We hypothesize that the efficacy of CI VWF concentrate in aVWD may be related to continuous provision of VWF, allowing binding and neutralization of anti-VWF IgG antibodies, and providing adequate circulating unbound VWF for appropriate hemostatic efficacy,” the researchers concluded.
The authors reported that they had no competing financial interests.
Acquired von Willebrand disease (aVWD) is a rare and serious condition associated with lymphoproliferative disorders, malignancy, autoimmune disorders, and cardiovascular disease. It is most commonly caused by monoclonal gammopathy of undetermined significance (MGUS), which acts to clear von Willebrand factor from the patient’s bloodstream. However, a continuous-infusion of plasma-derived von Willebrand factor (VWF) concentrate provided adequate hemostasis in aVWD resulting from MGUS, according to Kathryn E. Dane, PharmD, of Johns Hopkins University, Baltimore, and colleagues.
The infusion rapidly achieved target ristocetin cofactor activity with or without intravenous immunoglobulin in three patients, as detailed in the report published online in Blood Advances.
The three consecutive patients with aVWD were treated with plasma-derived VWF concentrate administered for periprocedural optimization (patient 1, an 85-year old woman) or to treat bleeding episodes (patient 2, an 88-year-old man; and patient 3, a 53-year-old woman). Factor VIII activity was measured via a 1-stage clotting test and von Willebrand factor activity was measured with a ristocetin cofactor assay.
Promising results
All three patients demonstrated increased VWF ristocetin cofactor and factor VIII activities within hours of initiation of the continuous infusion concentrate, according to the report.
“We hypothesize that the efficacy of CI VWF concentrate in aVWD may be related to continuous provision of VWF, allowing binding and neutralization of anti-VWF IgG antibodies, and providing adequate circulating unbound VWF for appropriate hemostatic efficacy,” the researchers concluded.
The authors reported that they had no competing financial interests.
FROM BLOOD ADVANCES
Recombinant factor IX fusion protein benefited untreated patients with hemophilia B
Recombinant factor IX Fc fusion protein was effective, both as prophylaxis and in the treatment of bleeding episodes in previously untreated boys (< 18 years of age) with hemophilia B, according to Beatrice Nolan, MD, of Children’s Health Ireland at Crumlin, Dublin, and colleagues.
PUPs B-LONG is an open-label, single-arm, multicenter, phase 3 trial (Clinicaltrials.gov: NCT02234310) of rFIXFc in 33 previously untreated patients (PUPs) with hemophilia B; 79% of the patients were younger than 1 year of age at study entry. The primary endpoint was occurrence of inhibitor development, with a secondary endpoint of annualized bleed rate, according to the results of the study, published online in Blood Advances.
At the onset of the study, 22 patients (67%) received on-demand treatment and 11 (33%) started with a prophylactic regimen. Seventeen (77%) of 22 patients who initially received on-demand treatment subsequently switched to prophylaxis, for a total of 28 patients receiving prophylaxis during the study, according to the researchers. Twenty-seven patients (82%) completed the study, and six (18%) discontinued early.
Promising results
The median patient annualized bleeding rate was 1.24 for patients receiving prophylaxis. Most (85%) bleeding episodes required only one infusion for bleed resolution, according to the researchers.
One patient developed a low-titer inhibitor after 11 exposure days to rFIXFc; no high-titer inhibitors were detected. However, 23 patients (70%) had 58 treatment-emergent serious adverse events, of which 2 were assessed as related to treatment (FIX inhibition and hypersensitivity in 1 patient, resulting in withdrawal).
“rFIXFc was generally well tolerated. The incidence of inhibitor development was consistent with other FIX products, with 1 low-titer inhibitor and no high-titer inhibitors detected. In addition, rFIXFc was effective, both as prophylaxis and in the treatment of bleeding episodes,” the researchers concluded.
The PUPs B-LONG study was sponsored by Sanofi and Sobi. Dr. Nolan reported personal fees from Sobi and sponsorship from Sanofi and several other pharmaceutical companies. The other authors reported financial support from a variety of pharmaceutical companies.
Recombinant factor IX Fc fusion protein was effective, both as prophylaxis and in the treatment of bleeding episodes in previously untreated boys (< 18 years of age) with hemophilia B, according to Beatrice Nolan, MD, of Children’s Health Ireland at Crumlin, Dublin, and colleagues.
PUPs B-LONG is an open-label, single-arm, multicenter, phase 3 trial (Clinicaltrials.gov: NCT02234310) of rFIXFc in 33 previously untreated patients (PUPs) with hemophilia B; 79% of the patients were younger than 1 year of age at study entry. The primary endpoint was occurrence of inhibitor development, with a secondary endpoint of annualized bleed rate, according to the results of the study, published online in Blood Advances.
At the onset of the study, 22 patients (67%) received on-demand treatment and 11 (33%) started with a prophylactic regimen. Seventeen (77%) of 22 patients who initially received on-demand treatment subsequently switched to prophylaxis, for a total of 28 patients receiving prophylaxis during the study, according to the researchers. Twenty-seven patients (82%) completed the study, and six (18%) discontinued early.
