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Oakland score identifies patients with lower GI bleed at low risk for adverse events
Background: The Oakland score was initially designed to be used in patients presenting with LGIB in the urgent, emergent, or primary care setting to help predict risk of readmission and determine if outpatient management is feasible. National guidelines in the United Kingdom have recommended use of the Oakland score despite limited external validation for the triage of patients with acute LGIB. This study aimed to externally validate the Oakland score in a large population in the United States and compare the performance at two thresholds.
Study design: Retrospective observational study.
Setting: 140 hospitals across the United States.
Synopsis: In this prognostic study, 38,067 patients were identified retrospectively using ICD-10 codes that were consistent with a diagnosis of LGIB and were admitted to the hospital. The Oakland score consisted of seven variables, including age, sex, prior hospitalization with LGIB, digital rectal exam results, heart rate, systolic blood pressure, and hemoglobin concentration. The primary outcome was safe discharge from the hospital, defined as absence of in-hospital rebleeding, RBC transfusion, therapeutic colonoscopy, mesenteric embolization or laparotomy for bleeding, in-hospital death, or readmission with subsequent LGIB in 28 days. In total, 47.9% of the identified patients experienced no adverse outcomes and were classified as meeting criteria for safe discharge. In addition, 8.7% of patients scored 8 points or fewer with a sensitivity of 98.4% and specificity of 16.0% for safe discharge. A sensitivity of 96% was maintained after increasing the threshold to 10 points or fewer with a specificity of 31.9%, suggesting the threshold can be increased while still maintaining adequate sensitivity. The study suggests that, by using the Oakland score threshold of 8, hospital admission may be avoided in low-risk patients leading to a savings of at least $44.5 million and even more if the threshold is increased to 10. Low specificity does present limitation of the score as some patients considered to be at risk for adverse events may have been safely discharged and managed as an outpatient, avoiding hospitalization.
Bottom line: The Oakland score was externally validated for use in assessing risk of adverse outcomes in patients with LGIB and had a high sensitivity but low specificity for identifying low-risk patients.
Citation: Oakland K et al. External validation of the Oakland score to assess safe hospital discharge among adult patients with acute lower gastrointestinal bleeding in the US. JAMA Netw Open. 2020 Jul 1;3:e209630. doi:
Dr. Steker is a hospitalist at Northwestern Memorial Hospital and instructor of medicine, Feinberg School of Medicine, both in Chicago.
Background: The Oakland score was initially designed to be used in patients presenting with LGIB in the urgent, emergent, or primary care setting to help predict risk of readmission and determine if outpatient management is feasible. National guidelines in the United Kingdom have recommended use of the Oakland score despite limited external validation for the triage of patients with acute LGIB. This study aimed to externally validate the Oakland score in a large population in the United States and compare the performance at two thresholds.
Study design: Retrospective observational study.
Setting: 140 hospitals across the United States.
Synopsis: In this prognostic study, 38,067 patients were identified retrospectively using ICD-10 codes that were consistent with a diagnosis of LGIB and were admitted to the hospital. The Oakland score consisted of seven variables, including age, sex, prior hospitalization with LGIB, digital rectal exam results, heart rate, systolic blood pressure, and hemoglobin concentration. The primary outcome was safe discharge from the hospital, defined as absence of in-hospital rebleeding, RBC transfusion, therapeutic colonoscopy, mesenteric embolization or laparotomy for bleeding, in-hospital death, or readmission with subsequent LGIB in 28 days. In total, 47.9% of the identified patients experienced no adverse outcomes and were classified as meeting criteria for safe discharge. In addition, 8.7% of patients scored 8 points or fewer with a sensitivity of 98.4% and specificity of 16.0% for safe discharge. A sensitivity of 96% was maintained after increasing the threshold to 10 points or fewer with a specificity of 31.9%, suggesting the threshold can be increased while still maintaining adequate sensitivity. The study suggests that, by using the Oakland score threshold of 8, hospital admission may be avoided in low-risk patients leading to a savings of at least $44.5 million and even more if the threshold is increased to 10. Low specificity does present limitation of the score as some patients considered to be at risk for adverse events may have been safely discharged and managed as an outpatient, avoiding hospitalization.
Bottom line: The Oakland score was externally validated for use in assessing risk of adverse outcomes in patients with LGIB and had a high sensitivity but low specificity for identifying low-risk patients.
Citation: Oakland K et al. External validation of the Oakland score to assess safe hospital discharge among adult patients with acute lower gastrointestinal bleeding in the US. JAMA Netw Open. 2020 Jul 1;3:e209630. doi:
Dr. Steker is a hospitalist at Northwestern Memorial Hospital and instructor of medicine, Feinberg School of Medicine, both in Chicago.
Background: The Oakland score was initially designed to be used in patients presenting with LGIB in the urgent, emergent, or primary care setting to help predict risk of readmission and determine if outpatient management is feasible. National guidelines in the United Kingdom have recommended use of the Oakland score despite limited external validation for the triage of patients with acute LGIB. This study aimed to externally validate the Oakland score in a large population in the United States and compare the performance at two thresholds.
Study design: Retrospective observational study.
Setting: 140 hospitals across the United States.
Synopsis: In this prognostic study, 38,067 patients were identified retrospectively using ICD-10 codes that were consistent with a diagnosis of LGIB and were admitted to the hospital. The Oakland score consisted of seven variables, including age, sex, prior hospitalization with LGIB, digital rectal exam results, heart rate, systolic blood pressure, and hemoglobin concentration. The primary outcome was safe discharge from the hospital, defined as absence of in-hospital rebleeding, RBC transfusion, therapeutic colonoscopy, mesenteric embolization or laparotomy for bleeding, in-hospital death, or readmission with subsequent LGIB in 28 days. In total, 47.9% of the identified patients experienced no adverse outcomes and were classified as meeting criteria for safe discharge. In addition, 8.7% of patients scored 8 points or fewer with a sensitivity of 98.4% and specificity of 16.0% for safe discharge. A sensitivity of 96% was maintained after increasing the threshold to 10 points or fewer with a specificity of 31.9%, suggesting the threshold can be increased while still maintaining adequate sensitivity. The study suggests that, by using the Oakland score threshold of 8, hospital admission may be avoided in low-risk patients leading to a savings of at least $44.5 million and even more if the threshold is increased to 10. Low specificity does present limitation of the score as some patients considered to be at risk for adverse events may have been safely discharged and managed as an outpatient, avoiding hospitalization.
Bottom line: The Oakland score was externally validated for use in assessing risk of adverse outcomes in patients with LGIB and had a high sensitivity but low specificity for identifying low-risk patients.
Citation: Oakland K et al. External validation of the Oakland score to assess safe hospital discharge among adult patients with acute lower gastrointestinal bleeding in the US. JAMA Netw Open. 2020 Jul 1;3:e209630. doi:
Dr. Steker is a hospitalist at Northwestern Memorial Hospital and instructor of medicine, Feinberg School of Medicine, both in Chicago.
Timing of endoscopy for acute upper GI bleeding
Background: Prior studies have failed to show a benefit to earlier endoscopic intervention in acute GI bleeding. However, those studies were performed in all-comers without attention to the varying risk within the patient population.
Study design: Randomized controlled trial.
Setting: Single center in Hong Kong.
Synopsis: Patients at high risk for further bleeding or death by clinical score were randomized to endoscopy within 6 hours (“urgent endoscopy”), vs. the following day (“early endoscopy”), of GI consultation. Those who required immediate endoscopic intervention because of hemodynamic instability were excluded. All were prescribed proton-pump inhibitor drip, with the addition of vasoactive drugs and antibiotics if there was a suspected variceal bleed. There was no difference in 30-day mortality between the two groups – 8.9% with urgent endoscopy and 6.6% with early endoscopy (HR, 1.35; 95% CI, 0.72-2.54). There was no difference in length of hospital stay or the number of transfusions. Earlier endoscopy within 6 hours was associated with a higher number of actively bleeding lesions requiring intervention and a nonstatistical increase in recurrent bleeding within 30 days. It is believed that more time on proton-pump inhibitor infusion prior to endoscopy allows for stabilization of bleeds, thus requiring less intervention when endoscopy does occur.
Bottom line: Early endoscopy within 6 hours was not beneficial for those at high risk for rebleeding and death from upper GI bleed.
Citation: Lau JYW et al. Timing of endoscopy for acute upper gastrointestinal bleeding. N Engl J Med. 2020;382:1299-308. doi:10.1056/NEJMoa1912484.
Dr. Lee is a hospitalist at Northwestern Memorial Hospital and Lurie Children’s Hospital and assistant professor of medicine, Feinberg School of Medicine, all in Chicago.
Background: Prior studies have failed to show a benefit to earlier endoscopic intervention in acute GI bleeding. However, those studies were performed in all-comers without attention to the varying risk within the patient population.
