Thrombosis

Image by Andre E.X. Brown

New research suggests a scoring system can predict the risk of thrombosis in patients with immune thrombocytopenia (ITP) who are taking anticoagulants.

Researchers tested their Thrombosis and Thrombocytopenia (TH2) risk assessment score in a small group of ITP patients on anticoagulants, and the score identified all seven patients who developed thrombosis.

The researchers also found that patients’ TH2 scores changed quickly—within a matter of days—which suggests they should be re-evaluated for thrombosis risk frequently.

Amaris K. Balitsky, MD, of McMaster University in Hamilton, Ontario, Canada, and her colleagues detailed this research in Blood.

About the score

To develop the TH2 score, the researchers conducted a review of the literature and existing tools used to assess the risk of thrombosis and bleeding. The resulting score consists of two thrombosis items and two bleeding items.

The thrombosis items are:

• High thrombotic risk, which includes patients with atrial fibrillation and a CHA2DS2-VASc score greater than five; unprovoked, recurrent, or cancer-associated thrombosis; or antiphospholipid antibody syndrome
• Receipt of ITP therapies known to increase the risk of thrombosis in the previous 14 days or splenectomy in the previous 30 days.

The score’s bleeding items are:

• Platelet count less than 20 x 10⁹/L
• Major bleeding (grade 2 bleeding that does not involve the skin) observed at a clinical encounter.

Each thrombosis item is assigned a score of +1, and each bleeding item is assigned a score of -1. A positive score or score of 0 suggests a net increased risk of thrombosis, and a negative score suggests a net increased risk of bleeding.

Patient population

The researchers tested the TH2 score in patients enrolled in the McMaster ITP Registry from 2010 to 2017.

There were 314 patients enrolled, but only 13 were receiving anticoagulation and had a platelet count less than 50 x 10⁹/L. Six of these patients were receiving anticoagulation for atrial fibrillation and seven for venous thrombosis. Four patients were taking antiplatelet agents as well.

The median follow up was 9 months (interquartile range, 4.5 to 24 months). During that time, there were 41 clinical encounters. Data on treatment decisions and clinical outcomes were available for 32 of these encounters.

Ten of the 13 patients had anticoagulation withheld at some point during their 22 clinical encounters. Major bleeding was present at five of the encounters. At 17 encounters, patients received additional ITP treatments.

Six of the 10 patients who stopped anticoagulation had new thrombotic events, and two of these events were fatal. Three of the patients had thrombotic events even though they resumed anticoagulation.

The remaining three patients (of the 13) did not stop anticoagulation. These patients received additional ITP treatments at six of their 10 clinical encounters.

Major bleeding was present at two of the 10 encounters, and one new thrombotic event occurred in a patient with metastatic squamous cell cancer (despite continued treatment with warfarin).

Testing the score

The TH2 score accurately predicted all seven thrombotic events.

There were four patients who initially had a negative TH2 score, which suggested an increased risk of bleeding.

However, these patients had a positive or 0 score—suggesting an increased risk of thrombosis—when they were assessed again, after their platelet counts increased above 50 x 10⁹/L.

The remaining three patients had initial scores of 0 and subsequent positive scores, both suggesting an increased risk of thrombosis.

The researchers said these findings suggest patients should be re-evaluated for thrombosis risk frequently, as ITP treatments are given and platelet counts increase.

“The results of our study suggest that the risk of thrombosis is high in patients with ITP who have a separate indication for anticoagulation, especially after ITP therapies are administered and the severe thrombocytopenia improves,” the researchers wrote. “Early resumption of anticoagulation should be considered in this population.”

The researchers also noted that this study was limited by its retrospective, single-center design and the small number of patients evaluated. Therefore, the TH2 score should be validated in additional, larger studies.

One researcher reported relationships with Amgen, Novartis, Rigel Pharmaceuticals, UCB, and Principia Biopharma. The other researchers said they had no competing financial interests.

Image by Andre E.X. Brown

New research suggests a scoring system can predict the risk of thrombosis in patients with immune thrombocytopenia (ITP) who are taking anticoagulants.

Researchers tested their Thrombosis and Thrombocytopenia (TH2) risk assessment score in a small group of ITP patients on anticoagulants, and the score identified all seven patients who developed thrombosis.

The researchers also found that patients’ TH2 scores changed quickly—within a matter of days—which suggests they should be re-evaluated for thrombosis risk frequently.

Amaris K. Balitsky, MD, of McMaster University in Hamilton, Ontario, Canada, and her colleagues detailed this research in Blood.

About the score

To develop the TH2 score, the researchers conducted a review of the literature and existing tools used to assess the risk of thrombosis and bleeding. The resulting score consists of two thrombosis items and two bleeding items.

The thrombosis items are:

• High thrombotic risk, which includes patients with atrial fibrillation and a CHA2DS2-VASc score greater than five; unprovoked, recurrent, or cancer-associated thrombosis; or antiphospholipid antibody syndrome
• Receipt of ITP therapies known to increase the risk of thrombosis in the previous 14 days or splenectomy in the previous 30 days.

The score’s bleeding items are:

• Platelet count less than 20 x 10⁹/L
• Major bleeding (grade 2 bleeding that does not involve the skin) observed at a clinical encounter.

Each thrombosis item is assigned a score of +1, and each bleeding item is assigned a score of -1. A positive score or score of 0 suggests a net increased risk of thrombosis, and a negative score suggests a net increased risk of bleeding.

Patient population

The researchers tested the TH2 score in patients enrolled in the McMaster ITP Registry from 2010 to 2017.

There were 314 patients enrolled, but only 13 were receiving anticoagulation and had a platelet count less than 50 x 10⁹/L. Six of these patients were receiving anticoagulation for atrial fibrillation and seven for venous thrombosis. Four patients were taking antiplatelet agents as well.

The median follow up was 9 months (interquartile range, 4.5 to 24 months). During that time, there were 41 clinical encounters. Data on treatment decisions and clinical outcomes were available for 32 of these encounters.

Ten of the 13 patients had anticoagulation withheld at some point during their 22 clinical encounters. Major bleeding was present at five of the encounters. At 17 encounters, patients received additional ITP treatments.

Six of the 10 patients who stopped anticoagulation had new thrombotic events, and two of these events were fatal. Three of the patients had thrombotic events even though they resumed anticoagulation.

The remaining three patients (of the 13) did not stop anticoagulation. These patients received additional ITP treatments at six of their 10 clinical encounters.

Major bleeding was present at two of the 10 encounters, and one new thrombotic event occurred in a patient with metastatic squamous cell cancer (despite continued treatment with warfarin).

Testing the score

The TH2 score accurately predicted all seven thrombotic events.

There were four patients who initially had a negative TH2 score, which suggested an increased risk of bleeding.

However, these patients had a positive or 0 score—suggesting an increased risk of thrombosis—when they were assessed again, after their platelet counts increased above 50 x 10⁹/L.

The remaining three patients had initial scores of 0 and subsequent positive scores, both suggesting an increased risk of thrombosis.

The researchers said these findings suggest patients should be re-evaluated for thrombosis risk frequently, as ITP treatments are given and platelet counts increase.

“The results of our study suggest that the risk of thrombosis is high in patients with ITP who have a separate indication for anticoagulation, especially after ITP therapies are administered and the severe thrombocytopenia improves,” the researchers wrote. “Early resumption of anticoagulation should be considered in this population.”

The researchers also noted that this study was limited by its retrospective, single-center design and the small number of patients evaluated. Therefore, the TH2 score should be validated in additional, larger studies.

One researcher reported relationships with Amgen, Novartis, Rigel Pharmaceuticals, UCB, and Principia Biopharma. The other researchers said they had no competing financial interests.

Image by Andre E.X. Brown

New research suggests a scoring system can predict the risk of thrombosis in patients with immune thrombocytopenia (ITP) who are taking anticoagulants.

Researchers tested their Thrombosis and Thrombocytopenia (TH2) risk assessment score in a small group of ITP patients on anticoagulants, and the score identified all seven patients who developed thrombosis.

The researchers also found that patients’ TH2 scores changed quickly—within a matter of days—which suggests they should be re-evaluated for thrombosis risk frequently.

Amaris K. Balitsky, MD, of McMaster University in Hamilton, Ontario, Canada, and her colleagues detailed this research in Blood.

About the score

To develop the TH2 score, the researchers conducted a review of the literature and existing tools used to assess the risk of thrombosis and bleeding. The resulting score consists of two thrombosis items and two bleeding items.

The thrombosis items are:

• High thrombotic risk, which includes patients with atrial fibrillation and a CHA2DS2-VASc score greater than five; unprovoked, recurrent, or cancer-associated thrombosis; or antiphospholipid antibody syndrome
• Receipt of ITP therapies known to increase the risk of thrombosis in the previous 14 days or splenectomy in the previous 30 days.

The score’s bleeding items are:

• Platelet count less than 20 x 10⁹/L
• Major bleeding (grade 2 bleeding that does not involve the skin) observed at a clinical encounter.

Each thrombosis item is assigned a score of +1, and each bleeding item is assigned a score of -1. A positive score or score of 0 suggests a net increased risk of thrombosis, and a negative score suggests a net increased risk of bleeding.

Patient population

The researchers tested the TH2 score in patients enrolled in the McMaster ITP Registry from 2010 to 2017.

There were 314 patients enrolled, but only 13 were receiving anticoagulation and had a platelet count less than 50 x 10⁹/L. Six of these patients were receiving anticoagulation for atrial fibrillation and seven for venous thrombosis. Four patients were taking antiplatelet agents as well.

The median follow up was 9 months (interquartile range, 4.5 to 24 months). During that time, there were 41 clinical encounters. Data on treatment decisions and clinical outcomes were available for 32 of these encounters.

Ten of the 13 patients had anticoagulation withheld at some point during their 22 clinical encounters. Major bleeding was present at five of the encounters. At 17 encounters, patients received additional ITP treatments.

Six of the 10 patients who stopped anticoagulation had new thrombotic events, and two of these events were fatal. Three of the patients had thrombotic events even though they resumed anticoagulation.

The remaining three patients (of the 13) did not stop anticoagulation. These patients received additional ITP treatments at six of their 10 clinical encounters.

Major bleeding was present at two of the 10 encounters, and one new thrombotic event occurred in a patient with metastatic squamous cell cancer (despite continued treatment with warfarin).

Testing the score

The TH2 score accurately predicted all seven thrombotic events.

There were four patients who initially had a negative TH2 score, which suggested an increased risk of bleeding.

However, these patients had a positive or 0 score—suggesting an increased risk of thrombosis—when they were assessed again, after their platelet counts increased above 50 x 10⁹/L.

The remaining three patients had initial scores of 0 and subsequent positive scores, both suggesting an increased risk of thrombosis.

The researchers said these findings suggest patients should be re-evaluated for thrombosis risk frequently, as ITP treatments are given and platelet counts increase.

“The results of our study suggest that the risk of thrombosis is high in patients with ITP who have a separate indication for anticoagulation, especially after ITP therapies are administered and the severe thrombocytopenia improves,” the researchers wrote. “Early resumption of anticoagulation should be considered in this population.”

The researchers also noted that this study was limited by its retrospective, single-center design and the small number of patients evaluated. Therefore, the TH2 score should be validated in additional, larger studies.

One researcher reported relationships with Amgen, Novartis, Rigel Pharmaceuticals, UCB, and Principia Biopharma. The other researchers said they had no competing financial interests.

Among direct oral anticoagulants, apixaban (Eliquis) has shown fewer stroke events and bleeding than warfarin in patients with atrial fibrillation, according to results of an updated comparative effectiveness review.

Dabigatran (Pradaxa), by contrast, has shown reductions in stroke events but a similar rate of bleeding events compared to warfarin, according to the report from the Duke Evidence-based Practice Center, Durham, N.C.

Rivaroxaban (Xarelto), meanwhile, is “similar in both benefits and harms with warfarin” in evidence to date, investigators wrote in the report, which was prepared for the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI).

