Thrombosis

Background: Anticoagulation for at-risk medical populations for posthospitalization thromboprophylaxis has been investigated in previous studies demonstrating a benefit in reducing risk of asymptomatic deep-vein thrombosis (DVT) development, but no studies have examined symptomatic DVTs.

Dr. Imber is an assistant professor in the division of hospital medicine, University of New Mexico.

Background: Anticoagulation for at-risk medical populations for posthospitalization thromboprophylaxis has been investigated in previous studies demonstrating a benefit in reducing risk of asymptomatic deep-vein thrombosis (DVT) development, but no studies have examined symptomatic DVTs.

Dr. Imber is an assistant professor in the division of hospital medicine, University of New Mexico.

Background: Anticoagulation for at-risk medical populations for posthospitalization thromboprophylaxis has been investigated in previous studies demonstrating a benefit in reducing risk of asymptomatic deep-vein thrombosis (DVT) development, but no studies have examined symptomatic DVTs.

Dr. Imber is an assistant professor in the division of hospital medicine, University of New Mexico.

Novartis has recalled three lots of 12.5-mg eltrombopag (Promacta) for oral suspension following discovery of possible contamination with peanut flour at a third-party manufacturing site.

Tablets at doses of 12.5 mg, 25 mg, 50 mg, and 75 mg are unaffected by this recall because they are not manufactured in the same facility. The recalled lots of medication were distributed between January and April 2019, but so far, Novartis has not received any reports of adverse events related to the recall.

Oral suspension of eltrombopag is indicated for certain patients with chronic immune thrombocytopenia, hepatitis C–associated thrombocytopenia, and severe aplastic anemia.

More information on the recalled lots and instructions on how to return the product can be found in the full announcement, which is also available through the Food and Drug Administration website.

[email protected]

Novartis has recalled three lots of 12.5-mg eltrombopag (Promacta) for oral suspension following discovery of possible contamination with peanut flour at a third-party manufacturing site.

Tablets at doses of 12.5 mg, 25 mg, 50 mg, and 75 mg are unaffected by this recall because they are not manufactured in the same facility. The recalled lots of medication were distributed between January and April 2019, but so far, Novartis has not received any reports of adverse events related to the recall.

Oral suspension of eltrombopag is indicated for certain patients with chronic immune thrombocytopenia, hepatitis C–associated thrombocytopenia, and severe aplastic anemia.

More information on the recalled lots and instructions on how to return the product can be found in the full announcement, which is also available through the Food and Drug Administration website.

[email protected]

Novartis has recalled three lots of 12.5-mg eltrombopag (Promacta) for oral suspension following discovery of possible contamination with peanut flour at a third-party manufacturing site.

Tablets at doses of 12.5 mg, 25 mg, 50 mg, and 75 mg are unaffected by this recall because they are not manufactured in the same facility. The recalled lots of medication were distributed between January and April 2019, but so far, Novartis has not received any reports of adverse events related to the recall.

Oral suspension of eltrombopag is indicated for certain patients with chronic immune thrombocytopenia, hepatitis C–associated thrombocytopenia, and severe aplastic anemia.

More information on the recalled lots and instructions on how to return the product can be found in the full announcement, which is also available through the Food and Drug Administration website.

[email protected]

GLASGOW – Neurological abnormalities and elevated troponin predict mortality in patients with thrombotic thrombocytopenic purpura (TTP), according to retrospective analysis of 475 patients from the United Kingdom TTP registry.

Will Pass/MDedge News

In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.

Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.

“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”

To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.

The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.

Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).

The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.

In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).

Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 10⁹/L.

Median platelet count upon presentation was 15 x 10⁹/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 10⁹/L.

Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.

Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.

The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.

Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.

Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).

“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”

The investigators reported having no conflicts of interest.
 

GLASGOW – Neurological abnormalities and elevated troponin predict mortality in patients with thrombotic thrombocytopenic purpura (TTP), according to retrospective analysis of 475 patients from the United Kingdom TTP registry.

Will Pass/MDedge News

In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.

Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.

“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”

To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.

The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.

Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).

The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.

In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).

Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 10⁹/L.