Study design: Randomized controlled trial.
Setting: Single center in Hong Kong.
Synopsis: Patients at high risk for further bleeding or death by clinical score were randomized to endoscopy within 6 hours (“urgent endoscopy”), vs. the following day (“early endoscopy”), of GI consultation. Those who required immediate endoscopic intervention because of hemodynamic instability were excluded. All were prescribed proton-pump inhibitor drip, with the addition of vasoactive drugs and antibiotics if there was a suspected variceal bleed. There was no difference in 30-day mortality between the two groups – 8.9% with urgent endoscopy and 6.6% with early endoscopy (HR, 1.35; 95% CI, 0.72-2.54). There was no difference in length of hospital stay or the number of transfusions. Earlier endoscopy within 6 hours was associated with a higher number of actively bleeding lesions requiring intervention and a nonstatistical increase in recurrent bleeding within 30 days. It is believed that more time on proton-pump inhibitor infusion prior to endoscopy allows for stabilization of bleeds, thus requiring less intervention when endoscopy does occur.
Bottom line: Early endoscopy within 6 hours was not beneficial for those at high risk for rebleeding and death from upper GI bleed.
Citation: Lau JYW et al. Timing of endoscopy for acute upper gastrointestinal bleeding. N Engl J Med. 2020;382:1299-308. doi:10.1056/NEJMoa1912484.
Dr. Lee is a hospitalist at Northwestern Memorial Hospital and Lurie Children’s Hospital and assistant professor of medicine, Feinberg School of Medicine, all in Chicago.
Background: Prior studies have failed to show a benefit to earlier endoscopic intervention in acute GI bleeding. However, those studies were performed in all-comers without attention to the varying risk within the patient population.
Study design: Randomized controlled trial.
Setting: Single center in Hong Kong.
Synopsis: Patients at high risk for further bleeding or death by clinical score were randomized to endoscopy within 6 hours (“urgent endoscopy”), vs. the following day (“early endoscopy”), of GI consultation. Those who required immediate endoscopic intervention because of hemodynamic instability were excluded. All were prescribed proton-pump inhibitor drip, with the addition of vasoactive drugs and antibiotics if there was a suspected variceal bleed. There was no difference in 30-day mortality between the two groups – 8.9% with urgent endoscopy and 6.6% with early endoscopy (HR, 1.35; 95% CI, 0.72-2.54). There was no difference in length of hospital stay or the number of transfusions. Earlier endoscopy within 6 hours was associated with a higher number of actively bleeding lesions requiring intervention and a nonstatistical increase in recurrent bleeding within 30 days. It is believed that more time on proton-pump inhibitor infusion prior to endoscopy allows for stabilization of bleeds, thus requiring less intervention when endoscopy does occur.
Bottom line: Early endoscopy within 6 hours was not beneficial for those at high risk for rebleeding and death from upper GI bleed.
Citation: Lau JYW et al. Timing of endoscopy for acute upper gastrointestinal bleeding. N Engl J Med. 2020;382:1299-308. doi:10.1056/NEJMoa1912484.
Dr. Lee is a hospitalist at Northwestern Memorial Hospital and Lurie Children’s Hospital and assistant professor of medicine, Feinberg School of Medicine, all in Chicago.
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.
Ticagrelor reversal agent achieves quick hemostasis: REVERSE-IT
The experimental monoclonal antibody bentracimab, which reverses the antiplatelet effects of ticagrelor, appears to be heading toward regulatory approval, on the basis of an interim analysis of the phase 3 REVERSE-IT trial.
“Rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases with no drug-related serious adverse events or allergic or infusion-related reactions,” reported Deepak L. Bhatt, MD, at the American Heart Association scientific sessions.
The interim analysis of this nonrandomized, single-arm study was requested by the Food and Drug Administration, which is considering a conditional accelerated approval of bentracimab (formerly PB2452) if efficacy and safety are established.
Upon administration, bentracimab binds to free ticagrelor so that ticagrelor cannot bind to the P2Y12 platelet receptor. This interrupts one of the key steps in the pathway of platelet aggregation.
REVERSE-IT is still enrolling patients. This interim analysis was conducted with the first 150 patients who met eligibility criteria and were treated. Of these, 142 patients were enrolled for an urgent surgical indication and 8 for a major bleeding indication. After some exclusions for lack of urgency and reclassifications following adjudication, there were 113 surgical cases and 9 major bleeding patients evaluable for hemostasis.
Platelet function assays test reversal
On the primary reversal endpoint, which was restoration of activity on the proprietary platelet function assays Verify Now and PRUTest, a rapid restoration of platelet function was achieved in both surgical and major-bleeding patients. Platelet reactivity climbed to near normal levels within 10 minutes of administration, and peak effects were sustained through the first 24 hours after administration.
On the basis of the platelet function assays, the pattern of response to bentracimab was “very similar in the surgical and bleeding patients,” reported Dr. Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Health, Boston.
The effect was also consistent across a broad array of prespecified subgroups, including stratifications by age, renal function, time from last dose of ticagrelor, race, and the presence of comorbidities, such as diabetes, renal dysfunction, hypertension, and history of MI.
Hemostasis documented in all but one patient
Adjudicated hemostasis was achieved in 100% of the 113 urgent surgical patients evaluated. In the nine major bleeding patients, six achieved excellent hemostasis and one achieved good hemostasis. One had poor hemostasis, and one was unevaluable.
Platelet rebound following bentracimab administration, measured by mean platelet volume, was not observed.
There were no serious adverse events, allergic reactions, or serious infusion-related reactions associated with the administration of bentracimab, Dr. Bhatt said.
While Dr. Bhatt acknowledged that the number of patients in the major-bleeding subgroup was small, he noted that the reduction in platelet reactivity relative to baseline was still significant. In addition, he characterized urgent surgery as “an excellent model of bleeding” and pointed out the consistency of results in the surgical and major-bleeding groups.
The interim results are also consistent with phase 1 data published 2 years ago, and with the subsequent phase 2 studies. All of these data are now under regulatory review both in the United States and in Europe, according to Dr. Bhatt.
No good current options for reversal
Evidence of efficacy and safety is encouraging, because current options for urgently reversing ticagrelor are “disappointing,” according to the invited discussant Gilles Montalescot, MD, PhD, professor of cardiology, Pitié-Salpêtrière Hôpital, Paris.
“Platelet transfusion has some value for clopidogrel and prasugrel, but it does not work for ticagrelor,” said Dr. Montalescot, referring to two other P2Y12 inhibitors. Substantiating the need for a reversal agent, he identified several other strategies that have proven ineffective, such as desmopressin and sorbent hemadsorption.
Overall, Dr. Montalescot acknowledged the need for a highly effective ticagrelor reversal agent, but he did have some criticisms of REVERSE-IT. For one, he was not convinced about the design.
“What was unethical in having a control group?” he asked, suggesting that it was feasible and would have addressed issues of relative efficacy and safety.
For example, the authors concluded that none of the thrombotic events were likely to be treatment related, but “four events occurred immediately after reversal without an alternate explanation,” Dr. Montalescot pointed out. “Was this a signal or background noise?”
Nevertheless, he agreed that the interim phase 3 data are consistent with the previously reported phase 2 studies, and he reiterated that a strategy to reverse ticagrelor’s effects is an important unmet need.
Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PhaseBio, which provided funding for the REVERSE-IT trial. Dr. Montalescot reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cell-Prothera, CSL-Behring, Europa, Idorsia, Servicer, Medtronic, Merck Sharpe & Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.
The experimental monoclonal antibody bentracimab, which reverses the antiplatelet effects of ticagrelor, appears to be heading toward regulatory approval, on the basis of an interim analysis of the phase 3 REVERSE-IT trial.
“Rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases with no drug-related serious adverse events or allergic or infusion-related reactions,” reported Deepak L. Bhatt, MD, at the American Heart Association scientific sessions.
The interim analysis of this nonrandomized, single-arm study was requested by the Food and Drug Administration, which is considering a conditional accelerated approval of bentracimab (formerly PB2452) if efficacy and safety are established.
Upon administration, bentracimab binds to free ticagrelor so that ticagrelor cannot bind to the P2Y12 platelet receptor. This interrupts one of the key steps in the pathway of platelet aggregation.
REVERSE-IT is still enrolling patients. This interim analysis was conducted with the first 150 patients who met eligibility criteria and were treated. Of these, 142 patients were enrolled for an urgent surgical indication and 8 for a major bleeding indication. After some exclusions for lack of urgency and reclassifications following adjudication, there were 113 surgical cases and 9 major bleeding patients evaluable for hemostasis.
Platelet function assays test reversal
On the primary reversal endpoint, which was restoration of activity on the proprietary platelet function assays Verify Now and PRUTest, a rapid restoration of platelet function was achieved in both surgical and major-bleeding patients. Platelet reactivity climbed to near normal levels within 10 minutes of administration, and peak effects were sustained through the first 24 hours after administration.