Finally, edoxaban (Savaysa) is “most likely similar” to warfarin with respect to preventing stroke or systemic embolism, with less risk for major bleeding and hemorrhagic stroke, investigators wrote in a summary of their findings on the AHRQ website.

“Effectiveness of these direct oral anticoagulants as compared to one another however is limited by the lack of randomized studies directly comparing their safety and effectiveness,” concluded investigators, led by Gillian D. Sanders, PhD, of Duke University.

The 612-page report details a systematic review based on 320 articles representing 185 unique studies. The review was designed to update a 2013 AHRQ report that evaluated evidence not only for treatment options to prevent stroke in patients with atrial fibrillation, but also for tools used to predict risk of stroke or bleeding.

In the 2013 report, investigators concluded that the newer anticoagulants showed “early promise” in reducing stroke and bleeding events compared with warfarin.

That earlier report said that CHA₂ and CHA₂DS₂-VASc had the best evidence to support prediction of stroke events, while HAS-BLED provided the best discrimination of bleeding risk.

The updated report adds the ABC stroke risk score as a tool that, along with CHADS2 and CHA2DS2-VASc, has the “best evidence” predicting thromboembolic risk, authors said.

Imaging tools, on the other hand, still need more evidence supporting their use to predict thromboembolic risk, Dr. Sanders and colleagues said in their report.

The literature review, which covered the January 2000 through February 2018, turned up 61 studies relevant to predicting thromboembolic risk, 38 on bleeding risk, and 117 on preventing thromboembolic events with anticoagulation therapies, antiplatelet therapies, or procedures.

Direct oral anticoagulants were evaluated in randomized clinical trials that were “often very large, of good quality, and considered definitive in the field,” Dr. Sanders and colleagues wrote in their report.

However, these trials were constrained to comparing direct oral anticoagulants with warfarin or aspirin, and have not involved head-to-head comparison among the newer agents, they added.

“Based on these trials though, clinical leaders and professional societies have determined that these newer agents are better than the prior lone treatment of warfarin in terms of stroke prevention, side effects, and risk of bleeding,” they said in the published report.
 

SOURCE: Sanders GD, et al. 2018 Oct 30. AHRQ Publication No. 18(19)-EHC018-EF.
 

Among direct oral anticoagulants, apixaban (Eliquis) has shown fewer stroke events and bleeding than warfarin in patients with atrial fibrillation, according to results of an updated comparative effectiveness review.

Dabigatran (Pradaxa), by contrast, has shown reductions in stroke events but a similar rate of bleeding events compared to warfarin, according to the report from the Duke Evidence-based Practice Center, Durham, N.C.

Rivaroxaban (Xarelto), meanwhile, is “similar in both benefits and harms with warfarin” in evidence to date, investigators wrote in the report, which was prepared for the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI).

Finally, edoxaban (Savaysa) is “most likely similar” to warfarin with respect to preventing stroke or systemic embolism, with less risk for major bleeding and hemorrhagic stroke, investigators wrote in a summary of their findings on the AHRQ website.

“Effectiveness of these direct oral anticoagulants as compared to one another however is limited by the lack of randomized studies directly comparing their safety and effectiveness,” concluded investigators, led by Gillian D. Sanders, PhD, of Duke University.

The 612-page report details a systematic review based on 320 articles representing 185 unique studies. The review was designed to update a 2013 AHRQ report that evaluated evidence not only for treatment options to prevent stroke in patients with atrial fibrillation, but also for tools used to predict risk of stroke or bleeding.

In the 2013 report, investigators concluded that the newer anticoagulants showed “early promise” in reducing stroke and bleeding events compared with warfarin.

That earlier report said that CHA₂ and CHA₂DS₂-VASc had the best evidence to support prediction of stroke events, while HAS-BLED provided the best discrimination of bleeding risk.

The updated report adds the ABC stroke risk score as a tool that, along with CHADS2 and CHA2DS2-VASc, has the “best evidence” predicting thromboembolic risk, authors said.

Imaging tools, on the other hand, still need more evidence supporting their use to predict thromboembolic risk, Dr. Sanders and colleagues said in their report.

The literature review, which covered the January 2000 through February 2018, turned up 61 studies relevant to predicting thromboembolic risk, 38 on bleeding risk, and 117 on preventing thromboembolic events with anticoagulation therapies, antiplatelet therapies, or procedures.

Direct oral anticoagulants were evaluated in randomized clinical trials that were “often very large, of good quality, and considered definitive in the field,” Dr. Sanders and colleagues wrote in their report.

However, these trials were constrained to comparing direct oral anticoagulants with warfarin or aspirin, and have not involved head-to-head comparison among the newer agents, they added.

“Based on these trials though, clinical leaders and professional societies have determined that these newer agents are better than the prior lone treatment of warfarin in terms of stroke prevention, side effects, and risk of bleeding,” they said in the published report.
 

SOURCE: Sanders GD, et al. 2018 Oct 30. AHRQ Publication No. 18(19)-EHC018-EF.
 

Among direct oral anticoagulants, apixaban (Eliquis) has shown fewer stroke events and bleeding than warfarin in patients with atrial fibrillation, according to results of an updated comparative effectiveness review.

Dabigatran (Pradaxa), by contrast, has shown reductions in stroke events but a similar rate of bleeding events compared to warfarin, according to the report from the Duke Evidence-based Practice Center, Durham, N.C.

Rivaroxaban (Xarelto), meanwhile, is “similar in both benefits and harms with warfarin” in evidence to date, investigators wrote in the report, which was prepared for the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI).

Finally, edoxaban (Savaysa) is “most likely similar” to warfarin with respect to preventing stroke or systemic embolism, with less risk for major bleeding and hemorrhagic stroke, investigators wrote in a summary of their findings on the AHRQ website.

“Effectiveness of these direct oral anticoagulants as compared to one another however is limited by the lack of randomized studies directly comparing their safety and effectiveness,” concluded investigators, led by Gillian D. Sanders, PhD, of Duke University.

The 612-page report details a systematic review based on 320 articles representing 185 unique studies. The review was designed to update a 2013 AHRQ report that evaluated evidence not only for treatment options to prevent stroke in patients with atrial fibrillation, but also for tools used to predict risk of stroke or bleeding.

In the 2013 report, investigators concluded that the newer anticoagulants showed “early promise” in reducing stroke and bleeding events compared with warfarin.

That earlier report said that CHA₂ and CHA₂DS₂-VASc had the best evidence to support prediction of stroke events, while HAS-BLED provided the best discrimination of bleeding risk.

The updated report adds the ABC stroke risk score as a tool that, along with CHADS2 and CHA2DS2-VASc, has the “best evidence” predicting thromboembolic risk, authors said.

Imaging tools, on the other hand, still need more evidence supporting their use to predict thromboembolic risk, Dr. Sanders and colleagues said in their report.

The literature review, which covered the January 2000 through February 2018, turned up 61 studies relevant to predicting thromboembolic risk, 38 on bleeding risk, and 117 on preventing thromboembolic events with anticoagulation therapies, antiplatelet therapies, or procedures.

Direct oral anticoagulants were evaluated in randomized clinical trials that were “often very large, of good quality, and considered definitive in the field,” Dr. Sanders and colleagues wrote in their report.

However, these trials were constrained to comparing direct oral anticoagulants with warfarin or aspirin, and have not involved head-to-head comparison among the newer agents, they added.

“Based on these trials though, clinical leaders and professional societies have determined that these newer agents are better than the prior lone treatment of warfarin in terms of stroke prevention, side effects, and risk of bleeding,” they said in the published report.
 

SOURCE: Sanders GD, et al. 2018 Oct 30. AHRQ Publication No. 18(19)-EHC018-EF.
 

Lab mouse

Investigators designed an antiplatelet vaccine they say could be a novel therapy to prevent recurrent ischemic stroke.

The vaccine inhibits S100A9 (S100 calcium-binding protein A9)/CD36 (cluster of differentiation 36) signaling in platelets, which is a key signal in arterial thrombosis but not hemostasis.

Mice immunized with the vaccine experienced an antithrombotic effect that lasted 84 days.

The vaccine inhibited thrombus formation without the risk of bleeding or adverse autoimmune responses.

The researchers say the vaccine worked as well as clopidogrel.

“Many stroke patients don’t take their blood thinning drugs as prescribed, which makes it more likely they will have another stroke,” said Hironori Nakagami, MD, of Osaka University Graduate School of Medicine in Japan.

“This vaccine might one day help solve this issue since it would only need to be injected periodically.”

Dr. Nakagami and his colleagues described the vaccine in Hypertension.

S100A9 had previously been reported to be a key molecule in the regulation of thrombus formation. The investigators therefore hypothesized that neutralizing S100A9 with a vaccine would provide sustained antithrombotic effects without increasing the risk of bleeding.

First, the researchers selected a region in S100A9 as a candidate target for the vaccine and conjugated it to keyhole limpet hemocyanin (KLH) as a carrier protein.

They also designed a S100A8 peptide vaccine. S100A8 forms a heterodimer with S100A9 but was not known to play a key role in thrombus formation.

The investigators then randomly assigned male C57BL/6J mice to receive either vaccine or KLH only as control.

The researchers vaccinated mice with S100A9 on days 0, 14, 28, and 126 with either 20 µg or 50 µg of S100A9 peptide. Other mice were vaccinated with S100A8 at a dose of 20 µg on days 0 and 14.

The vaccinated mice developed antibodies against either S100A8 or S100A9, the latter at the 50 µg dose of vaccine. The antibodies recognized the recombinant S100A8 and S100A9 without cross reactivity, which suggested specific binding of each induced antibody.

Assessing thrombus formation

The researchers examined the antithrombotic effects of S100A8 or S100A9 in mouse models of thrombotic middle cerebral artery (MCA) occlusion.

Twenty-one days after the final vaccination, mice immunized with S100A9 had significantly delayed MCA occlusion, with a greater antithrombotic effect in the 50 µg group.

This antithrombotic effect, the investigators said, was comparable to that observed in mice treated with clopidogrel at a dose of 6 mg/kg for 2 days.

The S100A8 vaccine did not prevent MCA occlusion, so the researchers focused on the S100A9 vaccine in subsequent experiments.

They studied the vaccine’s antithrombotic effects in a model of common carotid artery (CCA) occlusion and observed results similar to those seen in the MCA model.

Specifically, there was no significant difference in the CCA occlusion time between mice vaccinated with S100A9 and mice treated with clopidogrel.

The investigators also found the antithrombotic effect of the S100A9 vaccine lasted more than 2 months.

Post-stroke model

Dr. Nakagami and his colleagues then examined the antithrombotic effect of S100A9 in mice after a transient MCA stroke.

The researchers administered the S100A9 vaccine every 2 weeks, starting 1 week after the stroke, for a total of three times.

The vaccine induced anti-S100A9 antibodies, and the mice had significantly prolonged CCA occlusion times compared to KLH control mice. (The investigators said they assessed CCA occlusion because it was impossible to measure the regional cerebral blood flow after a transient MCA occlusion due to post-surgical cranial skin adhesions.)

This result suggested that S100A9 could prevent thrombus formation in mice that had already had a stroke.

Hemostatic parameters and safety

Additional experiments indicated that the S100A9 vaccine had no effect on hemostatic parameters as indicated by tail bleeding time, platelet count, activated partial thromboplastin time, and prothrombin time.

The researchers also evaluated the vaccine’s safety by examining immunologic responses.

Histological analysis at day 147 after the first immunization revealed no pathological changes, such as CD4+ T-cell infiltration or activation of F4/80+ microglia/macrophages.

The immunized mice had predominantly IgG1 responses. This indicated that the S100A9 vaccine selectively induced primary T helper 2 responses.

“We are continuing our research in hopes of being able to start clinical trials between 5 and 10 years from now, but there are differences between mice and humans in how the vaccine will be recognized by the immune system,” Dr. Nakagami explained.

“We should be able to overcome such problems and believe this vaccine provides a very promising strategy in secondary prevention of stroke.”

This research was funded by the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Japan Cardiovascular Research Foundation, the SENSHIN Medical Research Foundation, and the Japan Agency for Medical Research and Development.