Median platelet count upon presentation was 15 x 10⁹/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 10⁹/L.

Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.

Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.

The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.

Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.

Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).

“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”

The investigators reported having no conflicts of interest.
 

GLASGOW – Neurological abnormalities and elevated troponin predict mortality in patients with thrombotic thrombocytopenic purpura (TTP), according to retrospective analysis of 475 patients from the United Kingdom TTP registry.

Will Pass/MDedge News

In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.

Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.

“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”

To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.

The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.

Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).

The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.

In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).

Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 10⁹/L.

Median platelet count upon presentation was 15 x 10⁹/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 10⁹/L.

Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.

Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.

The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.

Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.

Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).

“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”

The investigators reported having no conflicts of interest.
 

NEW ORLEANS – In STEMI patients who aren’t able to undergo primary PCI, ticagrelor after fibrinolytic therapy offered no advantages over clopidogrel – a less potent and less costly antiplatelet agent – in rates of cardiovascular events or bleeding though 12 months of follow-up in the TREAT trial.

Bruce Jancin/MDedge News

“In terms of efficacy, it is appropriate to interpret TREAT statistically as a neutral trial,” Otavio Berwanger, MD, PhD, advised at the annual meeting of the American College of Cardiology.

TREAT (Ticagrelor in patients with ST-elevation myocardial infarction treated with pharmacological thrombolysis) was a 10-country, 152-site, randomized, open-label clinical trial of 3,799 STEMI (ST-elevation MI) patients treated with fibrinolytic therapy followed an average of 11 hours later by a loading dose of either ticagrelor (Brilinta) or clopidogrel, then 12 months of standard-dose maintenance therapy of their designated potent antiplatelet drug. The adherence rate was 90% at 12 months. Participating countries included Russia, China, Brazil, Australia, and Canada, but not the United States.

The primary efficacy endpoint was the 12-month composite of death from a vascular cause, MI, stroke, severe recurrent ischemia, TIA, or another arterial thrombotic event. The rate was 8% in the ticagrelor group and 9.1% with clopidogrel, a 12% relative risk reduction in favor of ticagrelor that was not statistically significant. But then, TREAT was underpowered to show a difference in efficacy. However, the 12% relative risk reduction mirrors that seen in the earlier PLATO trial of 18,624 patients with acute coronary syndrome who were randomized to ticagrelor or clopidogrel in conjunction with primary PCI, a difference that was statistically significant because of PLATO’s much larger size (N Engl J Med. 2009 Sep 10;361[11]:1045-57).

TREAT was sufficiently powered to assess safety. There was no significant between-group difference in TIMI major bleeding, the primary safety endpoint. However, the rate of total bleeding events was significantly higher in the ticagrelor arm, by a margin of 10.25% versus 6.15%. Moreover, the rate of TIMI clinically significant bleeding requiring medical attention was also higher in the ticagrelor group – 5.2% versus 3.8% – and the TIMI minimal bleeding rate of 5.85% in the ticagrelor group was more than double that in the clopidogrel arm, reported Dr. Berwanger of the Heart Hospital Research Institute in São Paolo.

These 12-month outcomes echo those previously reported at the 30-day mark in TREAT (JAMA Cardiol. 2018 May 1;3[5]:391-9).

Discussant C. Michael Gibson, MD, put TREAT in perspective: “Here we’re looking to see if there are differences between two thienopyridine inhibitors. There’s nothing really that important on the efficacy side, although there was 1.5% missingness in the study. And there was a higher number of total bleeds with ticagrelor.

“Some of the junior members of the audience may not be all that familiar with fibrinolysis. In the era where it was more prominent, reocclusion occurred in 5%-8% of patients. When it did occur, it led to a tripling of mortality. It’s important to note that the first study of a thienopyridine inhibitor added to lytics was CLARITY, almost 15 years ago, showing a reduction in death, MI, or reocclusion down from about 15% to 7% [N Engl J Med 2005; 352:1179-89]. So it should be very clear to the audience that reocclusion is a problem and the addition of a thienopyridine inhibitor improves that,” explained Dr. Gibson, professor of medicine at Harvard Medical School, Boston.