On the basis of the platelet function assays, the pattern of response to bentracimab was “very similar in the surgical and bleeding patients,” reported Dr. Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Health, Boston.
The effect was also consistent across a broad array of prespecified subgroups, including stratifications by age, renal function, time from last dose of ticagrelor, race, and the presence of comorbidities, such as diabetes, renal dysfunction, hypertension, and history of MI.
Hemostasis documented in all but one patient
Adjudicated hemostasis was achieved in 100% of the 113 urgent surgical patients evaluated. In the nine major bleeding patients, six achieved excellent hemostasis and one achieved good hemostasis. One had poor hemostasis, and one was unevaluable.
Platelet rebound following bentracimab administration, measured by mean platelet volume, was not observed.
There were no serious adverse events, allergic reactions, or serious infusion-related reactions associated with the administration of bentracimab, Dr. Bhatt said.
While Dr. Bhatt acknowledged that the number of patients in the major-bleeding subgroup was small, he noted that the reduction in platelet reactivity relative to baseline was still significant. In addition, he characterized urgent surgery as “an excellent model of bleeding” and pointed out the consistency of results in the surgical and major-bleeding groups.
The interim results are also consistent with phase 1 data published 2 years ago, and with the subsequent phase 2 studies. All of these data are now under regulatory review both in the United States and in Europe, according to Dr. Bhatt.
No good current options for reversal
Evidence of efficacy and safety is encouraging, because current options for urgently reversing ticagrelor are “disappointing,” according to the invited discussant Gilles Montalescot, MD, PhD, professor of cardiology, Pitié-Salpêtrière Hôpital, Paris.
“Platelet transfusion has some value for clopidogrel and prasugrel, but it does not work for ticagrelor,” said Dr. Montalescot, referring to two other P2Y12 inhibitors. Substantiating the need for a reversal agent, he identified several other strategies that have proven ineffective, such as desmopressin and sorbent hemadsorption.
Overall, Dr. Montalescot acknowledged the need for a highly effective ticagrelor reversal agent, but he did have some criticisms of REVERSE-IT. For one, he was not convinced about the design.
“What was unethical in having a control group?” he asked, suggesting that it was feasible and would have addressed issues of relative efficacy and safety.
For example, the authors concluded that none of the thrombotic events were likely to be treatment related, but “four events occurred immediately after reversal without an alternate explanation,” Dr. Montalescot pointed out. “Was this a signal or background noise?”
Nevertheless, he agreed that the interim phase 3 data are consistent with the previously reported phase 2 studies, and he reiterated that a strategy to reverse ticagrelor’s effects is an important unmet need.
Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PhaseBio, which provided funding for the REVERSE-IT trial. Dr. Montalescot reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cell-Prothera, CSL-Behring, Europa, Idorsia, Servicer, Medtronic, Merck Sharpe & Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.
The experimental monoclonal antibody bentracimab, which reverses the antiplatelet effects of ticagrelor, appears to be heading toward regulatory approval, on the basis of an interim analysis of the phase 3 REVERSE-IT trial.
“Rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases with no drug-related serious adverse events or allergic or infusion-related reactions,” reported Deepak L. Bhatt, MD, at the American Heart Association scientific sessions.
The interim analysis of this nonrandomized, single-arm study was requested by the Food and Drug Administration, which is considering a conditional accelerated approval of bentracimab (formerly PB2452) if efficacy and safety are established.
Upon administration, bentracimab binds to free ticagrelor so that ticagrelor cannot bind to the P2Y12 platelet receptor. This interrupts one of the key steps in the pathway of platelet aggregation.
REVERSE-IT is still enrolling patients. This interim analysis was conducted with the first 150 patients who met eligibility criteria and were treated. Of these, 142 patients were enrolled for an urgent surgical indication and 8 for a major bleeding indication. After some exclusions for lack of urgency and reclassifications following adjudication, there were 113 surgical cases and 9 major bleeding patients evaluable for hemostasis.
Platelet function assays test reversal
On the primary reversal endpoint, which was restoration of activity on the proprietary platelet function assays Verify Now and PRUTest, a rapid restoration of platelet function was achieved in both surgical and major-bleeding patients. Platelet reactivity climbed to near normal levels within 10 minutes of administration, and peak effects were sustained through the first 24 hours after administration.
On the basis of the platelet function assays, the pattern of response to bentracimab was “very similar in the surgical and bleeding patients,” reported Dr. Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Health, Boston.
The effect was also consistent across a broad array of prespecified subgroups, including stratifications by age, renal function, time from last dose of ticagrelor, race, and the presence of comorbidities, such as diabetes, renal dysfunction, hypertension, and history of MI.
Hemostasis documented in all but one patient
Adjudicated hemostasis was achieved in 100% of the 113 urgent surgical patients evaluated. In the nine major bleeding patients, six achieved excellent hemostasis and one achieved good hemostasis. One had poor hemostasis, and one was unevaluable.
Platelet rebound following bentracimab administration, measured by mean platelet volume, was not observed.
There were no serious adverse events, allergic reactions, or serious infusion-related reactions associated with the administration of bentracimab, Dr. Bhatt said.
While Dr. Bhatt acknowledged that the number of patients in the major-bleeding subgroup was small, he noted that the reduction in platelet reactivity relative to baseline was still significant. In addition, he characterized urgent surgery as “an excellent model of bleeding” and pointed out the consistency of results in the surgical and major-bleeding groups.
The interim results are also consistent with phase 1 data published 2 years ago, and with the subsequent phase 2 studies. All of these data are now under regulatory review both in the United States and in Europe, according to Dr. Bhatt.
No good current options for reversal
Evidence of efficacy and safety is encouraging, because current options for urgently reversing ticagrelor are “disappointing,” according to the invited discussant Gilles Montalescot, MD, PhD, professor of cardiology, Pitié-Salpêtrière Hôpital, Paris.
“Platelet transfusion has some value for clopidogrel and prasugrel, but it does not work for ticagrelor,” said Dr. Montalescot, referring to two other P2Y12 inhibitors. Substantiating the need for a reversal agent, he identified several other strategies that have proven ineffective, such as desmopressin and sorbent hemadsorption.
Overall, Dr. Montalescot acknowledged the need for a highly effective ticagrelor reversal agent, but he did have some criticisms of REVERSE-IT. For one, he was not convinced about the design.
“What was unethical in having a control group?” he asked, suggesting that it was feasible and would have addressed issues of relative efficacy and safety.
For example, the authors concluded that none of the thrombotic events were likely to be treatment related, but “four events occurred immediately after reversal without an alternate explanation,” Dr. Montalescot pointed out. “Was this a signal or background noise?”
Nevertheless, he agreed that the interim phase 3 data are consistent with the previously reported phase 2 studies, and he reiterated that a strategy to reverse ticagrelor’s effects is an important unmet need.
Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PhaseBio, which provided funding for the REVERSE-IT trial. Dr. Montalescot reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cell-Prothera, CSL-Behring, Europa, Idorsia, Servicer, Medtronic, Merck Sharpe & Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.
FROM AHA 2021
Genotype, need for transfusion predict death in VEXAS syndrome
Among patients with the recently defined severe autoinflammatory syndrome VEXAS, those who are transfusion dependent or have a specific amino acid substitution are at highest risk for death, whereas those with ear chondritis are at significantly lower risk, a multinational team of investigators has found.
Their study of mortality and predictors of survival among patients with genetically confirmed VEXAS showed that patients with a VEXAS variant resulting in an amino acid substitution of a methionine for a valine had a 3.5-fold higher risk for death, compared with patients with either a methionine-to-threonine substitution or a methionine-to-leucine swap.
Transfusion dependence was an independent predictor of mortality. Patients who became dependent on transfusions after symptom onset had a nearly threefold higher risk for death, reported Marcela A. Ferrada, MD, a clinical fellow at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
“These findings should inform risk assessment and clinical management in patients with VEXAS syndrome,” she said in an oral abstract presentation during the virtual annual meeting of the American College of Rheumatology.
“These genetic findings have proven right now to be not only diagnostic, but we have shown that they’re also prognostic, and we hope that this is going to help us identify patients who could have more aggressive treatment,” Dr. Ferrada said.
She also discussed her findings in a media briefing held 2 days prior to her plenary presentation. At that briefing, this news organization asked participating clinicians whether they had patients who they suspected may have had undiagnosed VEXAS.
“My answer to that is interesting,” replied moderator Vaneet Sandhu, MD, from Loma Linda (Calif.) University and Riverside University Health System.
“In the last couple of days, I’ve been reading about VEXAS, and actually texted one of my colleagues yesterday and said, ‘Hey, you know these patients we’ve been seeing who have these strange rashes and chondritis and have maybe a diagnosis of leukocytoclastic vasculitis or something else – are we not diagnosing these patients?’ ” she said.