Dr. Nakagami and five of the eleven authors have applied for a patent for the S100A9 vaccine.

Dr. Nakagami and five other authors are affiliated with departments at Osaka University that receive financial support from AnGes, DAICEL, FunPep, Novartis, Shionogi, Boehringer, and Rohto. One author is a founder, stockholder, and former board member of AnGes.

Lab mouse

Investigators designed an antiplatelet vaccine they say could be a novel therapy to prevent recurrent ischemic stroke.

The vaccine inhibits S100A9 (S100 calcium-binding protein A9)/CD36 (cluster of differentiation 36) signaling in platelets, which is a key signal in arterial thrombosis but not hemostasis.

Mice immunized with the vaccine experienced an antithrombotic effect that lasted 84 days.

The vaccine inhibited thrombus formation without the risk of bleeding or adverse autoimmune responses.

The researchers say the vaccine worked as well as clopidogrel.

“Many stroke patients don’t take their blood thinning drugs as prescribed, which makes it more likely they will have another stroke,” said Hironori Nakagami, MD, of Osaka University Graduate School of Medicine in Japan.

“This vaccine might one day help solve this issue since it would only need to be injected periodically.”

Dr. Nakagami and his colleagues described the vaccine in Hypertension.

S100A9 had previously been reported to be a key molecule in the regulation of thrombus formation. The investigators therefore hypothesized that neutralizing S100A9 with a vaccine would provide sustained antithrombotic effects without increasing the risk of bleeding.

First, the researchers selected a region in S100A9 as a candidate target for the vaccine and conjugated it to keyhole limpet hemocyanin (KLH) as a carrier protein.

They also designed a S100A8 peptide vaccine. S100A8 forms a heterodimer with S100A9 but was not known to play a key role in thrombus formation.

The investigators then randomly assigned male C57BL/6J mice to receive either vaccine or KLH only as control.

The researchers vaccinated mice with S100A9 on days 0, 14, 28, and 126 with either 20 µg or 50 µg of S100A9 peptide. Other mice were vaccinated with S100A8 at a dose of 20 µg on days 0 and 14.

The vaccinated mice developed antibodies against either S100A8 or S100A9, the latter at the 50 µg dose of vaccine. The antibodies recognized the recombinant S100A8 and S100A9 without cross reactivity, which suggested specific binding of each induced antibody.

Assessing thrombus formation

The researchers examined the antithrombotic effects of S100A8 or S100A9 in mouse models of thrombotic middle cerebral artery (MCA) occlusion.

Twenty-one days after the final vaccination, mice immunized with S100A9 had significantly delayed MCA occlusion, with a greater antithrombotic effect in the 50 µg group.

This antithrombotic effect, the investigators said, was comparable to that observed in mice treated with clopidogrel at a dose of 6 mg/kg for 2 days.

The S100A8 vaccine did not prevent MCA occlusion, so the researchers focused on the S100A9 vaccine in subsequent experiments.

They studied the vaccine’s antithrombotic effects in a model of common carotid artery (CCA) occlusion and observed results similar to those seen in the MCA model.

Specifically, there was no significant difference in the CCA occlusion time between mice vaccinated with S100A9 and mice treated with clopidogrel.

The investigators also found the antithrombotic effect of the S100A9 vaccine lasted more than 2 months.

Post-stroke model

Dr. Nakagami and his colleagues then examined the antithrombotic effect of S100A9 in mice after a transient MCA stroke.

The researchers administered the S100A9 vaccine every 2 weeks, starting 1 week after the stroke, for a total of three times.

The vaccine induced anti-S100A9 antibodies, and the mice had significantly prolonged CCA occlusion times compared to KLH control mice. (The investigators said they assessed CCA occlusion because it was impossible to measure the regional cerebral blood flow after a transient MCA occlusion due to post-surgical cranial skin adhesions.)

This result suggested that S100A9 could prevent thrombus formation in mice that had already had a stroke.

Hemostatic parameters and safety

Additional experiments indicated that the S100A9 vaccine had no effect on hemostatic parameters as indicated by tail bleeding time, platelet count, activated partial thromboplastin time, and prothrombin time.

The researchers also evaluated the vaccine’s safety by examining immunologic responses.

Histological analysis at day 147 after the first immunization revealed no pathological changes, such as CD4+ T-cell infiltration or activation of F4/80+ microglia/macrophages.

The immunized mice had predominantly IgG1 responses. This indicated that the S100A9 vaccine selectively induced primary T helper 2 responses.

“We are continuing our research in hopes of being able to start clinical trials between 5 and 10 years from now, but there are differences between mice and humans in how the vaccine will be recognized by the immune system,” Dr. Nakagami explained.

“We should be able to overcome such problems and believe this vaccine provides a very promising strategy in secondary prevention of stroke.”

This research was funded by the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Japan Cardiovascular Research Foundation, the SENSHIN Medical Research Foundation, and the Japan Agency for Medical Research and Development.

Dr. Nakagami and five of the eleven authors have applied for a patent for the S100A9 vaccine.

Dr. Nakagami and five other authors are affiliated with departments at Osaka University that receive financial support from AnGes, DAICEL, FunPep, Novartis, Shionogi, Boehringer, and Rohto. One author is a founder, stockholder, and former board member of AnGes.

Lab mouse

Investigators designed an antiplatelet vaccine they say could be a novel therapy to prevent recurrent ischemic stroke.

The vaccine inhibits S100A9 (S100 calcium-binding protein A9)/CD36 (cluster of differentiation 36) signaling in platelets, which is a key signal in arterial thrombosis but not hemostasis.

Mice immunized with the vaccine experienced an antithrombotic effect that lasted 84 days.

The vaccine inhibited thrombus formation without the risk of bleeding or adverse autoimmune responses.

The researchers say the vaccine worked as well as clopidogrel.

“Many stroke patients don’t take their blood thinning drugs as prescribed, which makes it more likely they will have another stroke,” said Hironori Nakagami, MD, of Osaka University Graduate School of Medicine in Japan.

“This vaccine might one day help solve this issue since it would only need to be injected periodically.”

Dr. Nakagami and his colleagues described the vaccine in Hypertension.

S100A9 had previously been reported to be a key molecule in the regulation of thrombus formation. The investigators therefore hypothesized that neutralizing S100A9 with a vaccine would provide sustained antithrombotic effects without increasing the risk of bleeding.

First, the researchers selected a region in S100A9 as a candidate target for the vaccine and conjugated it to keyhole limpet hemocyanin (KLH) as a carrier protein.

They also designed a S100A8 peptide vaccine. S100A8 forms a heterodimer with S100A9 but was not known to play a key role in thrombus formation.

The investigators then randomly assigned male C57BL/6J mice to receive either vaccine or KLH only as control.

The researchers vaccinated mice with S100A9 on days 0, 14, 28, and 126 with either 20 µg or 50 µg of S100A9 peptide. Other mice were vaccinated with S100A8 at a dose of 20 µg on days 0 and 14.

The vaccinated mice developed antibodies against either S100A8 or S100A9, the latter at the 50 µg dose of vaccine. The antibodies recognized the recombinant S100A8 and S100A9 without cross reactivity, which suggested specific binding of each induced antibody.

Assessing thrombus formation

The researchers examined the antithrombotic effects of S100A8 or S100A9 in mouse models of thrombotic middle cerebral artery (MCA) occlusion.

Twenty-one days after the final vaccination, mice immunized with S100A9 had significantly delayed MCA occlusion, with a greater antithrombotic effect in the 50 µg group.

This antithrombotic effect, the investigators said, was comparable to that observed in mice treated with clopidogrel at a dose of 6 mg/kg for 2 days.

The S100A8 vaccine did not prevent MCA occlusion, so the researchers focused on the S100A9 vaccine in subsequent experiments.

They studied the vaccine’s antithrombotic effects in a model of common carotid artery (CCA) occlusion and observed results similar to those seen in the MCA model.

Specifically, there was no significant difference in the CCA occlusion time between mice vaccinated with S100A9 and mice treated with clopidogrel.

The investigators also found the antithrombotic effect of the S100A9 vaccine lasted more than 2 months.

Post-stroke model

Dr. Nakagami and his colleagues then examined the antithrombotic effect of S100A9 in mice after a transient MCA stroke.

The researchers administered the S100A9 vaccine every 2 weeks, starting 1 week after the stroke, for a total of three times.

The vaccine induced anti-S100A9 antibodies, and the mice had significantly prolonged CCA occlusion times compared to KLH control mice. (The investigators said they assessed CCA occlusion because it was impossible to measure the regional cerebral blood flow after a transient MCA occlusion due to post-surgical cranial skin adhesions.)

This result suggested that S100A9 could prevent thrombus formation in mice that had already had a stroke.

Hemostatic parameters and safety

Additional experiments indicated that the S100A9 vaccine had no effect on hemostatic parameters as indicated by tail bleeding time, platelet count, activated partial thromboplastin time, and prothrombin time.

The researchers also evaluated the vaccine’s safety by examining immunologic responses.

Histological analysis at day 147 after the first immunization revealed no pathological changes, such as CD4+ T-cell infiltration or activation of F4/80+ microglia/macrophages.

The immunized mice had predominantly IgG1 responses. This indicated that the S100A9 vaccine selectively induced primary T helper 2 responses.

“We are continuing our research in hopes of being able to start clinical trials between 5 and 10 years from now, but there are differences between mice and humans in how the vaccine will be recognized by the immune system,” Dr. Nakagami explained.

“We should be able to overcome such problems and believe this vaccine provides a very promising strategy in secondary prevention of stroke.”

This research was funded by the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Japan Cardiovascular Research Foundation, the SENSHIN Medical Research Foundation, and the Japan Agency for Medical Research and Development.

Dr. Nakagami and five of the eleven authors have applied for a patent for the S100A9 vaccine.

Dr. Nakagami and five other authors are affiliated with departments at Osaka University that receive financial support from AnGes, DAICEL, FunPep, Novartis, Shionogi, Boehringer, and Rohto. One author is a founder, stockholder, and former board member of AnGes.

Warfarin tablets

The U.S. Food and Drug Administration (FDA) announced a Class I recall of test strips used with medical devices that monitor warfarin levels, which means use of these strips may cause serious injuries or death.

Roche Diagnostics has recalled certain test strip lots used with its CoaguChek test meter devices.

The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from January 12, 2018, to October 29, 2018.

The test strips are used with the CoaguChek XS plus, CoaguChek XS Pro, CoaguChek XS professional, CoaguChek XS PST, and CoaguChek Vantus test meter devices.

The FDA said patients and healthcare professionals should not rely on these test meter devices to monitor warfarin levels if they’re using test strips affected by the recall. Instead, patients should have blood drawn from a vein and have their levels measured by a laboratory test or use an alternative meter device.

“These strips are widely used, and we are working diligently to warn healthcare providers and the public about the dangers associated with this recall,” said Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.

“Using faulty strips can lead to serious errors in medication dosage that could cause serious harm or death in some patients. We are also working with the company on the swift removal of the recalled strips and to ensure the new corrected strips are distributed to patients and healthcare providers as quickly as possible.”

The FDA’s warning concerning the CoaguChek XS PT Test Strips is based on medical device reports submitted by Roche Diagnostics indicating that the test strips may provide results that are higher than the actual international normalized ratio (INR).

As a result of incorrect INR results, some patients may be prescribed an insufficient warfarin dose or instructed to interrupt warfarin use, which may increase the risk of thrombosis.

Approximately 90 medical device reports and two serious patient injuries involving strokes were reported to the FDA.

Roche Diagnostics attributes the cause of the problem to a recent recalibration of the test strips to a different international standard.

The company plans to provide new batches of recalibrated test strips, based on the previous international standard, to their customers by the end of November.

The FDA reviewed validation data submitted by the company for these recalibrated strips.

Patients who are using CoaguChek meters should contact their healthcare provider to get information about alternative test methods and to address questions regarding their individual testing schedule. Patients should also contact their self-testing service providers to find out when they will be getting their corrected test strips.

For questions about the recall or to report adverse reactions or quality problems, contact Roche Diagnostics Point of Care Technical Service at 1-800-428-4674.