The TREAT trial was funded by AstraZeneca. Dr. Berwanger reported receiving research grants from and serving as a consultant to that company and half a dozen others.

Simultaneously with the presentation, the TREAT study was published online (J Am Coll Cardiol. 2019 Mar 12. doi: 10.1016/j.jacc.2019.03.011).

[email protected]

NEW ORLEANS – In STEMI patients who aren’t able to undergo primary PCI, ticagrelor after fibrinolytic therapy offered no advantages over clopidogrel – a less potent and less costly antiplatelet agent – in rates of cardiovascular events or bleeding though 12 months of follow-up in the TREAT trial.

Bruce Jancin/MDedge News

“In terms of efficacy, it is appropriate to interpret TREAT statistically as a neutral trial,” Otavio Berwanger, MD, PhD, advised at the annual meeting of the American College of Cardiology.

TREAT (Ticagrelor in patients with ST-elevation myocardial infarction treated with pharmacological thrombolysis) was a 10-country, 152-site, randomized, open-label clinical trial of 3,799 STEMI (ST-elevation MI) patients treated with fibrinolytic therapy followed an average of 11 hours later by a loading dose of either ticagrelor (Brilinta) or clopidogrel, then 12 months of standard-dose maintenance therapy of their designated potent antiplatelet drug. The adherence rate was 90% at 12 months. Participating countries included Russia, China, Brazil, Australia, and Canada, but not the United States.

The primary efficacy endpoint was the 12-month composite of death from a vascular cause, MI, stroke, severe recurrent ischemia, TIA, or another arterial thrombotic event. The rate was 8% in the ticagrelor group and 9.1% with clopidogrel, a 12% relative risk reduction in favor of ticagrelor that was not statistically significant. But then, TREAT was underpowered to show a difference in efficacy. However, the 12% relative risk reduction mirrors that seen in the earlier PLATO trial of 18,624 patients with acute coronary syndrome who were randomized to ticagrelor or clopidogrel in conjunction with primary PCI, a difference that was statistically significant because of PLATO’s much larger size (N Engl J Med. 2009 Sep 10;361[11]:1045-57).

TREAT was sufficiently powered to assess safety. There was no significant between-group difference in TIMI major bleeding, the primary safety endpoint. However, the rate of total bleeding events was significantly higher in the ticagrelor arm, by a margin of 10.25% versus 6.15%. Moreover, the rate of TIMI clinically significant bleeding requiring medical attention was also higher in the ticagrelor group – 5.2% versus 3.8% – and the TIMI minimal bleeding rate of 5.85% in the ticagrelor group was more than double that in the clopidogrel arm, reported Dr. Berwanger of the Heart Hospital Research Institute in São Paolo.

These 12-month outcomes echo those previously reported at the 30-day mark in TREAT (JAMA Cardiol. 2018 May 1;3[5]:391-9).

Discussant C. Michael Gibson, MD, put TREAT in perspective: “Here we’re looking to see if there are differences between two thienopyridine inhibitors. There’s nothing really that important on the efficacy side, although there was 1.5% missingness in the study. And there was a higher number of total bleeds with ticagrelor.

“Some of the junior members of the audience may not be all that familiar with fibrinolysis. In the era where it was more prominent, reocclusion occurred in 5%-8% of patients. When it did occur, it led to a tripling of mortality. It’s important to note that the first study of a thienopyridine inhibitor added to lytics was CLARITY, almost 15 years ago, showing a reduction in death, MI, or reocclusion down from about 15% to 7% [N Engl J Med 2005; 352:1179-89]. So it should be very clear to the audience that reocclusion is a problem and the addition of a thienopyridine inhibitor improves that,” explained Dr. Gibson, professor of medicine at Harvard Medical School, Boston.

The TREAT trial was funded by AstraZeneca. Dr. Berwanger reported receiving research grants from and serving as a consultant to that company and half a dozen others.

Simultaneously with the presentation, the TREAT study was published online (J Am Coll Cardiol. 2019 Mar 12. doi: 10.1016/j.jacc.2019.03.011).