“I think we are looking at every patient with chondritis and reexamining their phenotype. We had dismissed certain symptoms because they didn’t fit the archetype for relapsing polychondritis, for example, but it could be VEXAS,” said Alfred Kim, MD, PhD, of Washington University in St. Louis, who also presented data during the briefing.
Three variants
VEXAS is caused by somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation.
The syndrome’s name is an acronym descriptive of the major features:
- Vacuoles in bone marrow cells.
- E-1 activating enzyme that UBA1 encodes for.
- X-linked.
- Autoinflammatory.
- Somatic mutation featuring hematologic mosaicism.
VEXAS results in rheumatologic, dermatologic, and hematologic symptoms that are often misdiagnosed as being caused by treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, giant cell arteritis, or myelodysplastic syndrome (MDS).
VEXAS was identified as a distinct syndrome within the past year by Dr. Ferrada and other investigators at NIAMS, the National Human Genome Research Institute, and other institutions.
In the study reported at ACR 2021, Dr. Ferrada and colleagues assessed 83 men who had been referred for genetic testing for VEXAS at the National Institutes of Health, in Bethesda, Md., and at Leeds (England) Teaching Hospitals NHS Trust.
All patients were confirmed to have VEXAS-defining genetic mutations in UBA1 by Sanger sequencing of peripheral blood samples. Only those patients with mutations at codon p.Met41 were included in the investigators’ analysis. Mutations at that site account for nearly all cases of VEXAS that have been identified to date.
The most common clinical manifestation of VEXAS was skin involvement, which occurred in all but one of the 83 patients. Other common manifestations included arthritis (58 patients), pulmonary infiltrates (57 patients), and ear chondritis (54 patients).
Fifteen patients were found to have the leucine variant, 18 had the valine variant, and 50 had the threonine variant. The median age at disease onset was 66 years in the leucine and threonine variant groups and 65 in the valine variant group.
The clinical diagnosis differed according to genotype: 4 of 18 patients (22%) with the valine variant were diagnosed with relapsing polychondritis, compared with 8 of 15 (53%) with the leucine variant and 31 of 50 (62%) with the threonine variant (P = .01).
In contrast, 55% of patients with valine genotype were diagnosed with undifferentiated fever, compared with 6% of those with the leucine and 16% with the threonine genotypes (P = .001). More patients with the leucine variant (60%) were diagnosed with Sweet syndrome, compared with 11% and 14% of patients with the valine and threonine variants, respectively (P = .001).
There was no significant difference among the three genotypes in the percentage of patients diagnosed with MDS.
The follow-up period ranged from 1 to 18 years (median, 4.7 years). The median survival time from disease onset for all patients was 10 years.
Among patients with the valine variant, median survival was 9 years, which was significantly less than among patients with the other two variants (P = .01).
In univariable analysis, independent predictors of mortality were ear chondritis (hazard ratio, 0.26; P = .005), transfusion dependence, a time-dependent variable (HR, 2.59; P = .03), and the valine variant (HR, 3.5; P = .008).
The association between VEXAS genotype and phenotype could be explained by the finding that, among patients with the valine variant, there was significantly less translation of the catalytically proficient UBA1b isoform than in patients with the other two variants, Dr. Ferrada said.
Therapeutic options
Dr. Ferrada noted that to date no drugs have been shown to provide consistent therapeutic benefits for patients with VEXAS, but evidence as to the etiology of the syndrome points to possible treatment approaches.
“All of these findings I think are extremely important to help us guide management of these patients, as we know that the mutation is located in the stem cells in the bone marrow. So we suspect that doing a bone marrow transplant in these patients is going to be curative,” Dr. Ferrada said during the briefing.
Investigators are planning a phase 2 trial of allogeneic hematopoietic stem cell transplant for patients with VEXAS.
The study was supported by the National Institutes of Health. Dr. Ferrada, Dr. Sandhu, and Dr. Kim have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among patients with the recently defined severe autoinflammatory syndrome VEXAS, those who are transfusion dependent or have a specific amino acid substitution are at highest risk for death, whereas those with ear chondritis are at significantly lower risk, a multinational team of investigators has found.
Their study of mortality and predictors of survival among patients with genetically confirmed VEXAS showed that patients with a VEXAS variant resulting in an amino acid substitution of a methionine for a valine had a 3.5-fold higher risk for death, compared with patients with either a methionine-to-threonine substitution or a methionine-to-leucine swap.
Transfusion dependence was an independent predictor of mortality. Patients who became dependent on transfusions after symptom onset had a nearly threefold higher risk for death, reported Marcela A. Ferrada, MD, a clinical fellow at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
“These findings should inform risk assessment and clinical management in patients with VEXAS syndrome,” she said in an oral abstract presentation during the virtual annual meeting of the American College of Rheumatology.
“These genetic findings have proven right now to be not only diagnostic, but we have shown that they’re also prognostic, and we hope that this is going to help us identify patients who could have more aggressive treatment,” Dr. Ferrada said.
She also discussed her findings in a media briefing held 2 days prior to her plenary presentation. At that briefing, this news organization asked participating clinicians whether they had patients who they suspected may have had undiagnosed VEXAS.
“My answer to that is interesting,” replied moderator Vaneet Sandhu, MD, from Loma Linda (Calif.) University and Riverside University Health System.
“In the last couple of days, I’ve been reading about VEXAS, and actually texted one of my colleagues yesterday and said, ‘Hey, you know these patients we’ve been seeing who have these strange rashes and chondritis and have maybe a diagnosis of leukocytoclastic vasculitis or something else – are we not diagnosing these patients?’ ” she said.
“I think we are looking at every patient with chondritis and reexamining their phenotype. We had dismissed certain symptoms because they didn’t fit the archetype for relapsing polychondritis, for example, but it could be VEXAS,” said Alfred Kim, MD, PhD, of Washington University in St. Louis, who also presented data during the briefing.
Three variants
VEXAS is caused by somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation.
The syndrome’s name is an acronym descriptive of the major features:
- Vacuoles in bone marrow cells.
- E-1 activating enzyme that UBA1 encodes for.
- X-linked.
- Autoinflammatory.
- Somatic mutation featuring hematologic mosaicism.
VEXAS results in rheumatologic, dermatologic, and hematologic symptoms that are often misdiagnosed as being caused by treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, giant cell arteritis, or myelodysplastic syndrome (MDS).
VEXAS was identified as a distinct syndrome within the past year by Dr. Ferrada and other investigators at NIAMS, the National Human Genome Research Institute, and other institutions.
In the study reported at ACR 2021, Dr. Ferrada and colleagues assessed 83 men who had been referred for genetic testing for VEXAS at the National Institutes of Health, in Bethesda, Md., and at Leeds (England) Teaching Hospitals NHS Trust.
All patients were confirmed to have VEXAS-defining genetic mutations in UBA1 by Sanger sequencing of peripheral blood samples. Only those patients with mutations at codon p.Met41 were included in the investigators’ analysis. Mutations at that site account for nearly all cases of VEXAS that have been identified to date.
The most common clinical manifestation of VEXAS was skin involvement, which occurred in all but one of the 83 patients. Other common manifestations included arthritis (58 patients), pulmonary infiltrates (57 patients), and ear chondritis (54 patients).
Fifteen patients were found to have the leucine variant, 18 had the valine variant, and 50 had the threonine variant. The median age at disease onset was 66 years in the leucine and threonine variant groups and 65 in the valine variant group.
The clinical diagnosis differed according to genotype: 4 of 18 patients (22%) with the valine variant were diagnosed with relapsing polychondritis, compared with 8 of 15 (53%) with the leucine variant and 31 of 50 (62%) with the threonine variant (P = .01).
In contrast, 55% of patients with valine genotype were diagnosed with undifferentiated fever, compared with 6% of those with the leucine and 16% with the threonine genotypes (P = .001). More patients with the leucine variant (60%) were diagnosed with Sweet syndrome, compared with 11% and 14% of patients with the valine and threonine variants, respectively (P = .001).
There was no significant difference among the three genotypes in the percentage of patients diagnosed with MDS.
The follow-up period ranged from 1 to 18 years (median, 4.7 years). The median survival time from disease onset for all patients was 10 years.
Among patients with the valine variant, median survival was 9 years, which was significantly less than among patients with the other two variants (P = .01).
In univariable analysis, independent predictors of mortality were ear chondritis (hazard ratio, 0.26; P = .005), transfusion dependence, a time-dependent variable (HR, 2.59; P = .03), and the valine variant (HR, 3.5; P = .008).
The association between VEXAS genotype and phenotype could be explained by the finding that, among patients with the valine variant, there was significantly less translation of the catalytically proficient UBA1b isoform than in patients with the other two variants, Dr. Ferrada said.
Therapeutic options
Dr. Ferrada noted that to date no drugs have been shown to provide consistent therapeutic benefits for patients with VEXAS, but evidence as to the etiology of the syndrome points to possible treatment approaches.