Adverse reactions can also be reported to the FDA through MedWatch, the agency’s voluntary reporting program.

Warfarin tablets

The U.S. Food and Drug Administration (FDA) announced a Class I recall of test strips used with medical devices that monitor warfarin levels, which means use of these strips may cause serious injuries or death.

Roche Diagnostics has recalled certain test strip lots used with its CoaguChek test meter devices.

The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from January 12, 2018, to October 29, 2018.

The test strips are used with the CoaguChek XS plus, CoaguChek XS Pro, CoaguChek XS professional, CoaguChek XS PST, and CoaguChek Vantus test meter devices.

The FDA said patients and healthcare professionals should not rely on these test meter devices to monitor warfarin levels if they’re using test strips affected by the recall. Instead, patients should have blood drawn from a vein and have their levels measured by a laboratory test or use an alternative meter device.

“These strips are widely used, and we are working diligently to warn healthcare providers and the public about the dangers associated with this recall,” said Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.

“Using faulty strips can lead to serious errors in medication dosage that could cause serious harm or death in some patients. We are also working with the company on the swift removal of the recalled strips and to ensure the new corrected strips are distributed to patients and healthcare providers as quickly as possible.”

The FDA’s warning concerning the CoaguChek XS PT Test Strips is based on medical device reports submitted by Roche Diagnostics indicating that the test strips may provide results that are higher than the actual international normalized ratio (INR).

As a result of incorrect INR results, some patients may be prescribed an insufficient warfarin dose or instructed to interrupt warfarin use, which may increase the risk of thrombosis.

Approximately 90 medical device reports and two serious patient injuries involving strokes were reported to the FDA.

Roche Diagnostics attributes the cause of the problem to a recent recalibration of the test strips to a different international standard.

The company plans to provide new batches of recalibrated test strips, based on the previous international standard, to their customers by the end of November.

The FDA reviewed validation data submitted by the company for these recalibrated strips.

Patients who are using CoaguChek meters should contact their healthcare provider to get information about alternative test methods and to address questions regarding their individual testing schedule. Patients should also contact their self-testing service providers to find out when they will be getting their corrected test strips.

For questions about the recall or to report adverse reactions or quality problems, contact Roche Diagnostics Point of Care Technical Service at 1-800-428-4674.

Adverse reactions can also be reported to the FDA through MedWatch, the agency’s voluntary reporting program.

Warfarin tablets

The U.S. Food and Drug Administration (FDA) announced a Class I recall of test strips used with medical devices that monitor warfarin levels, which means use of these strips may cause serious injuries or death.

Roche Diagnostics has recalled certain test strip lots used with its CoaguChek test meter devices.

The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from January 12, 2018, to October 29, 2018.

The test strips are used with the CoaguChek XS plus, CoaguChek XS Pro, CoaguChek XS professional, CoaguChek XS PST, and CoaguChek Vantus test meter devices.

The FDA said patients and healthcare professionals should not rely on these test meter devices to monitor warfarin levels if they’re using test strips affected by the recall. Instead, patients should have blood drawn from a vein and have their levels measured by a laboratory test or use an alternative meter device.

“These strips are widely used, and we are working diligently to warn healthcare providers and the public about the dangers associated with this recall,” said Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.

“Using faulty strips can lead to serious errors in medication dosage that could cause serious harm or death in some patients. We are also working with the company on the swift removal of the recalled strips and to ensure the new corrected strips are distributed to patients and healthcare providers as quickly as possible.”

The FDA’s warning concerning the CoaguChek XS PT Test Strips is based on medical device reports submitted by Roche Diagnostics indicating that the test strips may provide results that are higher than the actual international normalized ratio (INR).

As a result of incorrect INR results, some patients may be prescribed an insufficient warfarin dose or instructed to interrupt warfarin use, which may increase the risk of thrombosis.

Approximately 90 medical device reports and two serious patient injuries involving strokes were reported to the FDA.

Roche Diagnostics attributes the cause of the problem to a recent recalibration of the test strips to a different international standard.

The company plans to provide new batches of recalibrated test strips, based on the previous international standard, to their customers by the end of November.

The FDA reviewed validation data submitted by the company for these recalibrated strips.

Patients who are using CoaguChek meters should contact their healthcare provider to get information about alternative test methods and to address questions regarding their individual testing schedule. Patients should also contact their self-testing service providers to find out when they will be getting their corrected test strips.

For questions about the recall or to report adverse reactions or quality problems, contact Roche Diagnostics Point of Care Technical Service at 1-800-428-4674.

Adverse reactions can also be reported to the FDA through MedWatch, the agency’s voluntary reporting program.

MONTREAL – An extended time window for thrombolytic treatment of acute ischemic stroke patients using tissue plasminogen activator out to 9 hours from stroke onset was safe and effective using CT perfusion imaging and automated imaging processing software to select suitable patients in the EXTEND trial. This result matches the groundbreaking finding reported earlier in 2018 that used MRI to select patients for extended thrombolysis.

“To reproduce our results you need to set up CT perfusion” as well as the RAPID software for automated image processing to identify patients with a small infarct core and a large area of salvageable brain, said Henry Ma, MD, a stroke neurologist at Monash University, Melbourne, as he reported results from the trial at the World Stroke Congress. “EXTEND is the first positive thrombolysis trial in an extended time window using automated penumbral imaging.”

The new finding, from a trial with 225 randomized stroke patients, was especially notable because, by showing the validity of CT imaging for patient selection, it makes applying the extended time window for thrombolytic therapy more feasible for U.S. and Canadian stroke centers where CT imaging is much more common than MRI. A report from European investigators published in August 2018 from the WAKE-UP trial showed that thrombolysis with tissue plasminogen activator (tPA) was safe and effective when administered to patients who woke up with an acute ischemic stroke that had occurred more than 4.5 hours before treatment, but this study exclusively used MRI for patient selection (N Engl J Med. 2018 Aug 16;379[7]:611-22).

“In North America, our systems are more equipped for using CT,” commented Ashfaq Shuaib, MD, a professor of medicine and neurologist at the University of Alberta, Edmonton. Based on the WAKE-UP results, “MR would be preferred, but what we’ve been doing [since the WAKE-UP report] is if we see a CT scan that’s good we go ahead” with thrombolysis.

“Biologically, it doesn’t matter whether you use MR or CT; they both index the same underlying pathology. We’ve been hesitant to go beyond the MR finding from WAKE-UP, where there were data, but the findings from EXTEND were right in line with the WAKE-UP results, and that’s all we need to be reassured” that CT perfusion imaging also works for patient selection, commented Jeffrey L. Saver, MD, professor of medicine and director of the Comprehensive Stroke Center at the University of California, Los Angeles.

CT perfusion imaging and automated image processing “worked to select stroke patients” for an extended time window for treatment with mechanical thrombectomy in the DAWN (N Engl J Med. 2018 Jan 4;378[1]:11-21) and DEFUSE 3 (N Engl J Med. 2018 Feb 22;378[8]:308-18) trials, a history that makes the new finding of successfully using CT imaging to select patients who qualify for extended use of thrombolysis “a convincing result,” Dr. Saver said in an interview. The new EXTEND findings “will have a major impact” on using an extended time window for thrombolysis in U.S. practice, he predicted.

The EXTEND trial (Int J Stroke. 2012 Jan 1;7[1]:74-80) ran at 22 sites in Australia, 11 sites in Taiwan, and 1 center in New Zealand. Recruitment of patients into the study stopped early, after enrolling 225 patients, in June 2018, when results from WAKE-UP came out.

The EXTEND investigators enrolled patients who were either 4.5-9 hours out from the onset of their stroke or patients with a wake-up stroke with an uncertain onset. Participating centers could use either CT perfusion or MRI to identify candidates for treatment, and all used the RAPID software for image processing to identify patients with a perfusion lesion of at least 10 mL and an ischemic core volume no greater than 70 mL. Dr. Ma did not report what percentage of patients underwent imaging with each of these methods, but hinted that clinicians had used CT for a majority of the cases. The study randomized patients to receive either 0.9 mg/kg tPA or placebo, and by the trial protocol none of the enrolled patients received treatment with mechanical thrombectomy.

The trial’s primary endpoint was the percentage of patients with a modified Rankin Scale score of 0 or 1 at 90 days after their stroke, which was achieved by 44% more patients in the tPA group relative to the placebo arm after adjustment for age and baseline stroke severity, a statistically significant difference. The results were also positive for several secondary endpoints, such as recanalization 24 hours after treatment, which occurred in 67% of patients treated with tPA and 37% of the control patients, a statistically significant 68% relative improvement with thrombolysis.

Mortality at 90 days was similar in the two arms – 9% among the placebo patients and 12% among those who received tPA. The rate of symptomatic intracranial hemorrhage 36 hours after treatment was significantly higher among patients treated with tPA at 6%, compared with 1% in the placebo group, but the magnitude of this adverse effect was consistent with rates of intracranial hemorrhages previously reported in other studies of thrombolytic treatment for acute ischemic stroke, Dr. Ma said. The small number of increased intracranial hemorrhages “was not associated with increased mortality, and did not negate the positive result of an improved rate of excellent functional outcomes.”

These findings will likely spur further adoption of imaging processing software of the type used in EXTEND by U.S. stroke centers, Dr. Saver predicted.

“More and more centers have been getting this [software], and now they have two reasons to have it: to identify patients for an extended window for mechanical thrombectomy and to identify patients for an extended window for thrombolysis. It is a compelling case to have the imaging software as widely disseminated as possible. Centers that want to do the best for patients should have this imaging-processing software,” Dr. Saver said.

Dr. Ma and Dr. Shuaib reported no disclosures. Dr. Saver has received research funding and personal fees from Medtronic-Abbott and Neuravia.

[email protected]

SOURCE: Ma H et al. Int J. Stroke. 2018 Oct;13(2S):235, Abstract 1014.

MONTREAL – An extended time window for thrombolytic treatment of acute ischemic stroke patients using tissue plasminogen activator out to 9 hours from stroke onset was safe and effective using CT perfusion imaging and automated imaging processing software to select suitable patients in the EXTEND trial. This result matches the groundbreaking finding reported earlier in 2018 that used MRI to select patients for extended thrombolysis.

“To reproduce our results you need to set up CT perfusion” as well as the RAPID software for automated image processing to identify patients with a small infarct core and a large area of salvageable brain, said Henry Ma, MD, a stroke neurologist at Monash University, Melbourne, as he reported results from the trial at the World Stroke Congress. “EXTEND is the first positive thrombolysis trial in an extended time window using automated penumbral imaging.”

The new finding, from a trial with 225 randomized stroke patients, was especially notable because, by showing the validity of CT imaging for patient selection, it makes applying the extended time window for thrombolytic therapy more feasible for U.S. and Canadian stroke centers where CT imaging is much more common than MRI. A report from European investigators published in August 2018 from the WAKE-UP trial showed that thrombolysis with tissue plasminogen activator (tPA) was safe and effective when administered to patients who woke up with an acute ischemic stroke that had occurred more than 4.5 hours before treatment, but this study exclusively used MRI for patient selection (N Engl J Med. 2018 Aug 16;379[7]:611-22).

“In North America, our systems are more equipped for using CT,” commented Ashfaq Shuaib, MD, a professor of medicine and neurologist at the University of Alberta, Edmonton. Based on the WAKE-UP results, “MR would be preferred, but what we’ve been doing [since the WAKE-UP report] is if we see a CT scan that’s good we go ahead” with thrombolysis.

“Biologically, it doesn’t matter whether you use MR or CT; they both index the same underlying pathology. We’ve been hesitant to go beyond the MR finding from WAKE-UP, where there were data, but the findings from EXTEND were right in line with the WAKE-UP results, and that’s all we need to be reassured” that CT perfusion imaging also works for patient selection, commented Jeffrey L. Saver, MD, professor of medicine and director of the Comprehensive Stroke Center at the University of California, Los Angeles.