[email protected]

NEW ORLEANS – In STEMI patients who aren’t able to undergo primary PCI, ticagrelor after fibrinolytic therapy offered no advantages over clopidogrel – a less potent and less costly antiplatelet agent – in rates of cardiovascular events or bleeding though 12 months of follow-up in the TREAT trial.

Bruce Jancin/MDedge News

“In terms of efficacy, it is appropriate to interpret TREAT statistically as a neutral trial,” Otavio Berwanger, MD, PhD, advised at the annual meeting of the American College of Cardiology.

TREAT (Ticagrelor in patients with ST-elevation myocardial infarction treated with pharmacological thrombolysis) was a 10-country, 152-site, randomized, open-label clinical trial of 3,799 STEMI (ST-elevation MI) patients treated with fibrinolytic therapy followed an average of 11 hours later by a loading dose of either ticagrelor (Brilinta) or clopidogrel, then 12 months of standard-dose maintenance therapy of their designated potent antiplatelet drug. The adherence rate was 90% at 12 months. Participating countries included Russia, China, Brazil, Australia, and Canada, but not the United States.

The primary efficacy endpoint was the 12-month composite of death from a vascular cause, MI, stroke, severe recurrent ischemia, TIA, or another arterial thrombotic event. The rate was 8% in the ticagrelor group and 9.1% with clopidogrel, a 12% relative risk reduction in favor of ticagrelor that was not statistically significant. But then, TREAT was underpowered to show a difference in efficacy. However, the 12% relative risk reduction mirrors that seen in the earlier PLATO trial of 18,624 patients with acute coronary syndrome who were randomized to ticagrelor or clopidogrel in conjunction with primary PCI, a difference that was statistically significant because of PLATO’s much larger size (N Engl J Med. 2009 Sep 10;361[11]:1045-57).

TREAT was sufficiently powered to assess safety. There was no significant between-group difference in TIMI major bleeding, the primary safety endpoint. However, the rate of total bleeding events was significantly higher in the ticagrelor arm, by a margin of 10.25% versus 6.15%. Moreover, the rate of TIMI clinically significant bleeding requiring medical attention was also higher in the ticagrelor group – 5.2% versus 3.8% – and the TIMI minimal bleeding rate of 5.85% in the ticagrelor group was more than double that in the clopidogrel arm, reported Dr. Berwanger of the Heart Hospital Research Institute in São Paolo.

These 12-month outcomes echo those previously reported at the 30-day mark in TREAT (JAMA Cardiol. 2018 May 1;3[5]:391-9).

Discussant C. Michael Gibson, MD, put TREAT in perspective: “Here we’re looking to see if there are differences between two thienopyridine inhibitors. There’s nothing really that important on the efficacy side, although there was 1.5% missingness in the study. And there was a higher number of total bleeds with ticagrelor.

“Some of the junior members of the audience may not be all that familiar with fibrinolysis. In the era where it was more prominent, reocclusion occurred in 5%-8% of patients. When it did occur, it led to a tripling of mortality. It’s important to note that the first study of a thienopyridine inhibitor added to lytics was CLARITY, almost 15 years ago, showing a reduction in death, MI, or reocclusion down from about 15% to 7% [N Engl J Med 2005; 352:1179-89]. So it should be very clear to the audience that reocclusion is a problem and the addition of a thienopyridine inhibitor improves that,” explained Dr. Gibson, professor of medicine at Harvard Medical School, Boston.

The TREAT trial was funded by AstraZeneca. Dr. Berwanger reported receiving research grants from and serving as a consultant to that company and half a dozen others.

Simultaneously with the presentation, the TREAT study was published online (J Am Coll Cardiol. 2019 Mar 12. doi: 10.1016/j.jacc.2019.03.011).

[email protected]

Clinical question: Is an oral direct factor Xa inhibitor an effective alternative to low-molecular-weight heparin (LMWH) in treating cancer related venous thromboembolism (VTE)?

Background: LMWH has been the standard of care for treatment in patients with VTE and cancer. A newer class of drug, the direct factor Xa inhibitors, have been shown to be noninferior to vitamin K antagonists (VKAs) in treatment of VTE in noncancer patients, but little is known about their use in patients with cancer.

Study Design: Randomized, open-label, multicenter pilot trial.