“All of these findings I think are extremely important to help us guide management of these patients, as we know that the mutation is located in the stem cells in the bone marrow. So we suspect that doing a bone marrow transplant in these patients is going to be curative,” Dr. Ferrada said during the briefing.
Investigators are planning a phase 2 trial of allogeneic hematopoietic stem cell transplant for patients with VEXAS.
The study was supported by the National Institutes of Health. Dr. Ferrada, Dr. Sandhu, and Dr. Kim have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among patients with the recently defined severe autoinflammatory syndrome VEXAS, those who are transfusion dependent or have a specific amino acid substitution are at highest risk for death, whereas those with ear chondritis are at significantly lower risk, a multinational team of investigators has found.
Their study of mortality and predictors of survival among patients with genetically confirmed VEXAS showed that patients with a VEXAS variant resulting in an amino acid substitution of a methionine for a valine had a 3.5-fold higher risk for death, compared with patients with either a methionine-to-threonine substitution or a methionine-to-leucine swap.
Transfusion dependence was an independent predictor of mortality. Patients who became dependent on transfusions after symptom onset had a nearly threefold higher risk for death, reported Marcela A. Ferrada, MD, a clinical fellow at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
“These findings should inform risk assessment and clinical management in patients with VEXAS syndrome,” she said in an oral abstract presentation during the virtual annual meeting of the American College of Rheumatology.
“These genetic findings have proven right now to be not only diagnostic, but we have shown that they’re also prognostic, and we hope that this is going to help us identify patients who could have more aggressive treatment,” Dr. Ferrada said.
She also discussed her findings in a media briefing held 2 days prior to her plenary presentation. At that briefing, this news organization asked participating clinicians whether they had patients who they suspected may have had undiagnosed VEXAS.
“My answer to that is interesting,” replied moderator Vaneet Sandhu, MD, from Loma Linda (Calif.) University and Riverside University Health System.
“In the last couple of days, I’ve been reading about VEXAS, and actually texted one of my colleagues yesterday and said, ‘Hey, you know these patients we’ve been seeing who have these strange rashes and chondritis and have maybe a diagnosis of leukocytoclastic vasculitis or something else – are we not diagnosing these patients?’ ” she said.
“I think we are looking at every patient with chondritis and reexamining their phenotype. We had dismissed certain symptoms because they didn’t fit the archetype for relapsing polychondritis, for example, but it could be VEXAS,” said Alfred Kim, MD, PhD, of Washington University in St. Louis, who also presented data during the briefing.
Three variants
VEXAS is caused by somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation.
The syndrome’s name is an acronym descriptive of the major features:
- Vacuoles in bone marrow cells.
- E-1 activating enzyme that UBA1 encodes for.
- X-linked.
- Autoinflammatory.
- Somatic mutation featuring hematologic mosaicism.
VEXAS results in rheumatologic, dermatologic, and hematologic symptoms that are often misdiagnosed as being caused by treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, giant cell arteritis, or myelodysplastic syndrome (MDS).
VEXAS was identified as a distinct syndrome within the past year by Dr. Ferrada and other investigators at NIAMS, the National Human Genome Research Institute, and other institutions.
In the study reported at ACR 2021, Dr. Ferrada and colleagues assessed 83 men who had been referred for genetic testing for VEXAS at the National Institutes of Health, in Bethesda, Md., and at Leeds (England) Teaching Hospitals NHS Trust.
All patients were confirmed to have VEXAS-defining genetic mutations in UBA1 by Sanger sequencing of peripheral blood samples. Only those patients with mutations at codon p.Met41 were included in the investigators’ analysis. Mutations at that site account for nearly all cases of VEXAS that have been identified to date.
The most common clinical manifestation of VEXAS was skin involvement, which occurred in all but one of the 83 patients. Other common manifestations included arthritis (58 patients), pulmonary infiltrates (57 patients), and ear chondritis (54 patients).
Fifteen patients were found to have the leucine variant, 18 had the valine variant, and 50 had the threonine variant. The median age at disease onset was 66 years in the leucine and threonine variant groups and 65 in the valine variant group.
The clinical diagnosis differed according to genotype: 4 of 18 patients (22%) with the valine variant were diagnosed with relapsing polychondritis, compared with 8 of 15 (53%) with the leucine variant and 31 of 50 (62%) with the threonine variant (P = .01).
In contrast, 55% of patients with valine genotype were diagnosed with undifferentiated fever, compared with 6% of those with the leucine and 16% with the threonine genotypes (P = .001). More patients with the leucine variant (60%) were diagnosed with Sweet syndrome, compared with 11% and 14% of patients with the valine and threonine variants, respectively (P = .001).
There was no significant difference among the three genotypes in the percentage of patients diagnosed with MDS.
The follow-up period ranged from 1 to 18 years (median, 4.7 years). The median survival time from disease onset for all patients was 10 years.
Among patients with the valine variant, median survival was 9 years, which was significantly less than among patients with the other two variants (P = .01).
In univariable analysis, independent predictors of mortality were ear chondritis (hazard ratio, 0.26; P = .005), transfusion dependence, a time-dependent variable (HR, 2.59; P = .03), and the valine variant (HR, 3.5; P = .008).
The association between VEXAS genotype and phenotype could be explained by the finding that, among patients with the valine variant, there was significantly less translation of the catalytically proficient UBA1b isoform than in patients with the other two variants, Dr. Ferrada said.
Therapeutic options
Dr. Ferrada noted that to date no drugs have been shown to provide consistent therapeutic benefits for patients with VEXAS, but evidence as to the etiology of the syndrome points to possible treatment approaches.
“All of these findings I think are extremely important to help us guide management of these patients, as we know that the mutation is located in the stem cells in the bone marrow. So we suspect that doing a bone marrow transplant in these patients is going to be curative,” Dr. Ferrada said during the briefing.
Investigators are planning a phase 2 trial of allogeneic hematopoietic stem cell transplant for patients with VEXAS.
The study was supported by the National Institutes of Health. Dr. Ferrada, Dr. Sandhu, and Dr. Kim have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACR 2021
Risk-based antenatal type-and-screen blood testing safe and economical
Implementing a selective type-and-screen blood testing policy in the labor and delivery unit was associated with projected annual savings of close to $200,000, a large single-center study found. Furthermore, there was no evidence of increased maternal morbidity in the university-based facility performing more than 4,400 deliveries per year, according to Ashley E. Benson, MD, MA, of the department of obstetrics and gynecology at the University of Utah, Salt Lake City, and colleagues.
The study, published in Obstetrics & Gynecology, evaluated patient safety, resource utilization, and transfusion-related costs after a policy change from universal type and screen to selective, risk-based type and screen on admission to labor and delivery.
“There had been some national interest in moving toward decreased resource utilization, and findings that universal screening was not cost effective,” Dr. Benson, who has since relocated to Oregon Health & Science University, Portland, said in an interview. An earlier cost-effective modeling study at her center had suggested that universal test and screen was not cost effective and likely not safer either. “So based on that data we felt an implementation study was warranted.”
The switch to a selective policy was made in 2018, after which her group compared outcomes from October 2017 to September 2019, looking those both 1 year preimplementation and 1 year post implementation.
One year post implementation, the following outcomes emerged, compared with preimplementation:
- Overall projected saving of $181,000 a year in the maternity unit
- Lower mean monthly type- and screen-related costs, such as those for ABO typing, antibody screen, and antibody workup. cross-matches, hold clots, and transfused products: $9,753 vs. $20,676 in the preimplementation year (P < .001)
- A lower mean monthly cost of total transfusion preparedness: $25,090 vs. $39,211 (P < .001)
- No differences in emergency-release transfusion events (four vs. three, P = .99),the study’s primary safety outcome
- Fewer emergency-release red blood cell units transfused (9 vs. 24, P = .002) and O-negative RBC units transfused (8 vs. 18, P = .016)
- No differences in hysterectomies (0.05% vs. 0.1%, P = .44) and ICU admissions (0.45% vs. 0.51%, P = .43)
“In a year of selective type and screen, we saw a 51% reduction in costs related to type and screen, and a 38% reduction in overall transfusion-related costs,” the authors wrote. “This study supports other literature suggesting that more judicious use of type and screen may be safe and cost effective.”
Dr. Benson said the results were positively received when presented a meeting 2 years ago but the published version has yet to prompt feedback.
The study
Antepartum patients underwent transfusion preparedness tests according to the center’s standard antenatal admission order sets and were risk stratified in alignment with California Maternal Quality Care Collaborative recommendations. The mean maternal age of patients in both time periods was similar at just over 29 years and the mean gestational age at delivery was just under 38 weeks.