CT perfusion imaging and automated image processing “worked to select stroke patients” for an extended time window for treatment with mechanical thrombectomy in the DAWN (N Engl J Med. 2018 Jan 4;378[1]:11-21) and DEFUSE 3 (N Engl J Med. 2018 Feb 22;378[8]:308-18) trials, a history that makes the new finding of successfully using CT imaging to select patients who qualify for extended use of thrombolysis “a convincing result,” Dr. Saver said in an interview. The new EXTEND findings “will have a major impact” on using an extended time window for thrombolysis in U.S. practice, he predicted.

The EXTEND trial (Int J Stroke. 2012 Jan 1;7[1]:74-80) ran at 22 sites in Australia, 11 sites in Taiwan, and 1 center in New Zealand. Recruitment of patients into the study stopped early, after enrolling 225 patients, in June 2018, when results from WAKE-UP came out.

The EXTEND investigators enrolled patients who were either 4.5-9 hours out from the onset of their stroke or patients with a wake-up stroke with an uncertain onset. Participating centers could use either CT perfusion or MRI to identify candidates for treatment, and all used the RAPID software for image processing to identify patients with a perfusion lesion of at least 10 mL and an ischemic core volume no greater than 70 mL. Dr. Ma did not report what percentage of patients underwent imaging with each of these methods, but hinted that clinicians had used CT for a majority of the cases. The study randomized patients to receive either 0.9 mg/kg tPA or placebo, and by the trial protocol none of the enrolled patients received treatment with mechanical thrombectomy.

The trial’s primary endpoint was the percentage of patients with a modified Rankin Scale score of 0 or 1 at 90 days after their stroke, which was achieved by 44% more patients in the tPA group relative to the placebo arm after adjustment for age and baseline stroke severity, a statistically significant difference. The results were also positive for several secondary endpoints, such as recanalization 24 hours after treatment, which occurred in 67% of patients treated with tPA and 37% of the control patients, a statistically significant 68% relative improvement with thrombolysis.

Mortality at 90 days was similar in the two arms – 9% among the placebo patients and 12% among those who received tPA. The rate of symptomatic intracranial hemorrhage 36 hours after treatment was significantly higher among patients treated with tPA at 6%, compared with 1% in the placebo group, but the magnitude of this adverse effect was consistent with rates of intracranial hemorrhages previously reported in other studies of thrombolytic treatment for acute ischemic stroke, Dr. Ma said. The small number of increased intracranial hemorrhages “was not associated with increased mortality, and did not negate the positive result of an improved rate of excellent functional outcomes.”

These findings will likely spur further adoption of imaging processing software of the type used in EXTEND by U.S. stroke centers, Dr. Saver predicted.

“More and more centers have been getting this [software], and now they have two reasons to have it: to identify patients for an extended window for mechanical thrombectomy and to identify patients for an extended window for thrombolysis. It is a compelling case to have the imaging software as widely disseminated as possible. Centers that want to do the best for patients should have this imaging-processing software,” Dr. Saver said.

Dr. Ma and Dr. Shuaib reported no disclosures. Dr. Saver has received research funding and personal fees from Medtronic-Abbott and Neuravia.

[email protected]

SOURCE: Ma H et al. Int J. Stroke. 2018 Oct;13(2S):235, Abstract 1014.

MONTREAL – An extended time window for thrombolytic treatment of acute ischemic stroke patients using tissue plasminogen activator out to 9 hours from stroke onset was safe and effective using CT perfusion imaging and automated imaging processing software to select suitable patients in the EXTEND trial. This result matches the groundbreaking finding reported earlier in 2018 that used MRI to select patients for extended thrombolysis.

“To reproduce our results you need to set up CT perfusion” as well as the RAPID software for automated image processing to identify patients with a small infarct core and a large area of salvageable brain, said Henry Ma, MD, a stroke neurologist at Monash University, Melbourne, as he reported results from the trial at the World Stroke Congress. “EXTEND is the first positive thrombolysis trial in an extended time window using automated penumbral imaging.”

The new finding, from a trial with 225 randomized stroke patients, was especially notable because, by showing the validity of CT imaging for patient selection, it makes applying the extended time window for thrombolytic therapy more feasible for U.S. and Canadian stroke centers where CT imaging is much more common than MRI. A report from European investigators published in August 2018 from the WAKE-UP trial showed that thrombolysis with tissue plasminogen activator (tPA) was safe and effective when administered to patients who woke up with an acute ischemic stroke that had occurred more than 4.5 hours before treatment, but this study exclusively used MRI for patient selection (N Engl J Med. 2018 Aug 16;379[7]:611-22).

“In North America, our systems are more equipped for using CT,” commented Ashfaq Shuaib, MD, a professor of medicine and neurologist at the University of Alberta, Edmonton. Based on the WAKE-UP results, “MR would be preferred, but what we’ve been doing [since the WAKE-UP report] is if we see a CT scan that’s good we go ahead” with thrombolysis.

“Biologically, it doesn’t matter whether you use MR or CT; they both index the same underlying pathology. We’ve been hesitant to go beyond the MR finding from WAKE-UP, where there were data, but the findings from EXTEND were right in line with the WAKE-UP results, and that’s all we need to be reassured” that CT perfusion imaging also works for patient selection, commented Jeffrey L. Saver, MD, professor of medicine and director of the Comprehensive Stroke Center at the University of California, Los Angeles.

CT perfusion imaging and automated image processing “worked to select stroke patients” for an extended time window for treatment with mechanical thrombectomy in the DAWN (N Engl J Med. 2018 Jan 4;378[1]:11-21) and DEFUSE 3 (N Engl J Med. 2018 Feb 22;378[8]:308-18) trials, a history that makes the new finding of successfully using CT imaging to select patients who qualify for extended use of thrombolysis “a convincing result,” Dr. Saver said in an interview. The new EXTEND findings “will have a major impact” on using an extended time window for thrombolysis in U.S. practice, he predicted.

The EXTEND trial (Int J Stroke. 2012 Jan 1;7[1]:74-80) ran at 22 sites in Australia, 11 sites in Taiwan, and 1 center in New Zealand. Recruitment of patients into the study stopped early, after enrolling 225 patients, in June 2018, when results from WAKE-UP came out.

The EXTEND investigators enrolled patients who were either 4.5-9 hours out from the onset of their stroke or patients with a wake-up stroke with an uncertain onset. Participating centers could use either CT perfusion or MRI to identify candidates for treatment, and all used the RAPID software for image processing to identify patients with a perfusion lesion of at least 10 mL and an ischemic core volume no greater than 70 mL. Dr. Ma did not report what percentage of patients underwent imaging with each of these methods, but hinted that clinicians had used CT for a majority of the cases. The study randomized patients to receive either 0.9 mg/kg tPA or placebo, and by the trial protocol none of the enrolled patients received treatment with mechanical thrombectomy.

The trial’s primary endpoint was the percentage of patients with a modified Rankin Scale score of 0 or 1 at 90 days after their stroke, which was achieved by 44% more patients in the tPA group relative to the placebo arm after adjustment for age and baseline stroke severity, a statistically significant difference. The results were also positive for several secondary endpoints, such as recanalization 24 hours after treatment, which occurred in 67% of patients treated with tPA and 37% of the control patients, a statistically significant 68% relative improvement with thrombolysis.

Mortality at 90 days was similar in the two arms – 9% among the placebo patients and 12% among those who received tPA. The rate of symptomatic intracranial hemorrhage 36 hours after treatment was significantly higher among patients treated with tPA at 6%, compared with 1% in the placebo group, but the magnitude of this adverse effect was consistent with rates of intracranial hemorrhages previously reported in other studies of thrombolytic treatment for acute ischemic stroke, Dr. Ma said. The small number of increased intracranial hemorrhages “was not associated with increased mortality, and did not negate the positive result of an improved rate of excellent functional outcomes.”

These findings will likely spur further adoption of imaging processing software of the type used in EXTEND by U.S. stroke centers, Dr. Saver predicted.

“More and more centers have been getting this [software], and now they have two reasons to have it: to identify patients for an extended window for mechanical thrombectomy and to identify patients for an extended window for thrombolysis. It is a compelling case to have the imaging software as widely disseminated as possible. Centers that want to do the best for patients should have this imaging-processing software,” Dr. Saver said.

Dr. Ma and Dr. Shuaib reported no disclosures. Dr. Saver has received research funding and personal fees from Medtronic-Abbott and Neuravia.

[email protected]

SOURCE: Ma H et al. Int J. Stroke. 2018 Oct;13(2S):235, Abstract 1014.

BOSTON – Avoiding missed doses of venous thromboembolism (VTE) prophylaxis could result in a reduction in VTE rates, a speaker said at the annual clinical congress of the American College of Surgeons.

Andrew Bowser/MDedge News

The VTE rate dropped by about one-quarter in the trauma care pathway at the University of Pittsburgh Medical Center (UPMC) after implementation of algorithms to risk-stratify patients and guide nursing staff, said Matthew D. Neal, MD, FACS, the Roberta G. Simmons Assistant Professor of Surgery at the University of Pittsburgh.

By incorporating algorithms into the electronic health record (EHR), UPMC was able to realize a “dramatic” 72% reduction in missed doses, from 4,331 missed doses in 2014 to 1,193 in 2015, Dr. Neal told attendees in a session focused on hot topics in surgical patient safety.

That decrease in missed doses has translated into a decreased rate of VTE, from an already relatively low rate of 1.5% in 2015, to 1.1% in 2017, representing a 26.7% reduction, according to data Dr. Neal shared in his podium presentation.

“This has been a sustainable event for us, largely linked to the implementation of an EHR-guided risk assessment pathway to guide the implementation of VTE prophylaxis,” he said.

The change was safe, he added, noting that, since utilization of this pathway, there have been no significant increases in the rate of bleeding events among patients who have mandatory orders.

These results corroborate those of some previous investigations, including one key study from the Johns Hopkins Hospital that described the adoption of a mandatory computerized clinical decision support tool to improve adherence to best practices for VTE prophylaxis.

After incorporation of the tool in the computerized order entry system, there was a significant increase in VTE prophylaxis, translating into a significant drop in preventable harm from VTE, from 1.0% to 0.17% (P = .04), investigators reported in JAMA Surgery.

Reducing missed doses is one of the major contributing factors to decreased VTE rates, according to Dr. Neal.



Missed doses of enoxaparin correlate with increased incidence of deep vein thrombosis (DVT) in trauma and general surgery patients, according to results of one prospective study Dr. Neal described. In that study of 202 patients, reported in JAMA Surgery, DVTs were seen in 23.5% of patients with missed doses, compared with 4.8 for patients with no missed doses (P < .01).

“We need to understand how to risk assess and how to utilize our EHR as a tool,” Dr. Neal told attendees.

Dr. Neal reported disclosures related to Janssen Pharmaceuticals, CSL Behring, Accriva Diagnostics, and Haemonetics, as well as a U.S. patent for a treatment of infectious and inflammatory disorders, and laboratory funding from the National Institutes of Health, Department of Defense, and the Biomedical Advanced Research and Development Authority.
 

SOURCE: Neal MD. Presentation at the American College of Surgeons Clinical Congress. 2018 Oct 25.

BOSTON – Avoiding missed doses of venous thromboembolism (VTE) prophylaxis could result in a reduction in VTE rates, a speaker said at the annual clinical congress of the American College of Surgeons.

Andrew Bowser/MDedge News

The VTE rate dropped by about one-quarter in the trauma care pathway at the University of Pittsburgh Medical Center (UPMC) after implementation of algorithms to risk-stratify patients and guide nursing staff, said Matthew D. Neal, MD, FACS, the Roberta G. Simmons Assistant Professor of Surgery at the University of Pittsburgh.

By incorporating algorithms into the electronic health record (EHR), UPMC was able to realize a “dramatic” 72% reduction in missed doses, from 4,331 missed doses in 2014 to 1,193 in 2015, Dr. Neal told attendees in a session focused on hot topics in surgical patient safety.

That decrease in missed doses has translated into a decreased rate of VTE, from an already relatively low rate of 1.5% in 2015, to 1.1% in 2017, representing a 26.7% reduction, according to data Dr. Neal shared in his podium presentation.