Setting: United Kingdom; patients were recruited through the Clinical Trials Unit at the University of Warwick, Coventry.

Synopsis: The authors randomly assigned 406 cancer patients with diagnosed VTE either to the LMWH group or to the oral direct factor Xa inhibitor group to evaluate the primary endpoint of VTE reoccurrence and secondary endpoints of major bleeding or clinically relevant but not major bleeding (CRNMB). Rivaroxaban was noninferior to dalteparin in preventing VTE reoccurrence, with a 6-month VTE reoccurrence rate for dalteparin of 11% (95% confidence interval, 7%-16%) and a reoccurrence rate of 6% for rivaroxaban (95% CI, 2%-9%). Rates of major bleeding events were similar, although patients with esophageal or gastroesophageal cancers tended to experience more major bleeds with rivaroxaban than with dalteparin (4 of 11 vs. 1 of 19). CRNMB was 4% for dalteparin and 13% for rivaroxaban (hazard ratio, 3.76; 95% CI, 1.64-8.69). Limitations include slow recruitment, high mortality rate, and the treatment length being only 6 months.

Bottom line: In this small study, rivaroxaban was equally effective at reducing the rate of reoccurrence of cancer related VTE at 6 months but had higher rates of CRNMB. Patients with GI cancers may be at higher risk for major GI bleeding with rivaroxaban.

Citation: Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10. 36(20):2017-23.

Dr. Marten is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Clinical question: Is an oral direct factor Xa inhibitor an effective alternative to low-molecular-weight heparin (LMWH) in treating cancer related venous thromboembolism (VTE)?

Background: LMWH has been the standard of care for treatment in patients with VTE and cancer. A newer class of drug, the direct factor Xa inhibitors, have been shown to be noninferior to vitamin K antagonists (VKAs) in treatment of VTE in noncancer patients, but little is known about their use in patients with cancer.

Study Design: Randomized, open-label, multicenter pilot trial.

Setting: United Kingdom; patients were recruited through the Clinical Trials Unit at the University of Warwick, Coventry.

Synopsis: The authors randomly assigned 406 cancer patients with diagnosed VTE either to the LMWH group or to the oral direct factor Xa inhibitor group to evaluate the primary endpoint of VTE reoccurrence and secondary endpoints of major bleeding or clinically relevant but not major bleeding (CRNMB). Rivaroxaban was noninferior to dalteparin in preventing VTE reoccurrence, with a 6-month VTE reoccurrence rate for dalteparin of 11% (95% confidence interval, 7%-16%) and a reoccurrence rate of 6% for rivaroxaban (95% CI, 2%-9%). Rates of major bleeding events were similar, although patients with esophageal or gastroesophageal cancers tended to experience more major bleeds with rivaroxaban than with dalteparin (4 of 11 vs. 1 of 19). CRNMB was 4% for dalteparin and 13% for rivaroxaban (hazard ratio, 3.76; 95% CI, 1.64-8.69). Limitations include slow recruitment, high mortality rate, and the treatment length being only 6 months.

Bottom line: In this small study, rivaroxaban was equally effective at reducing the rate of reoccurrence of cancer related VTE at 6 months but had higher rates of CRNMB. Patients with GI cancers may be at higher risk for major GI bleeding with rivaroxaban.

Citation: Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10. 36(20):2017-23.

Dr. Marten is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Clinical question: Is an oral direct factor Xa inhibitor an effective alternative to low-molecular-weight heparin (LMWH) in treating cancer related venous thromboembolism (VTE)?

Background: LMWH has been the standard of care for treatment in patients with VTE and cancer. A newer class of drug, the direct factor Xa inhibitors, have been shown to be noninferior to vitamin K antagonists (VKAs) in treatment of VTE in noncancer patients, but little is known about their use in patients with cancer.

Study Design: Randomized, open-label, multicenter pilot trial.

Setting: United Kingdom; patients were recruited through the Clinical Trials Unit at the University of Warwick, Coventry.