Under the new policy, a “hold clot” is obtained for women stratified as low or medium risk on admission. In this instance, a tube of patient blood is held in the blood bank but processed only if needed, as in the event of active hemorrhage or an order for transfusion. A blood cross-match is obtained on all women stratified as high risk or having a prior positive antibody screen.
Relevant costs were the direct costs of transfusion-related testing in the labor and delivery unit from a health system perspective.
Obstetric hemorrhage is the leading cause of maternal death worldwide, the authors pointed out. While transfusion in obstetric patients occurs in only 1% or 2% of all deliveries it is nevertheless difficult to predict which patients will need transfusion, with only 2%-8% of those stratified as high risk ultimately requiring transfusion. Although obstetric hemorrhage safety bundles recommend risk stratification on admission to labor and delivery with selective type and screen for higher-risk individuals, for safety and simplicity’s sake, many labor and delivery units perform universal type and screen.
The authors cautioned that these results occurred in an academic tertiary care center with systems fine-tuned to deal with active hemorrhage and deliver timely transfusable blood. “At the moment we don’t have enough data to say whether the selective approach would be safe in hospitals with more limited blood bank capacity and access and fewer transfusion specialists in a setting optimized to respond to emergent needs, Dr. Benson said.
Katayoun F. M. Fomani, MD, a transfusion medicine specialist and medical director of blood bank and transfusion services at Long Island Jewish Medical Center, New York, agreed. “This approach only works in a controlled environment such as in this study where eligible women were assessed antenatally at the same center, but it would not work at every institution,” she said in an interview. “In addition, all patients were assessed according to the California Collaborative guideline, which itself increases the safety level but is not followed everywhere.”
The obstetric division at her hospital in New York adheres to the universal type and screen. “We have patients coming in from outside whose antenatal testing was not done at our hospital,” she said. “For this selective approach to work you need a controlled population and the electronic resources and personnel to follow each patient carefully.”
The authors indicated no specific funding for this study and disclosed no potential conflicts of interest. Dr. Fomani had no potential competing interests to declare.
Implementing a selective type-and-screen blood testing policy in the labor and delivery unit was associated with projected annual savings of close to $200,000, a large single-center study found. Furthermore, there was no evidence of increased maternal morbidity in the university-based facility performing more than 4,400 deliveries per year, according to Ashley E. Benson, MD, MA, of the department of obstetrics and gynecology at the University of Utah, Salt Lake City, and colleagues.
The study, published in Obstetrics & Gynecology, evaluated patient safety, resource utilization, and transfusion-related costs after a policy change from universal type and screen to selective, risk-based type and screen on admission to labor and delivery.
“There had been some national interest in moving toward decreased resource utilization, and findings that universal screening was not cost effective,” Dr. Benson, who has since relocated to Oregon Health & Science University, Portland, said in an interview. An earlier cost-effective modeling study at her center had suggested that universal test and screen was not cost effective and likely not safer either. “So based on that data we felt an implementation study was warranted.”
The switch to a selective policy was made in 2018, after which her group compared outcomes from October 2017 to September 2019, looking those both 1 year preimplementation and 1 year post implementation.
One year post implementation, the following outcomes emerged, compared with preimplementation:
- Overall projected saving of $181,000 a year in the maternity unit
- Lower mean monthly type- and screen-related costs, such as those for ABO typing, antibody screen, and antibody workup. cross-matches, hold clots, and transfused products: $9,753 vs. $20,676 in the preimplementation year (P < .001)
- A lower mean monthly cost of total transfusion preparedness: $25,090 vs. $39,211 (P < .001)
- No differences in emergency-release transfusion events (four vs. three, P = .99),the study’s primary safety outcome
- Fewer emergency-release red blood cell units transfused (9 vs. 24, P = .002) and O-negative RBC units transfused (8 vs. 18, P = .016)
- No differences in hysterectomies (0.05% vs. 0.1%, P = .44) and ICU admissions (0.45% vs. 0.51%, P = .43)
“In a year of selective type and screen, we saw a 51% reduction in costs related to type and screen, and a 38% reduction in overall transfusion-related costs,” the authors wrote. “This study supports other literature suggesting that more judicious use of type and screen may be safe and cost effective.”
Dr. Benson said the results were positively received when presented a meeting 2 years ago but the published version has yet to prompt feedback.
The study
Antepartum patients underwent transfusion preparedness tests according to the center’s standard antenatal admission order sets and were risk stratified in alignment with California Maternal Quality Care Collaborative recommendations. The mean maternal age of patients in both time periods was similar at just over 29 years and the mean gestational age at delivery was just under 38 weeks.
Under the new policy, a “hold clot” is obtained for women stratified as low or medium risk on admission. In this instance, a tube of patient blood is held in the blood bank but processed only if needed, as in the event of active hemorrhage or an order for transfusion. A blood cross-match is obtained on all women stratified as high risk or having a prior positive antibody screen.
Relevant costs were the direct costs of transfusion-related testing in the labor and delivery unit from a health system perspective.
Obstetric hemorrhage is the leading cause of maternal death worldwide, the authors pointed out. While transfusion in obstetric patients occurs in only 1% or 2% of all deliveries it is nevertheless difficult to predict which patients will need transfusion, with only 2%-8% of those stratified as high risk ultimately requiring transfusion. Although obstetric hemorrhage safety bundles recommend risk stratification on admission to labor and delivery with selective type and screen for higher-risk individuals, for safety and simplicity’s sake, many labor and delivery units perform universal type and screen.
The authors cautioned that these results occurred in an academic tertiary care center with systems fine-tuned to deal with active hemorrhage and deliver timely transfusable blood. “At the moment we don’t have enough data to say whether the selective approach would be safe in hospitals with more limited blood bank capacity and access and fewer transfusion specialists in a setting optimized to respond to emergent needs, Dr. Benson said.
Katayoun F. M. Fomani, MD, a transfusion medicine specialist and medical director of blood bank and transfusion services at Long Island Jewish Medical Center, New York, agreed. “This approach only works in a controlled environment such as in this study where eligible women were assessed antenatally at the same center, but it would not work at every institution,” she said in an interview. “In addition, all patients were assessed according to the California Collaborative guideline, which itself increases the safety level but is not followed everywhere.”
The obstetric division at her hospital in New York adheres to the universal type and screen. “We have patients coming in from outside whose antenatal testing was not done at our hospital,” she said. “For this selective approach to work you need a controlled population and the electronic resources and personnel to follow each patient carefully.”
The authors indicated no specific funding for this study and disclosed no potential conflicts of interest. Dr. Fomani had no potential competing interests to declare.
Implementing a selective type-and-screen blood testing policy in the labor and delivery unit was associated with projected annual savings of close to $200,000, a large single-center study found. Furthermore, there was no evidence of increased maternal morbidity in the university-based facility performing more than 4,400 deliveries per year, according to Ashley E. Benson, MD, MA, of the department of obstetrics and gynecology at the University of Utah, Salt Lake City, and colleagues.
The study, published in Obstetrics & Gynecology, evaluated patient safety, resource utilization, and transfusion-related costs after a policy change from universal type and screen to selective, risk-based type and screen on admission to labor and delivery.
“There had been some national interest in moving toward decreased resource utilization, and findings that universal screening was not cost effective,” Dr. Benson, who has since relocated to Oregon Health & Science University, Portland, said in an interview. An earlier cost-effective modeling study at her center had suggested that universal test and screen was not cost effective and likely not safer either. “So based on that data we felt an implementation study was warranted.”
The switch to a selective policy was made in 2018, after which her group compared outcomes from October 2017 to September 2019, looking those both 1 year preimplementation and 1 year post implementation.
One year post implementation, the following outcomes emerged, compared with preimplementation:
- Overall projected saving of $181,000 a year in the maternity unit
- Lower mean monthly type- and screen-related costs, such as those for ABO typing, antibody screen, and antibody workup. cross-matches, hold clots, and transfused products: $9,753 vs. $20,676 in the preimplementation year (P < .001)
- A lower mean monthly cost of total transfusion preparedness: $25,090 vs. $39,211 (P < .001)
- No differences in emergency-release transfusion events (four vs. three, P = .99),the study’s primary safety outcome
- Fewer emergency-release red blood cell units transfused (9 vs. 24, P = .002) and O-negative RBC units transfused (8 vs. 18, P = .016)
- No differences in hysterectomies (0.05% vs. 0.1%, P = .44) and ICU admissions (0.45% vs. 0.51%, P = .43)
“In a year of selective type and screen, we saw a 51% reduction in costs related to type and screen, and a 38% reduction in overall transfusion-related costs,” the authors wrote. “This study supports other literature suggesting that more judicious use of type and screen may be safe and cost effective.”
Dr. Benson said the results were positively received when presented a meeting 2 years ago but the published version has yet to prompt feedback.
The study
Antepartum patients underwent transfusion preparedness tests according to the center’s standard antenatal admission order sets and were risk stratified in alignment with California Maternal Quality Care Collaborative recommendations. The mean maternal age of patients in both time periods was similar at just over 29 years and the mean gestational age at delivery was just under 38 weeks.