Promising results
The median patient annualized bleeding rate was 1.24 for patients receiving prophylaxis. Most (85%) bleeding episodes required only one infusion for bleed resolution, according to the researchers.
One patient developed a low-titer inhibitor after 11 exposure days to rFIXFc; no high-titer inhibitors were detected. However, 23 patients (70%) had 58 treatment-emergent serious adverse events, of which 2 were assessed as related to treatment (FIX inhibition and hypersensitivity in 1 patient, resulting in withdrawal).
“rFIXFc was generally well tolerated. The incidence of inhibitor development was consistent with other FIX products, with 1 low-titer inhibitor and no high-titer inhibitors detected. In addition, rFIXFc was effective, both as prophylaxis and in the treatment of bleeding episodes,” the researchers concluded.
The PUPs B-LONG study was sponsored by Sanofi and Sobi. Dr. Nolan reported personal fees from Sobi and sponsorship from Sanofi and several other pharmaceutical companies. The other authors reported financial support from a variety of pharmaceutical companies.
Recombinant factor IX Fc fusion protein was effective, both as prophylaxis and in the treatment of bleeding episodes in previously untreated boys (< 18 years of age) with hemophilia B, according to Beatrice Nolan, MD, of Children’s Health Ireland at Crumlin, Dublin, and colleagues.
PUPs B-LONG is an open-label, single-arm, multicenter, phase 3 trial (Clinicaltrials.gov: NCT02234310) of rFIXFc in 33 previously untreated patients (PUPs) with hemophilia B; 79% of the patients were younger than 1 year of age at study entry. The primary endpoint was occurrence of inhibitor development, with a secondary endpoint of annualized bleed rate, according to the results of the study, published online in Blood Advances.
At the onset of the study, 22 patients (67%) received on-demand treatment and 11 (33%) started with a prophylactic regimen. Seventeen (77%) of 22 patients who initially received on-demand treatment subsequently switched to prophylaxis, for a total of 28 patients receiving prophylaxis during the study, according to the researchers. Twenty-seven patients (82%) completed the study, and six (18%) discontinued early.
Promising results
The median patient annualized bleeding rate was 1.24 for patients receiving prophylaxis. Most (85%) bleeding episodes required only one infusion for bleed resolution, according to the researchers.
One patient developed a low-titer inhibitor after 11 exposure days to rFIXFc; no high-titer inhibitors were detected. However, 23 patients (70%) had 58 treatment-emergent serious adverse events, of which 2 were assessed as related to treatment (FIX inhibition and hypersensitivity in 1 patient, resulting in withdrawal).
“rFIXFc was generally well tolerated. The incidence of inhibitor development was consistent with other FIX products, with 1 low-titer inhibitor and no high-titer inhibitors detected. In addition, rFIXFc was effective, both as prophylaxis and in the treatment of bleeding episodes,” the researchers concluded.
The PUPs B-LONG study was sponsored by Sanofi and Sobi. Dr. Nolan reported personal fees from Sobi and sponsorship from Sanofi and several other pharmaceutical companies. The other authors reported financial support from a variety of pharmaceutical companies.
FROM BLOOD ADVANCES
Bleeding events tied to higher mortality in patients with factor V inhibition
Coagulation factor V (FV) inhibitor is a rare disease with a mortality rate of nearly 15%. Increased mortality was significantly associated with the incidence of major bleeding, according to a review of PubMed case reports published in Thrombosis Update.
FV autoantibodies are most often detected in patients in the postoperative state, in those who have received a blood transfusion, in patients treated with antibiotics, and in those with immune diseases, according to the online report by Hideo Wada, MD, PhD, of the Mie Prefectural General Medical Center, Yokkaichi, Japan, and colleagues. These patients who acquired immune FV inhibitor (AIFVD) vary widely in symptoms from asymptomatic to mild or severe hemorrhagic manifestations, with some reports of thrombotic complications, the authors added.
Their review assessed the PubMed literature from Jan. 1, 1968, to July 31, 2020, and found 212 case reports on acquired FV deficiency. Of these, 150 cases with confirmed FV inhibitor positivity were included. The 150 reported cases of FV inhibitor were primarily from the United States (n = 48) and Japan (n = 43). The median patient age was 68.0 years, and the female to male ratio of patients was 0.47, according to the authors. The largest associated percentage of underlying conditions were postoperative state (25.3%), idiopathic (18.7%), infection (12.7%) and malignant neoplasms and autoimmune disease, at 7.3% each.
Major bleeds
A total of 73 cases were positive for major bleeding (48.7%) and 30 cases were negative (20.0%), while the rest were undetermined (31.3%). The FV activity was ≤ 28% in all patients with FV inhibitor.
The overall mortality rate was 14.6%, with half of the nonsurvivors dying of major bleeding. The mortality rate was more than twofold higher in the group with major bleeding (23.3% mortality) compared to the group without major bleeding (10.0%), yielding an odds ratio of 2.73 of death because of a major bleed. The most frequent types of fatal bleeding were intracranial bleeding and gastrointestinal bleeding. Of the 20 deaths reported in 135 patients with data, the causes of death were major bleeding (12 patients), infection (6 patients) and thrombosis (2 patients). Remission was observed in three of the nonsurvivors, indicating that even after remission, patients with FV inhibitor might still be susceptible to infection or thrombosis, according to the authors.