Synopsis: The authors randomly assigned 406 cancer patients with diagnosed VTE either to the LMWH group or to the oral direct factor Xa inhibitor group to evaluate the primary endpoint of VTE reoccurrence and secondary endpoints of major bleeding or clinically relevant but not major bleeding (CRNMB). Rivaroxaban was noninferior to dalteparin in preventing VTE reoccurrence, with a 6-month VTE reoccurrence rate for dalteparin of 11% (95% confidence interval, 7%-16%) and a reoccurrence rate of 6% for rivaroxaban (95% CI, 2%-9%). Rates of major bleeding events were similar, although patients with esophageal or gastroesophageal cancers tended to experience more major bleeds with rivaroxaban than with dalteparin (4 of 11 vs. 1 of 19). CRNMB was 4% for dalteparin and 13% for rivaroxaban (hazard ratio, 3.76; 95% CI, 1.64-8.69). Limitations include slow recruitment, high mortality rate, and the treatment length being only 6 months.

Bottom line: In this small study, rivaroxaban was equally effective at reducing the rate of reoccurrence of cancer related VTE at 6 months but had higher rates of CRNMB. Patients with GI cancers may be at higher risk for major GI bleeding with rivaroxaban.

Citation: Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10. 36(20):2017-23.

Dr. Marten is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Clinical question: How does inferior vena cava (IVC) filter placement affect 30-day mortality in patients with venous thromboembolism (VTE) with increased risk of bleeding when anticoagulation is not feasible?

Background: Standard treatment for VTE, including deep venous thrombosis (DVT) and pulmonary embolism (PE), is anticoagulation. However, for patients with active bleeding or increased risk of bleeding, anticoagulation may be contraindicated. In these circumstances, placing an IVC filter is recommended by major professional societies; however, the mortality benefit of IVC filter placement is uncertain.

Study design: A retrospective cohort study.

Setting: State Inpatient and Emergency Department Databases from California, Florida, and New York hospitals from 2005 to 2012.

Synopsis: The authors compared the 30-day mortality rates in 45,771 hospitalized adult patients with inpatient diagnosis codes of PE and/or DVT, as well as a contraindication to anticoagulation, who underwent IVC filter placement with 80,259 similar patients who did not undergo IVC filter placement. Baseline characteristics and coexisting conditions were similar in the two populations. The authors found that patients with IVC filter placement had an increased risk of 30-day mortality, compared with patients without an IVC filter placed (HR, 1.18; 95% CI, 1.13-1.22; P less than .001).

This study used observational data derived from reimbursement codes, which lacked unmeasured confounders (for example, severity of VTE and fragility score), so randomized, controlled trials are required to confirm the results. Nevertheless, this study should prompt physicians to carefully consider decisions to place an IVC filter in the setting of a contraindication to anticoagulation.

Bottom line: IVC filter placement in patients with VTE and contraindication for anticoagulation was associated with an increased 30-day mortality. Randomized, controlled trials are required to confirm the observed results.

Citation: Turner TE et al. Association of inferior vena cava filter placement for venous thromboembolic disease and a contraindication to anticoagulation with 30-day mortality. JAMA Network Open. 2018;1(3):e180452.

Dr. Kobaidze is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Clinical question: How does inferior vena cava (IVC) filter placement affect 30-day mortality in patients with venous thromboembolism (VTE) with increased risk of bleeding when anticoagulation is not feasible?

Background: Standard treatment for VTE, including deep venous thrombosis (DVT) and pulmonary embolism (PE), is anticoagulation. However, for patients with active bleeding or increased risk of bleeding, anticoagulation may be contraindicated. In these circumstances, placing an IVC filter is recommended by major professional societies; however, the mortality benefit of IVC filter placement is uncertain.

Study design: A retrospective cohort study.

Setting: State Inpatient and Emergency Department Databases from California, Florida, and New York hospitals from 2005 to 2012.

Synopsis: The authors compared the 30-day mortality rates in 45,771 hospitalized adult patients with inpatient diagnosis codes of PE and/or DVT, as well as a contraindication to anticoagulation, who underwent IVC filter placement with 80,259 similar patients who did not undergo IVC filter placement. Baseline characteristics and coexisting conditions were similar in the two populations. The authors found that patients with IVC filter placement had an increased risk of 30-day mortality, compared with patients without an IVC filter placed (HR, 1.18; 95% CI, 1.13-1.22; P less than .001).