Under the new policy, a “hold clot” is obtained for women stratified as low or medium risk on admission. In this instance, a tube of patient blood is held in the blood bank but processed only if needed, as in the event of active hemorrhage or an order for transfusion. A blood cross-match is obtained on all women stratified as high risk or having a prior positive antibody screen.
Relevant costs were the direct costs of transfusion-related testing in the labor and delivery unit from a health system perspective.
Obstetric hemorrhage is the leading cause of maternal death worldwide, the authors pointed out. While transfusion in obstetric patients occurs in only 1% or 2% of all deliveries it is nevertheless difficult to predict which patients will need transfusion, with only 2%-8% of those stratified as high risk ultimately requiring transfusion. Although obstetric hemorrhage safety bundles recommend risk stratification on admission to labor and delivery with selective type and screen for higher-risk individuals, for safety and simplicity’s sake, many labor and delivery units perform universal type and screen.
The authors cautioned that these results occurred in an academic tertiary care center with systems fine-tuned to deal with active hemorrhage and deliver timely transfusable blood. “At the moment we don’t have enough data to say whether the selective approach would be safe in hospitals with more limited blood bank capacity and access and fewer transfusion specialists in a setting optimized to respond to emergent needs, Dr. Benson said.
Katayoun F. M. Fomani, MD, a transfusion medicine specialist and medical director of blood bank and transfusion services at Long Island Jewish Medical Center, New York, agreed. “This approach only works in a controlled environment such as in this study where eligible women were assessed antenatally at the same center, but it would not work at every institution,” she said in an interview. “In addition, all patients were assessed according to the California Collaborative guideline, which itself increases the safety level but is not followed everywhere.”
The obstetric division at her hospital in New York adheres to the universal type and screen. “We have patients coming in from outside whose antenatal testing was not done at our hospital,” she said. “For this selective approach to work you need a controlled population and the electronic resources and personnel to follow each patient carefully.”
The authors indicated no specific funding for this study and disclosed no potential conflicts of interest. Dr. Fomani had no potential competing interests to declare.
FROM OBSTETRICS & GYNECOLOGY
Antithrombotic therapy not warranted in COVID-19 outpatients
Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.
Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.
“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”
The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.
The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.
The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.
Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.
The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.
The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.
The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.
The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.
The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.
Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.
The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.
No major bleeding events were reported.
The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.
Safety and efficacy results were similar in all randomly assigned patients.
The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.
“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”
“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.
Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
Robust evidence
“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.
“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.
The ACTIV-4B trial has immediate implications for clinical practice, he added.
“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”
ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.
“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.
The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.
Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.
“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”
The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.
The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.
The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.
Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.
The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.
The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.
The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.
The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.
The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.
Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.
The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.
No major bleeding events were reported.
The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.
Safety and efficacy results were similar in all randomly assigned patients.
The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.
“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”
“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.
Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
Robust evidence
“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.
“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.
The ACTIV-4B trial has immediate implications for clinical practice, he added.
“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”
ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.
“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.
The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.
Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.
“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”
The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.
The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.
The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.
Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.
The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.
The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.
The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.
The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.
The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.
Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.
The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.
No major bleeding events were reported.
The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.
Safety and efficacy results were similar in all randomly assigned patients.
The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.
“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”
“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.
Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
Robust evidence
“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.
“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.
The ACTIV-4B trial has immediate implications for clinical practice, he added.
“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”
ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.
“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.
The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
Autopsy findings reveal venous thromboembolism in patients with COVID-19
Background: Despite the increased mortality rate of the novel coronavirus compared with influenza, little is understood about its pathogenicity. Prior studies have identified D-dimer levels, high Sequential Organ Failure Assessment score, and older age as markers for more severe disease and mortality. The specific cause of death of COVID-19 remains largely unknown.
Study design: Prospective cohort study.
Setting: Single academic center in Germany.
Synopsis: A complete autopsy was performed on 12 consecutive COVID-19 patient deaths at a single center. Seven had evidence of venous thromboembolism (VTE): three with bilateral lower extremity deep venous thrombosis (DVT) and four with massive pulmonary embolism/associated lower-extremity DVT. Prior to death, VTE was suspected clinically in only a single patient.
This small case series piques interest in the potential underrecognized thromboembolic pathology of COVID-19. While not practice changing, this study highlights the importance of hospitalists staying attuned to further studies regarding VTE prophylaxis in COVID-19.
Bottom line: Autopsies of COVID-19 patients revealed a high incidence of thromboembolic events; COVID-19–induced coagulopathy may play an underrecognized role in pathogenesis.
Citation: Wichmann D et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020;173(4):268-77.
Dr. Fletcher is a hospitalist at the Lexington (Ky.) VA Health Care System.
Background: Despite the increased mortality rate of the novel coronavirus compared with influenza, little is understood about its pathogenicity. Prior studies have identified D-dimer levels, high Sequential Organ Failure Assessment score, and older age as markers for more severe disease and mortality. The specific cause of death of COVID-19 remains largely unknown.
Study design: Prospective cohort study.
Setting: Single academic center in Germany.
Synopsis: A complete autopsy was performed on 12 consecutive COVID-19 patient deaths at a single center. Seven had evidence of venous thromboembolism (VTE): three with bilateral lower extremity deep venous thrombosis (DVT) and four with massive pulmonary embolism/associated lower-extremity DVT. Prior to death, VTE was suspected clinically in only a single patient.
This small case series piques interest in the potential underrecognized thromboembolic pathology of COVID-19. While not practice changing, this study highlights the importance of hospitalists staying attuned to further studies regarding VTE prophylaxis in COVID-19.
Bottom line: Autopsies of COVID-19 patients revealed a high incidence of thromboembolic events; COVID-19–induced coagulopathy may play an underrecognized role in pathogenesis.
Citation: Wichmann D et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020;173(4):268-77.
Dr. Fletcher is a hospitalist at the Lexington (Ky.) VA Health Care System.
Background: Despite the increased mortality rate of the novel coronavirus compared with influenza, little is understood about its pathogenicity. Prior studies have identified D-dimer levels, high Sequential Organ Failure Assessment score, and older age as markers for more severe disease and mortality. The specific cause of death of COVID-19 remains largely unknown.
Study design: Prospective cohort study.
Setting: Single academic center in Germany.
Synopsis: A complete autopsy was performed on 12 consecutive COVID-19 patient deaths at a single center. Seven had evidence of venous thromboembolism (VTE): three with bilateral lower extremity deep venous thrombosis (DVT) and four with massive pulmonary embolism/associated lower-extremity DVT. Prior to death, VTE was suspected clinically in only a single patient.
This small case series piques interest in the potential underrecognized thromboembolic pathology of COVID-19. While not practice changing, this study highlights the importance of hospitalists staying attuned to further studies regarding VTE prophylaxis in COVID-19.
Bottom line: Autopsies of COVID-19 patients revealed a high incidence of thromboembolic events; COVID-19–induced coagulopathy may play an underrecognized role in pathogenesis.
Citation: Wichmann D et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020;173(4):268-77.
Dr. Fletcher is a hospitalist at the Lexington (Ky.) VA Health Care System.
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
Unexpected thrombocytosis could flag occult cancer
A routine blood test may pack a bigger punch than previously suspected, suggests a recent analysis of over 3 million Canadian patient records.
A finding of thrombocytosis (platelet count >450 x 109/L) was associated with a greatly increased risk for some cancers up to 5 years later.
Overall, a high platelet count increased by 2.7 times the odds of receiving a solid-tumor cancer diagnosis within 2 years (95% confidence interval, 2.6-2.8).
The cancers most likely to be associated with unexpected thrombocytosis were those notorious for late-stage diagnosis due to a lack of early symptoms.
The risk was highest (23.3 times) for ovarian cancer. The risk was 3.8 times higher for pancreatic cancer and 3.5 times higher for cervical cancer.
Lung cancer was 4.4 times more likely within 2 years among patients with thrombocytosis compared to patients with normal platelet counts.
Conversely, breast, prostate, and thyroid cancers were not linked to the finding of thrombocytosis.
The study results were published online in JAMA Network Open on Aug. 12).
One of the authors of the article, Stephen A. Narod, MD, director of the Familial Breast Cancer Research Unit at the Women’s College Research Institute, Toronto, said the results were not unexpected but “very striking.”
“I had a hunch we were going to see this because I’ve seen this in other databases,” said Dr. Narod. “I think what struck me about it was how ubiquitous it was.”
Dr. Narod urged physicians, especially those in primary care, to take note: “If the platelets are high, I would certainly have a concern about lung cancer, colon cancer, and ovarian cancer.”
Dr. Narod and coauthor Vasily Giannakeas, a PhD candidate, pointed out that in their analysis that they were unable to single out cases in which a blood test was performed because the patient complained of symptoms that are associated with cancer. In those cases, thrombocytosis may have been diagnostic, rather than a lifesaving serendipitous finding.