“This has been a sustainable event for us, largely linked to the implementation of an EHR-guided risk assessment pathway to guide the implementation of VTE prophylaxis,” he said.

The change was safe, he added, noting that, since utilization of this pathway, there have been no significant increases in the rate of bleeding events among patients who have mandatory orders.

These results corroborate those of some previous investigations, including one key study from the Johns Hopkins Hospital that described the adoption of a mandatory computerized clinical decision support tool to improve adherence to best practices for VTE prophylaxis.

After incorporation of the tool in the computerized order entry system, there was a significant increase in VTE prophylaxis, translating into a significant drop in preventable harm from VTE, from 1.0% to 0.17% (P = .04), investigators reported in JAMA Surgery.

Reducing missed doses is one of the major contributing factors to decreased VTE rates, according to Dr. Neal.



Missed doses of enoxaparin correlate with increased incidence of deep vein thrombosis (DVT) in trauma and general surgery patients, according to results of one prospective study Dr. Neal described. In that study of 202 patients, reported in JAMA Surgery, DVTs were seen in 23.5% of patients with missed doses, compared with 4.8 for patients with no missed doses (P < .01).

“We need to understand how to risk assess and how to utilize our EHR as a tool,” Dr. Neal told attendees.

Dr. Neal reported disclosures related to Janssen Pharmaceuticals, CSL Behring, Accriva Diagnostics, and Haemonetics, as well as a U.S. patent for a treatment of infectious and inflammatory disorders, and laboratory funding from the National Institutes of Health, Department of Defense, and the Biomedical Advanced Research and Development Authority.
 

SOURCE: Neal MD. Presentation at the American College of Surgeons Clinical Congress. 2018 Oct 25.

BOSTON – Avoiding missed doses of venous thromboembolism (VTE) prophylaxis could result in a reduction in VTE rates, a speaker said at the annual clinical congress of the American College of Surgeons.

Andrew Bowser/MDedge News

The VTE rate dropped by about one-quarter in the trauma care pathway at the University of Pittsburgh Medical Center (UPMC) after implementation of algorithms to risk-stratify patients and guide nursing staff, said Matthew D. Neal, MD, FACS, the Roberta G. Simmons Assistant Professor of Surgery at the University of Pittsburgh.

By incorporating algorithms into the electronic health record (EHR), UPMC was able to realize a “dramatic” 72% reduction in missed doses, from 4,331 missed doses in 2014 to 1,193 in 2015, Dr. Neal told attendees in a session focused on hot topics in surgical patient safety.

That decrease in missed doses has translated into a decreased rate of VTE, from an already relatively low rate of 1.5% in 2015, to 1.1% in 2017, representing a 26.7% reduction, according to data Dr. Neal shared in his podium presentation.

“This has been a sustainable event for us, largely linked to the implementation of an EHR-guided risk assessment pathway to guide the implementation of VTE prophylaxis,” he said.

The change was safe, he added, noting that, since utilization of this pathway, there have been no significant increases in the rate of bleeding events among patients who have mandatory orders.

These results corroborate those of some previous investigations, including one key study from the Johns Hopkins Hospital that described the adoption of a mandatory computerized clinical decision support tool to improve adherence to best practices for VTE prophylaxis.

After incorporation of the tool in the computerized order entry system, there was a significant increase in VTE prophylaxis, translating into a significant drop in preventable harm from VTE, from 1.0% to 0.17% (P = .04), investigators reported in JAMA Surgery.

Reducing missed doses is one of the major contributing factors to decreased VTE rates, according to Dr. Neal.



Missed doses of enoxaparin correlate with increased incidence of deep vein thrombosis (DVT) in trauma and general surgery patients, according to results of one prospective study Dr. Neal described. In that study of 202 patients, reported in JAMA Surgery, DVTs were seen in 23.5% of patients with missed doses, compared with 4.8 for patients with no missed doses (P < .01).

“We need to understand how to risk assess and how to utilize our EHR as a tool,” Dr. Neal told attendees.

Dr. Neal reported disclosures related to Janssen Pharmaceuticals, CSL Behring, Accriva Diagnostics, and Haemonetics, as well as a U.S. patent for a treatment of infectious and inflammatory disorders, and laboratory funding from the National Institutes of Health, Department of Defense, and the Biomedical Advanced Research and Development Authority.
 

SOURCE: Neal MD. Presentation at the American College of Surgeons Clinical Congress. 2018 Oct 25.

The Food and Drug Administration has granted OMS721 orphan designation for the treatment of hematopoietic stem cell transplant–associated thrombotic microangiopathy (HSCT-TMA).

OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.

The FDA previously granted OMS721 breakthrough therapy designation for HSCT-TMA and orphan designation for the prevention of complement-mediated TMA, including HSCT-TMA.

Omeros, the company developing OMS721, has established a compassionate use program for OMS721, which is active in the United States and Europe.

Phase 3 clinical programs are in progress for OMS721 in atypical hemolytic uremic syndrome, immunoglobulin A nephropathy, and HSCT-TMA. Two phase 2 trials of OMS721 – one in TMA and one in immunoglobulin A nephropathy – are ongoing.

Omeros announced results from the phase 2 TMA trial (NCT02222545) in February. The study includes adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post transplant. Patients receive weekly OMS721 treatments for 4-8 weeks at the discretion of the investigator.

At the time of Omeros’s announcement, 18 HSCT-TMA patients had been treated.

These patients had a significantly longer median overall survival at 347 days, compared with historical controls at 21 days (P less than .0001).

Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.

The mean platelet count increased from 18,100 x 10⁶/mL at baseline to 52,300 x 10⁶/mL (P = .017). The mean lactate dehydrogenase decreased from 591 U/L to 250 U/L (P less than .001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P = .003).

The most commonly reported adverse events were diarrhea and neutropenia. Four deaths occurred during the study. One of these – attributable to acute renal and respiratory failure – was considered possibly related to OMS721.

[email protected]

The Food and Drug Administration has granted OMS721 orphan designation for the treatment of hematopoietic stem cell transplant–associated thrombotic microangiopathy (HSCT-TMA).

OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.

The FDA previously granted OMS721 breakthrough therapy designation for HSCT-TMA and orphan designation for the prevention of complement-mediated TMA, including HSCT-TMA.

Omeros, the company developing OMS721, has established a compassionate use program for OMS721, which is active in the United States and Europe.

Phase 3 clinical programs are in progress for OMS721 in atypical hemolytic uremic syndrome, immunoglobulin A nephropathy, and HSCT-TMA. Two phase 2 trials of OMS721 – one in TMA and one in immunoglobulin A nephropathy – are ongoing.

Omeros announced results from the phase 2 TMA trial (NCT02222545) in February. The study includes adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post transplant. Patients receive weekly OMS721 treatments for 4-8 weeks at the discretion of the investigator.

At the time of Omeros’s announcement, 18 HSCT-TMA patients had been treated.

These patients had a significantly longer median overall survival at 347 days, compared with historical controls at 21 days (P less than .0001).

Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.

The mean platelet count increased from 18,100 x 10⁶/mL at baseline to 52,300 x 10⁶/mL (P = .017). The mean lactate dehydrogenase decreased from 591 U/L to 250 U/L (P less than .001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P = .003).

The most commonly reported adverse events were diarrhea and neutropenia. Four deaths occurred during the study. One of these – attributable to acute renal and respiratory failure – was considered possibly related to OMS721.

[email protected]

The Food and Drug Administration has granted OMS721 orphan designation for the treatment of hematopoietic stem cell transplant–associated thrombotic microangiopathy (HSCT-TMA).

OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.

The FDA previously granted OMS721 breakthrough therapy designation for HSCT-TMA and orphan designation for the prevention of complement-mediated TMA, including HSCT-TMA.

Omeros, the company developing OMS721, has established a compassionate use program for OMS721, which is active in the United States and Europe.

Phase 3 clinical programs are in progress for OMS721 in atypical hemolytic uremic syndrome, immunoglobulin A nephropathy, and HSCT-TMA. Two phase 2 trials of OMS721 – one in TMA and one in immunoglobulin A nephropathy – are ongoing.

Omeros announced results from the phase 2 TMA trial (NCT02222545) in February. The study includes adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post transplant. Patients receive weekly OMS721 treatments for 4-8 weeks at the discretion of the investigator.

At the time of Omeros’s announcement, 18 HSCT-TMA patients had been treated.

These patients had a significantly longer median overall survival at 347 days, compared with historical controls at 21 days (P less than .0001).

Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.

The mean platelet count increased from 18,100 x 10⁶/mL at baseline to 52,300 x 10⁶/mL (P = .017). The mean lactate dehydrogenase decreased from 591 U/L to 250 U/L (P less than .001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P = .003).

The most commonly reported adverse events were diarrhea and neutropenia. Four deaths occurred during the study. One of these – attributable to acute renal and respiratory failure – was considered possibly related to OMS721.

[email protected]

Laparoscopic gynecologic surgery is associated with a significantly lower risk of postoperative venous thromboembolism (VTE) than laparotomy, according to a study published in Obstetrics & Gynecology.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The retrospective cohort study looked at data from 37,485 patients who underwent 43,751 gynecologic surgical procedures, including hysterectomy and myomectomy, at two tertiary care academic hospitals.

Overall, 96 patients (0.2%) were diagnosed with postoperative venous thromboembolism. However patients who underwent laparoscopic or vaginal surgery had a significant 78% and 93% lower risk of venous thromboembolism, respectively, than those who underwent laparotomy, even after adjusting for potential confounders such as age, cancer, race, pharmacologic thromboprophylaxis, and surgical time.

The incidence of postoperative thromboembolism was significantly higher among patients undergoing gynecologic surgery for cancer (1.1%). The incidence among those undergoing surgery for benign indications was only 0.2%, and the highest incidence was among patients with cancer who underwent laparotomy (2.2%).

“This study adds to data demonstrating that venous thromboembolism is rare in gynecologic surgery, particularly when a patient undergoes a minimally invasive procedure for benign indications,” wrote Dr. Elisa M. Jorgensen of Beth Israel Deaconess Medical Center, and her coauthors.

Among the 8,273 patients who underwent a hysterectomy, there were 55 cases of venous thromboembolism – representing an 0.7% incidence. However patients who underwent laparotomy had a 1% incidence of postoperative venous thromboembolism, while those who underwent laparoscopic hysterectomy had an 0.3% incidence and those who underwent vaginal hysterectomy had an 0.1% incidence.

Laparotomy was the most common mode of surgery for hysterectomy – accounting for 57% of operations – while 34% were laparoscopic and 9% were vaginal.

However, the authors noted that the use of laparoscopy increased and laparotomy declined over the 9 years of the study. In 2006, 12% of hysterectomies were laparoscopic, compared with 55% in 2015, while over that same period the percentage of laparotomies dropped from 74% to 41%, and the percentage of vaginal procedures declined from 14% to 4%.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

“Because current practice guidelines do not account for mode of surgery, we find them to be insufficient for the modern gynecologic surgeon to counsel patients on their individual venous thromboembolism risk or to make ideal decisions regarding selection of thromboprophylaxis,” Dr. Jorgenson and her associates wrote.

Only 5 patients of the 2,851 who underwent myomectomy developed postoperative VTE – an overall incidence of 0.2% – and the authors said numbers were too small to analyze. Vaginal or hysteroscopic myomectomy was the most common surgical method, accounting for 62% of procedures, compared with 23% for laparotomies and 15% for laparoscopies.

More than 90% of patients who experienced postoperative thromboembolism had received some form of thromboprophylaxis before surgery, either mechanical, pharmacologic, or both. In comparison, only 55% of the group who didn’t experience thromboembolism had received thromboprophylaxis.

“The high rate of prophylaxis among patients who developed postoperative venous thromboembolism may reflect surgeons’ abilities to preoperatively identify patients at increased risk, guiding appropriate selection of thromboprophylaxis,” Dr. Jorgenson and her associates wrote.

Addressing the study’s limitations, the authors noted that they were not able to capture data on patients’ body mass index and also were unable to account for patients who might have been diagnosed and treated for postoperative VTE at other hospitals.