“[Major bleeding] should be treated aggressively; however, the best treatment is not clear and even patients in remission should be followed closely due to the risk of death from infection or thrombosis,” the authors concluded.
They reported having no conflicts of interest.
Coagulation factor V (FV) inhibitor is a rare disease with a mortality rate of nearly 15%. Increased mortality was significantly associated with the incidence of major bleeding, according to a review of PubMed case reports published in Thrombosis Update.
FV autoantibodies are most often detected in patients in the postoperative state, in those who have received a blood transfusion, in patients treated with antibiotics, and in those with immune diseases, according to the online report by Hideo Wada, MD, PhD, of the Mie Prefectural General Medical Center, Yokkaichi, Japan, and colleagues. These patients who acquired immune FV inhibitor (AIFVD) vary widely in symptoms from asymptomatic to mild or severe hemorrhagic manifestations, with some reports of thrombotic complications, the authors added.
Their review assessed the PubMed literature from Jan. 1, 1968, to July 31, 2020, and found 212 case reports on acquired FV deficiency. Of these, 150 cases with confirmed FV inhibitor positivity were included. The 150 reported cases of FV inhibitor were primarily from the United States (n = 48) and Japan (n = 43). The median patient age was 68.0 years, and the female to male ratio of patients was 0.47, according to the authors. The largest associated percentage of underlying conditions were postoperative state (25.3%), idiopathic (18.7%), infection (12.7%) and malignant neoplasms and autoimmune disease, at 7.3% each.
Major bleeds
A total of 73 cases were positive for major bleeding (48.7%) and 30 cases were negative (20.0%), while the rest were undetermined (31.3%). The FV activity was ≤ 28% in all patients with FV inhibitor.
The overall mortality rate was 14.6%, with half of the nonsurvivors dying of major bleeding. The mortality rate was more than twofold higher in the group with major bleeding (23.3% mortality) compared to the group without major bleeding (10.0%), yielding an odds ratio of 2.73 of death because of a major bleed. The most frequent types of fatal bleeding were intracranial bleeding and gastrointestinal bleeding. Of the 20 deaths reported in 135 patients with data, the causes of death were major bleeding (12 patients), infection (6 patients) and thrombosis (2 patients). Remission was observed in three of the nonsurvivors, indicating that even after remission, patients with FV inhibitor might still be susceptible to infection or thrombosis, according to the authors.
“[Major bleeding] should be treated aggressively; however, the best treatment is not clear and even patients in remission should be followed closely due to the risk of death from infection or thrombosis,” the authors concluded.
They reported having no conflicts of interest.
Coagulation factor V (FV) inhibitor is a rare disease with a mortality rate of nearly 15%. Increased mortality was significantly associated with the incidence of major bleeding, according to a review of PubMed case reports published in Thrombosis Update.
FV autoantibodies are most often detected in patients in the postoperative state, in those who have received a blood transfusion, in patients treated with antibiotics, and in those with immune diseases, according to the online report by Hideo Wada, MD, PhD, of the Mie Prefectural General Medical Center, Yokkaichi, Japan, and colleagues. These patients who acquired immune FV inhibitor (AIFVD) vary widely in symptoms from asymptomatic to mild or severe hemorrhagic manifestations, with some reports of thrombotic complications, the authors added.
Their review assessed the PubMed literature from Jan. 1, 1968, to July 31, 2020, and found 212 case reports on acquired FV deficiency. Of these, 150 cases with confirmed FV inhibitor positivity were included. The 150 reported cases of FV inhibitor were primarily from the United States (n = 48) and Japan (n = 43). The median patient age was 68.0 years, and the female to male ratio of patients was 0.47, according to the authors. The largest associated percentage of underlying conditions were postoperative state (25.3%), idiopathic (18.7%), infection (12.7%) and malignant neoplasms and autoimmune disease, at 7.3% each.
Major bleeds
A total of 73 cases were positive for major bleeding (48.7%) and 30 cases were negative (20.0%), while the rest were undetermined (31.3%). The FV activity was ≤ 28% in all patients with FV inhibitor.
The overall mortality rate was 14.6%, with half of the nonsurvivors dying of major bleeding. The mortality rate was more than twofold higher in the group with major bleeding (23.3% mortality) compared to the group without major bleeding (10.0%), yielding an odds ratio of 2.73 of death because of a major bleed. The most frequent types of fatal bleeding were intracranial bleeding and gastrointestinal bleeding. Of the 20 deaths reported in 135 patients with data, the causes of death were major bleeding (12 patients), infection (6 patients) and thrombosis (2 patients). Remission was observed in three of the nonsurvivors, indicating that even after remission, patients with FV inhibitor might still be susceptible to infection or thrombosis, according to the authors.
“[Major bleeding] should be treated aggressively; however, the best treatment is not clear and even patients in remission should be followed closely due to the risk of death from infection or thrombosis,” the authors concluded.
They reported having no conflicts of interest.
FROM THROMBOSIS UPDATE