Similar findings were reported recently from the United Kingdom.
A study by Sarah Bailey, PhD, MPH, and colleagues that was published last year in the British Journal of General Practice also found a connection between cancer incidence and platelet count. Dr. Bailey is a senior research fellow at the University of Exeter, England.
However, unlike in the Canadian study, the team led by Dr. Bailey was able to distinguish those patients for whom there were alarm symptoms for cancer. Dr. Bailey and colleagues found that two-thirds of men older than 65 had “no recorded alarm features of cancer in the 21 days before their index platelet count.”
Although this suggests that a routine finding of thrombocytosis could uncover unsuspected cancers, Dr. Bailey is cautious about hailing platelet counts as a new cancer-screening tool.
In emailed comments, Dr. Bailey said, “The crucial part of our study is that it was conducted with patients who were ill enough to see their GP [general practitioner]. Opportunistic measurement in patients who are asymptomatic would be quite a different thing. We would have to study the platelet count and subsequent cancers in asymptomatic patients to know if that was worth doing.”
Perhaps most helpfully, the U.K. study showed that cancer risk was increased even among some patients with normal platelet counts. For example, for men aged 60 and older, lung cancer was 4.7 times more likely among those with high-normal counts (≥326 x 109/L).
Because of this somewhat alarming finding, Dr. Bailey suggested moving away from a focus on absolute values. Rising platelet counts might be more clinically useful, she said.
“Physicians should be on the lookout for any unexplained increase in an individual’s platelet count, irrespective of whether the increased value is over or under the local threshold that is applied to define thrombocytosis,” concluded Dr. Bailey.
Dr. Narod has disclosed no relevant financial relationships. Dr. Bailey is a research fellow of the CanTest Collaborative.
A version of this article first appeared on Medscape.com.
A routine blood test may pack a bigger punch than previously suspected, suggests a recent analysis of over 3 million Canadian patient records.
A finding of thrombocytosis (platelet count >450 x 109/L) was associated with a greatly increased risk for some cancers up to 5 years later.
Overall, a high platelet count increased by 2.7 times the odds of receiving a solid-tumor cancer diagnosis within 2 years (95% confidence interval, 2.6-2.8).
The cancers most likely to be associated with unexpected thrombocytosis were those notorious for late-stage diagnosis due to a lack of early symptoms.
The risk was highest (23.3 times) for ovarian cancer. The risk was 3.8 times higher for pancreatic cancer and 3.5 times higher for cervical cancer.
Lung cancer was 4.4 times more likely within 2 years among patients with thrombocytosis compared to patients with normal platelet counts.
Conversely, breast, prostate, and thyroid cancers were not linked to the finding of thrombocytosis.
The study results were published online in JAMA Network Open on Aug. 12).
One of the authors of the article, Stephen A. Narod, MD, director of the Familial Breast Cancer Research Unit at the Women’s College Research Institute, Toronto, said the results were not unexpected but “very striking.”
“I had a hunch we were going to see this because I’ve seen this in other databases,” said Dr. Narod. “I think what struck me about it was how ubiquitous it was.”
Dr. Narod urged physicians, especially those in primary care, to take note: “If the platelets are high, I would certainly have a concern about lung cancer, colon cancer, and ovarian cancer.”
Dr. Narod and coauthor Vasily Giannakeas, a PhD candidate, pointed out that in their analysis that they were unable to single out cases in which a blood test was performed because the patient complained of symptoms that are associated with cancer. In those cases, thrombocytosis may have been diagnostic, rather than a lifesaving serendipitous finding.
Similar findings were reported recently from the United Kingdom.
A study by Sarah Bailey, PhD, MPH, and colleagues that was published last year in the British Journal of General Practice also found a connection between cancer incidence and platelet count. Dr. Bailey is a senior research fellow at the University of Exeter, England.
However, unlike in the Canadian study, the team led by Dr. Bailey was able to distinguish those patients for whom there were alarm symptoms for cancer. Dr. Bailey and colleagues found that two-thirds of men older than 65 had “no recorded alarm features of cancer in the 21 days before their index platelet count.”
Although this suggests that a routine finding of thrombocytosis could uncover unsuspected cancers, Dr. Bailey is cautious about hailing platelet counts as a new cancer-screening tool.
In emailed comments, Dr. Bailey said, “The crucial part of our study is that it was conducted with patients who were ill enough to see their GP [general practitioner]. Opportunistic measurement in patients who are asymptomatic would be quite a different thing. We would have to study the platelet count and subsequent cancers in asymptomatic patients to know if that was worth doing.”
Perhaps most helpfully, the U.K. study showed that cancer risk was increased even among some patients with normal platelet counts. For example, for men aged 60 and older, lung cancer was 4.7 times more likely among those with high-normal counts (≥326 x 109/L).
Because of this somewhat alarming finding, Dr. Bailey suggested moving away from a focus on absolute values. Rising platelet counts might be more clinically useful, she said.
“Physicians should be on the lookout for any unexplained increase in an individual’s platelet count, irrespective of whether the increased value is over or under the local threshold that is applied to define thrombocytosis,” concluded Dr. Bailey.
Dr. Narod has disclosed no relevant financial relationships. Dr. Bailey is a research fellow of the CanTest Collaborative.
A version of this article first appeared on Medscape.com.
A routine blood test may pack a bigger punch than previously suspected, suggests a recent analysis of over 3 million Canadian patient records.
A finding of thrombocytosis (platelet count >450 x 109/L) was associated with a greatly increased risk for some cancers up to 5 years later.
Overall, a high platelet count increased by 2.7 times the odds of receiving a solid-tumor cancer diagnosis within 2 years (95% confidence interval, 2.6-2.8).
The cancers most likely to be associated with unexpected thrombocytosis were those notorious for late-stage diagnosis due to a lack of early symptoms.
The risk was highest (23.3 times) for ovarian cancer. The risk was 3.8 times higher for pancreatic cancer and 3.5 times higher for cervical cancer.
Lung cancer was 4.4 times more likely within 2 years among patients with thrombocytosis compared to patients with normal platelet counts.
Conversely, breast, prostate, and thyroid cancers were not linked to the finding of thrombocytosis.
The study results were published online in JAMA Network Open on Aug. 12).
One of the authors of the article, Stephen A. Narod, MD, director of the Familial Breast Cancer Research Unit at the Women’s College Research Institute, Toronto, said the results were not unexpected but “very striking.”
“I had a hunch we were going to see this because I’ve seen this in other databases,” said Dr. Narod. “I think what struck me about it was how ubiquitous it was.”
Dr. Narod urged physicians, especially those in primary care, to take note: “If the platelets are high, I would certainly have a concern about lung cancer, colon cancer, and ovarian cancer.”
Dr. Narod and coauthor Vasily Giannakeas, a PhD candidate, pointed out that in their analysis that they were unable to single out cases in which a blood test was performed because the patient complained of symptoms that are associated with cancer. In those cases, thrombocytosis may have been diagnostic, rather than a lifesaving serendipitous finding.
Similar findings were reported recently from the United Kingdom.
A study by Sarah Bailey, PhD, MPH, and colleagues that was published last year in the British Journal of General Practice also found a connection between cancer incidence and platelet count. Dr. Bailey is a senior research fellow at the University of Exeter, England.
However, unlike in the Canadian study, the team led by Dr. Bailey was able to distinguish those patients for whom there were alarm symptoms for cancer. Dr. Bailey and colleagues found that two-thirds of men older than 65 had “no recorded alarm features of cancer in the 21 days before their index platelet count.”
Although this suggests that a routine finding of thrombocytosis could uncover unsuspected cancers, Dr. Bailey is cautious about hailing platelet counts as a new cancer-screening tool.
In emailed comments, Dr. Bailey said, “The crucial part of our study is that it was conducted with patients who were ill enough to see their GP [general practitioner]. Opportunistic measurement in patients who are asymptomatic would be quite a different thing. We would have to study the platelet count and subsequent cancers in asymptomatic patients to know if that was worth doing.”
Perhaps most helpfully, the U.K. study showed that cancer risk was increased even among some patients with normal platelet counts. For example, for men aged 60 and older, lung cancer was 4.7 times more likely among those with high-normal counts (≥326 x 109/L).
Because of this somewhat alarming finding, Dr. Bailey suggested moving away from a focus on absolute values. Rising platelet counts might be more clinically useful, she said.
“Physicians should be on the lookout for any unexplained increase in an individual’s platelet count, irrespective of whether the increased value is over or under the local threshold that is applied to define thrombocytosis,” concluded Dr. Bailey.
Dr. Narod has disclosed no relevant financial relationships. Dr. Bailey is a research fellow of the CanTest Collaborative.
A version of this article first appeared on Medscape.com.