No conflicts of interest were declared.

SOURCE: Jorgensen EM et al. Obstet Gynecol. 2018 Nov;132:1275-84.

Laparoscopic gynecologic surgery is associated with a significantly lower risk of postoperative venous thromboembolism (VTE) than laparotomy, according to a study published in Obstetrics & Gynecology.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The retrospective cohort study looked at data from 37,485 patients who underwent 43,751 gynecologic surgical procedures, including hysterectomy and myomectomy, at two tertiary care academic hospitals.

Overall, 96 patients (0.2%) were diagnosed with postoperative venous thromboembolism. However patients who underwent laparoscopic or vaginal surgery had a significant 78% and 93% lower risk of venous thromboembolism, respectively, than those who underwent laparotomy, even after adjusting for potential confounders such as age, cancer, race, pharmacologic thromboprophylaxis, and surgical time.

The incidence of postoperative thromboembolism was significantly higher among patients undergoing gynecologic surgery for cancer (1.1%). The incidence among those undergoing surgery for benign indications was only 0.2%, and the highest incidence was among patients with cancer who underwent laparotomy (2.2%).

“This study adds to data demonstrating that venous thromboembolism is rare in gynecologic surgery, particularly when a patient undergoes a minimally invasive procedure for benign indications,” wrote Dr. Elisa M. Jorgensen of Beth Israel Deaconess Medical Center, and her coauthors.

Among the 8,273 patients who underwent a hysterectomy, there were 55 cases of venous thromboembolism – representing an 0.7% incidence. However patients who underwent laparotomy had a 1% incidence of postoperative venous thromboembolism, while those who underwent laparoscopic hysterectomy had an 0.3% incidence and those who underwent vaginal hysterectomy had an 0.1% incidence.

Laparotomy was the most common mode of surgery for hysterectomy – accounting for 57% of operations – while 34% were laparoscopic and 9% were vaginal.

However, the authors noted that the use of laparoscopy increased and laparotomy declined over the 9 years of the study. In 2006, 12% of hysterectomies were laparoscopic, compared with 55% in 2015, while over that same period the percentage of laparotomies dropped from 74% to 41%, and the percentage of vaginal procedures declined from 14% to 4%.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

“Because current practice guidelines do not account for mode of surgery, we find them to be insufficient for the modern gynecologic surgeon to counsel patients on their individual venous thromboembolism risk or to make ideal decisions regarding selection of thromboprophylaxis,” Dr. Jorgenson and her associates wrote.

Only 5 patients of the 2,851 who underwent myomectomy developed postoperative VTE – an overall incidence of 0.2% – and the authors said numbers were too small to analyze. Vaginal or hysteroscopic myomectomy was the most common surgical method, accounting for 62% of procedures, compared with 23% for laparotomies and 15% for laparoscopies.

More than 90% of patients who experienced postoperative thromboembolism had received some form of thromboprophylaxis before surgery, either mechanical, pharmacologic, or both. In comparison, only 55% of the group who didn’t experience thromboembolism had received thromboprophylaxis.

“The high rate of prophylaxis among patients who developed postoperative venous thromboembolism may reflect surgeons’ abilities to preoperatively identify patients at increased risk, guiding appropriate selection of thromboprophylaxis,” Dr. Jorgenson and her associates wrote.

Addressing the study’s limitations, the authors noted that they were not able to capture data on patients’ body mass index and also were unable to account for patients who might have been diagnosed and treated for postoperative VTE at other hospitals.

No conflicts of interest were declared.

SOURCE: Jorgensen EM et al. Obstet Gynecol. 2018 Nov;132:1275-84.

Laparoscopic gynecologic surgery is associated with a significantly lower risk of postoperative venous thromboembolism (VTE) than laparotomy, according to a study published in Obstetrics & Gynecology.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The retrospective cohort study looked at data from 37,485 patients who underwent 43,751 gynecologic surgical procedures, including hysterectomy and myomectomy, at two tertiary care academic hospitals.

Overall, 96 patients (0.2%) were diagnosed with postoperative venous thromboembolism. However patients who underwent laparoscopic or vaginal surgery had a significant 78% and 93% lower risk of venous thromboembolism, respectively, than those who underwent laparotomy, even after adjusting for potential confounders such as age, cancer, race, pharmacologic thromboprophylaxis, and surgical time.

The incidence of postoperative thromboembolism was significantly higher among patients undergoing gynecologic surgery for cancer (1.1%). The incidence among those undergoing surgery for benign indications was only 0.2%, and the highest incidence was among patients with cancer who underwent laparotomy (2.2%).

“This study adds to data demonstrating that venous thromboembolism is rare in gynecologic surgery, particularly when a patient undergoes a minimally invasive procedure for benign indications,” wrote Dr. Elisa M. Jorgensen of Beth Israel Deaconess Medical Center, and her coauthors.

Among the 8,273 patients who underwent a hysterectomy, there were 55 cases of venous thromboembolism – representing an 0.7% incidence. However patients who underwent laparotomy had a 1% incidence of postoperative venous thromboembolism, while those who underwent laparoscopic hysterectomy had an 0.3% incidence and those who underwent vaginal hysterectomy had an 0.1% incidence.

Laparotomy was the most common mode of surgery for hysterectomy – accounting for 57% of operations – while 34% were laparoscopic and 9% were vaginal.

However, the authors noted that the use of laparoscopy increased and laparotomy declined over the 9 years of the study. In 2006, 12% of hysterectomies were laparoscopic, compared with 55% in 2015, while over that same period the percentage of laparotomies dropped from 74% to 41%, and the percentage of vaginal procedures declined from 14% to 4%.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

“Because current practice guidelines do not account for mode of surgery, we find them to be insufficient for the modern gynecologic surgeon to counsel patients on their individual venous thromboembolism risk or to make ideal decisions regarding selection of thromboprophylaxis,” Dr. Jorgenson and her associates wrote.

Only 5 patients of the 2,851 who underwent myomectomy developed postoperative VTE – an overall incidence of 0.2% – and the authors said numbers were too small to analyze. Vaginal or hysteroscopic myomectomy was the most common surgical method, accounting for 62% of procedures, compared with 23% for laparotomies and 15% for laparoscopies.

More than 90% of patients who experienced postoperative thromboembolism had received some form of thromboprophylaxis before surgery, either mechanical, pharmacologic, or both. In comparison, only 55% of the group who didn’t experience thromboembolism had received thromboprophylaxis.

“The high rate of prophylaxis among patients who developed postoperative venous thromboembolism may reflect surgeons’ abilities to preoperatively identify patients at increased risk, guiding appropriate selection of thromboprophylaxis,” Dr. Jorgenson and her associates wrote.

Addressing the study’s limitations, the authors noted that they were not able to capture data on patients’ body mass index and also were unable to account for patients who might have been diagnosed and treated for postoperative VTE at other hospitals.

No conflicts of interest were declared.

SOURCE: Jorgensen EM et al. Obstet Gynecol. 2018 Nov;132:1275-84.

Photo by Sage Ross

Putting patients on aspirin following a knee replacement is a safe, cost-effective alternative to treatment with anticoagulants, according to researchers.

A study of more than 40,000 patients revealed a similar incidence of venous thromboembolism (VTE) or death after total knee arthroplasty (TKA) in patients receiving aspirin and patients receiving anticoagulants.

“Aspirin alone may provide similar protection compared to anticoagulation treatments,” said Brian R. Hallstrom, MD, of the University of Michigan in Ann Arbor.

He and his colleagues compared aspirin to anticoagulants after TKA and detailed their findings in JAMA Surgery.

The researchers evaluated 41,537 patients who underwent TKA and received:

• No pharmacological VTE prophylaxis (n=668; 1.6%)
• Aspirin only (n=12,831; 30.9%)
• Only an anticoagulant (n=22,620; 54.5%)
• Both aspirin and an anticoagulant (n=5418; 13.0%).

Anticoagulants included low-molecular-weight heparin, warfarin, and factor Xa inhibitors.

About 87% of all patients (n=36,113) were also using intermittent pneumatic compression stockings.

Safety and efficacy

The study’s primary outcome was a composite of VTE and death. It occurred in:

• 4.79% (32/668) of patients not on pharmacological prophylaxis
• 1.16% (149/12,831) of patients who received aspirin alone
• 1.42% (321/22,620) of patients on anticoagulation alone
• 1.31% (71/5418) of patients who received both aspirin and anticoagulation.

In a multivariable analysis adjusted for confounding, aspirin was noninferior to the other prophylaxis regimens for the outcome of VTE or death. The adjusted odds ratio was 0.85 (P=0.007).

Bleeding was a secondary outcome of this study, and it occurred in:

• 1.50% (10/668) of patients not on pharmacological prophylaxis
• 0.90% (116/12,831) of patients who received aspirin alone
• 1.14% (258/22,620) of patients who received anticoagulation
• 1.35% (73/5,418) of patients who received both aspirin and anticoagulation.

In an adjusted analysis, aspirin was noninferior to the other prophylaxis regimens for the outcome of bleeding. The adjusted odds ratio was 0.80 (P<0.001).

Other benefits

Aspirin provides other benefits aside from similar safety and efficacy as anticoagulants, according to the researchers.

“Aspirin is easy to take and much less expensive,” Dr. Hallstrom noted. “Patients can get it over the counter for pennies, while the other anticoagulants require monitoring, injections, frequent dose adjustments and are extremely expensive.”

Dr. Hallstrom and his colleagues said the reported cost for a 30-day supply of rivaroxaban is approximately $379 to $450, and the estimated cost of heparin is $450 to $890.

Although warfarin costs a few dollars for a 30-day supply, its cost approaches that of the other anticoagulants when doctor visits for monitoring are factored in, the researchers noted.

In contrast, aspirin costs approximately $2 a month.

Dr. Hallstrom and his colleagues did note that, although this study suggests aspirin can prevent VTE as well as anticoagulants, doctors need to consider factors such as a patient’s history of clots, obesity, and ability to mobilize after surgery.

Photo by Sage Ross

Putting patients on aspirin following a knee replacement is a safe, cost-effective alternative to treatment with anticoagulants, according to researchers.

A study of more than 40,000 patients revealed a similar incidence of venous thromboembolism (VTE) or death after total knee arthroplasty (TKA) in patients receiving aspirin and patients receiving anticoagulants.

“Aspirin alone may provide similar protection compared to anticoagulation treatments,” said Brian R. Hallstrom, MD, of the University of Michigan in Ann Arbor.

He and his colleagues compared aspirin to anticoagulants after TKA and detailed their findings in JAMA Surgery.

The researchers evaluated 41,537 patients who underwent TKA and received:

• No pharmacological VTE prophylaxis (n=668; 1.6%)
• Aspirin only (n=12,831; 30.9%)
• Only an anticoagulant (n=22,620; 54.5%)
• Both aspirin and an anticoagulant (n=5418; 13.0%).

Anticoagulants included low-molecular-weight heparin, warfarin, and factor Xa inhibitors.

About 87% of all patients (n=36,113) were also using intermittent pneumatic compression stockings.

Safety and efficacy

The study’s primary outcome was a composite of VTE and death. It occurred in:

• 4.79% (32/668) of patients not on pharmacological prophylaxis
• 1.16% (149/12,831) of patients who received aspirin alone
• 1.42% (321/22,620) of patients on anticoagulation alone
• 1.31% (71/5418) of patients who received both aspirin and anticoagulation.

In a multivariable analysis adjusted for confounding, aspirin was noninferior to the other prophylaxis regimens for the outcome of VTE or death. The adjusted odds ratio was 0.85 (P=0.007).

Bleeding was a secondary outcome of this study, and it occurred in:

• 1.50% (10/668) of patients not on pharmacological prophylaxis
• 0.90% (116/12,831) of patients who received aspirin alone
• 1.14% (258/22,620) of patients who received anticoagulation
• 1.35% (73/5,418) of patients who received both aspirin and anticoagulation.

In an adjusted analysis, aspirin was noninferior to the other prophylaxis regimens for the outcome of bleeding. The adjusted odds ratio was 0.80 (P<0.001).

Other benefits

Aspirin provides other benefits aside from similar safety and efficacy as anticoagulants, according to the researchers.

“Aspirin is easy to take and much less expensive,” Dr. Hallstrom noted. “Patients can get it over the counter for pennies, while the other anticoagulants require monitoring, injections, frequent dose adjustments and are extremely expensive.”

Dr. Hallstrom and his colleagues said the reported cost for a 30-day supply of rivaroxaban is approximately $379 to $450, and the estimated cost of heparin is $450 to $890.

Although warfarin costs a few dollars for a 30-day supply, its cost approaches that of the other anticoagulants when doctor visits for monitoring are factored in, the researchers noted.

In contrast, aspirin costs approximately $2 a month.

Dr. Hallstrom and his colleagues did note that, although this study suggests aspirin can prevent VTE as well as anticoagulants, doctors need to consider factors such as a patient’s history of clots, obesity, and ability to mobilize after surgery.

Photo by Sage Ross

Putting patients on aspirin following a knee replacement is a safe, cost-effective alternative to treatment with anticoagulants, according to researchers.

A study of more than 40,000 patients revealed a similar incidence of venous thromboembolism (VTE) or death after total knee arthroplasty (TKA) in patients receiving aspirin and patients receiving anticoagulants.

“Aspirin alone may provide similar protection compared to anticoagulation treatments,” said Brian R. Hallstrom, MD, of the University of Michigan in Ann Arbor.

He and his colleagues compared aspirin to anticoagulants after TKA and detailed their findings in JAMA Surgery.

The researchers evaluated 41,537 patients who underwent TKA and received:

• No pharmacological VTE prophylaxis (n=668; 1.6%)
• Aspirin only (n=12,831; 30.9%)
• Only an anticoagulant (n=22,620; 54.5%)
• Both aspirin and an anticoagulant (n=5418; 13.0%).

Anticoagulants included low-molecular-weight heparin, warfarin, and factor Xa inhibitors.

About 87% of all patients (n=36,113) were also using intermittent pneumatic compression stockings.

Safety and efficacy

The study’s primary outcome was a composite of VTE and death. It occurred in:

• 4.79% (32/668) of patients not on pharmacological prophylaxis
• 1.16% (149/12,831) of patients who received aspirin alone
• 1.42% (321/22,620) of patients on anticoagulation alone
• 1.31% (71/5418) of patients who received both aspirin and anticoagulation.

In a multivariable analysis adjusted for confounding, aspirin was noninferior to the other prophylaxis regimens for the outcome of VTE or death. The adjusted odds ratio was 0.85 (P=0.007).

Bleeding was a secondary outcome of this study, and it occurred in:

• 1.50% (10/668) of patients not on pharmacological prophylaxis
• 0.90% (116/12,831) of patients who received aspirin alone
• 1.14% (258/22,620) of patients who received anticoagulation
• 1.35% (73/5,418) of patients who received both aspirin and anticoagulation.

In an adjusted analysis, aspirin was noninferior to the other prophylaxis regimens for the outcome of bleeding. The adjusted odds ratio was 0.80 (P<0.001).

Other benefits

Aspirin provides other benefits aside from similar safety and efficacy as anticoagulants, according to the researchers.

“Aspirin is easy to take and much less expensive,” Dr. Hallstrom noted. “Patients can get it over the counter for pennies, while the other anticoagulants require monitoring, injections, frequent dose adjustments and are extremely expensive.”

Dr. Hallstrom and his colleagues said the reported cost for a 30-day supply of rivaroxaban is approximately $379 to $450, and the estimated cost of heparin is $450 to $890.

Although warfarin costs a few dollars for a 30-day supply, its cost approaches that of the other anticoagulants when doctor visits for monitoring are factored in, the researchers noted.

In contrast, aspirin costs approximately $2 a month.

Dr. Hallstrom and his colleagues did note that, although this study suggests aspirin can prevent VTE as well as anticoagulants, doctors need to consider factors such as a patient’s history of clots, obesity, and ability to mobilize after surgery.

Concerns may be unfounded for risks of earlier-onset cardiovascular disease in men with hemophilia A, according to investigators.

Cardiovascular comorbidities between groups were generally comparable, regardless of hemophilia A status, reported lead author Thomas J. Humphries, MD, of Bayer, and his colleagues.

“To date, there have been conflicting data in the literature regarding the risks of [cardiovascular] comorbidities in patients with hemophilia A, compared with the general population,” the investigators wrote in Advances in Medical Sciences. “Some studies have reported lower mortality from [cardiovascular] diseases and/or decreased atherogenesis in patients with hemophilia … conversely, other reports indicate comparable or higher [cardiovascular] comorbidities in patients with hemophilia, compared with the general population.”

In two previous commercial database reviews conducted by Dr. Humphries and his colleagues, cardiovascular disease appeared to occur more commonly and at a younger age in men with hemophilia A. More concerning, patients aged under 40 years showed elevated incidence of stroke and thrombosis. The authors sought to clarify these findings in the present study.

The retrospective chart review involved 74 men with hemophilia A and 222 men without the condition, matched by study year, payer type, race, and age. Patients presented at any of 31 medical facilities within the Henry Ford Health System in Detroit. Diagnoses were made between Jan. 1, 1995, and Dec. 31, 2014.

For the most part there were no significant differences in cardiovascular disease prevalence between the two cohorts. Rates of hypertension, obesity, coronary artery disease, heart failure, stroke, venous and arterial thrombosis, ventricular arrhythmias, atrial fibrillation, and chronic renal disease were numerically higher in the control group, but those differences were not statistically significant. There were significantly higher prevalence rates for diabetes (P = .0108) and hyperlipidemia (P = .0001) in the control group versus patients with hemophilia A.

The investigators pointed out that meaningful statistical differences using standardized differences were not reached for venous and arterial thrombosis and atrial fibrillation.

“It is worth noting that in the hemophilia A group, hypertension appeared first in the 18- to 29-year age group, as did venous thrombosis,” the investigators wrote, suggesting that monitoring, starting in the late teens, may be warranted.

The investigators also noted multiple study limitations, notably the small sample size, compared with commercial databases that were reviewed in previous studies. Additionally, the severity of disease was unknown for some of the hemophilia A patients and the study only followed patients for 1 year.

“The results of this retrospective chart review did not confirm diffuse statistically significant differences in [cardiovascular] comorbidities and their earlier onset in hemophilia A versus controls,” the investigators concluded.

The study was funded by Bayer. Three of the authors were employed by Bayer when the study was conducted. Other authors reported employment with Xcenda and the Henry Ford Health System and research funding from Xcenda.

SOURCE: Humphries TJ et al. Adv Med Sci. 2018;63(2):329-33.

Concerns may be unfounded for risks of earlier-onset cardiovascular disease in men with hemophilia A, according to investigators.

Cardiovascular comorbidities between groups were generally comparable, regardless of hemophilia A status, reported lead author Thomas J. Humphries, MD, of Bayer, and his colleagues.

“To date, there have been conflicting data in the literature regarding the risks of [cardiovascular] comorbidities in patients with hemophilia A, compared with the general population,” the investigators wrote in Advances in Medical Sciences. “Some studies have reported lower mortality from [cardiovascular] diseases and/or decreased atherogenesis in patients with hemophilia … conversely, other reports indicate comparable or higher [cardiovascular] comorbidities in patients with hemophilia, compared with the general population.”

In two previous commercial database reviews conducted by Dr. Humphries and his colleagues, cardiovascular disease appeared to occur more commonly and at a younger age in men with hemophilia A. More concerning, patients aged under 40 years showed elevated incidence of stroke and thrombosis. The authors sought to clarify these findings in the present study.

The retrospective chart review involved 74 men with hemophilia A and 222 men without the condition, matched by study year, payer type, race, and age. Patients presented at any of 31 medical facilities within the Henry Ford Health System in Detroit. Diagnoses were made between Jan. 1, 1995, and Dec. 31, 2014.

For the most part there were no significant differences in cardiovascular disease prevalence between the two cohorts. Rates of hypertension, obesity, coronary artery disease, heart failure, stroke, venous and arterial thrombosis, ventricular arrhythmias, atrial fibrillation, and chronic renal disease were numerically higher in the control group, but those differences were not statistically significant. There were significantly higher prevalence rates for diabetes (P = .0108) and hyperlipidemia (P = .0001) in the control group versus patients with hemophilia A.

The investigators pointed out that meaningful statistical differences using standardized differences were not reached for venous and arterial thrombosis and atrial fibrillation.

“It is worth noting that in the hemophilia A group, hypertension appeared first in the 18- to 29-year age group, as did venous thrombosis,” the investigators wrote, suggesting that monitoring, starting in the late teens, may be warranted.

The investigators also noted multiple study limitations, notably the small sample size, compared with commercial databases that were reviewed in previous studies. Additionally, the severity of disease was unknown for some of the hemophilia A patients and the study only followed patients for 1 year.

“The results of this retrospective chart review did not confirm diffuse statistically significant differences in [cardiovascular] comorbidities and their earlier onset in hemophilia A versus controls,” the investigators concluded.

The study was funded by Bayer. Three of the authors were employed by Bayer when the study was conducted. Other authors reported employment with Xcenda and the Henry Ford Health System and research funding from Xcenda.

SOURCE: Humphries TJ et al. Adv Med Sci. 2018;63(2):329-33.

Concerns may be unfounded for risks of earlier-onset cardiovascular disease in men with hemophilia A, according to investigators.

Cardiovascular comorbidities between groups were generally comparable, regardless of hemophilia A status, reported lead author Thomas J. Humphries, MD, of Bayer, and his colleagues.

“To date, there have been conflicting data in the literature regarding the risks of [cardiovascular] comorbidities in patients with hemophilia A, compared with the general population,” the investigators wrote in Advances in Medical Sciences. “Some studies have reported lower mortality from [cardiovascular] diseases and/or decreased atherogenesis in patients with hemophilia … conversely, other reports indicate comparable or higher [cardiovascular] comorbidities in patients with hemophilia, compared with the general population.”

In two previous commercial database reviews conducted by Dr. Humphries and his colleagues, cardiovascular disease appeared to occur more commonly and at a younger age in men with hemophilia A. More concerning, patients aged under 40 years showed elevated incidence of stroke and thrombosis. The authors sought to clarify these findings in the present study.

The retrospective chart review involved 74 men with hemophilia A and 222 men without the condition, matched by study year, payer type, race, and age. Patients presented at any of 31 medical facilities within the Henry Ford Health System in Detroit. Diagnoses were made between Jan. 1, 1995, and Dec. 31, 2014.

For the most part there were no significant differences in cardiovascular disease prevalence between the two cohorts. Rates of hypertension, obesity, coronary artery disease, heart failure, stroke, venous and arterial thrombosis, ventricular arrhythmias, atrial fibrillation, and chronic renal disease were numerically higher in the control group, but those differences were not statistically significant. There were significantly higher prevalence rates for diabetes (P = .0108) and hyperlipidemia (P = .0001) in the control group versus patients with hemophilia A.

The investigators pointed out that meaningful statistical differences using standardized differences were not reached for venous and arterial thrombosis and atrial fibrillation.

“It is worth noting that in the hemophilia A group, hypertension appeared first in the 18- to 29-year age group, as did venous thrombosis,” the investigators wrote, suggesting that monitoring, starting in the late teens, may be warranted.

The investigators also noted multiple study limitations, notably the small sample size, compared with commercial databases that were reviewed in previous studies. Additionally, the severity of disease was unknown for some of the hemophilia A patients and the study only followed patients for 1 year.

“The results of this retrospective chart review did not confirm diffuse statistically significant differences in [cardiovascular] comorbidities and their earlier onset in hemophilia A versus controls,” the investigators concluded.

The study was funded by Bayer. Three of the authors were employed by Bayer when the study was conducted. Other authors reported employment with Xcenda and the Henry Ford Health System and research funding from Xcenda.

SOURCE: Humphries TJ et al. Adv Med Sci. 2018;63(2):329-33.