This study used observational data derived from reimbursement codes, which lacked unmeasured confounders (for example, severity of VTE and fragility score), so randomized, controlled trials are required to confirm the results. Nevertheless, this study should prompt physicians to carefully consider decisions to place an IVC filter in the setting of a contraindication to anticoagulation.

Bottom line: IVC filter placement in patients with VTE and contraindication for anticoagulation was associated with an increased 30-day mortality. Randomized, controlled trials are required to confirm the observed results.

Citation: Turner TE et al. Association of inferior vena cava filter placement for venous thromboembolic disease and a contraindication to anticoagulation with 30-day mortality. JAMA Network Open. 2018;1(3):e180452.

Dr. Kobaidze is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Clinical question: How does inferior vena cava (IVC) filter placement affect 30-day mortality in patients with venous thromboembolism (VTE) with increased risk of bleeding when anticoagulation is not feasible?

Background: Standard treatment for VTE, including deep venous thrombosis (DVT) and pulmonary embolism (PE), is anticoagulation. However, for patients with active bleeding or increased risk of bleeding, anticoagulation may be contraindicated. In these circumstances, placing an IVC filter is recommended by major professional societies; however, the mortality benefit of IVC filter placement is uncertain.

Study design: A retrospective cohort study.

Setting: State Inpatient and Emergency Department Databases from California, Florida, and New York hospitals from 2005 to 2012.

Synopsis: The authors compared the 30-day mortality rates in 45,771 hospitalized adult patients with inpatient diagnosis codes of PE and/or DVT, as well as a contraindication to anticoagulation, who underwent IVC filter placement with 80,259 similar patients who did not undergo IVC filter placement. Baseline characteristics and coexisting conditions were similar in the two populations. The authors found that patients with IVC filter placement had an increased risk of 30-day mortality, compared with patients without an IVC filter placed (HR, 1.18; 95% CI, 1.13-1.22; P less than .001).

This study used observational data derived from reimbursement codes, which lacked unmeasured confounders (for example, severity of VTE and fragility score), so randomized, controlled trials are required to confirm the results. Nevertheless, this study should prompt physicians to carefully consider decisions to place an IVC filter in the setting of a contraindication to anticoagulation.

Bottom line: IVC filter placement in patients with VTE and contraindication for anticoagulation was associated with an increased 30-day mortality. Randomized, controlled trials are required to confirm the observed results.

Citation: Turner TE et al. Association of inferior vena cava filter placement for venous thromboembolic disease and a contraindication to anticoagulation with 30-day mortality. JAMA Network Open. 2018;1(3):e180452.

Dr. Kobaidze is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.

A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.

“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”

In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”

Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).

These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).

During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.

“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”

Once in circulation, histones can make a bad situation even worse.

“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”

“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.

Based on this hypothesis, the investigators developed an anti-histone therapy.

“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”

Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said. 

Concluding his presentation, he looked to the future.

“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.

“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.

The investigators declared no conflicts of interest.

SOURCE: Moxon et al. BSH 2019. Abstract OR-034.

GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.

A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.

“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”

In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”

Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).

These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).

During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.

“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”

Once in circulation, histones can make a bad situation even worse.

“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”

“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.

Based on this hypothesis, the investigators developed an anti-histone therapy.

“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”

Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said. 

Concluding his presentation, he looked to the future.

“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.

“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.

The investigators declared no conflicts of interest.

SOURCE: Moxon et al. BSH 2019. Abstract OR-034.

GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.

A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.

“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”

In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”

Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).

These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).

During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.

“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”

Once in circulation, histones can make a bad situation even worse.

“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”

“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.

Based on this hypothesis, the investigators developed an anti-histone therapy.

“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”

Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said. 

Concluding his presentation, he looked to the future.

“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.

“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.

The investigators declared no conflicts of interest.

SOURCE: Moxon et al. BSH 2019. Abstract OR-034.

NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.

“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.

Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.

“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.

The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.

The only adverse events observed in blinded assessment were minor injection site issues.

PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.

[email protected]

NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.

“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.

Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.

“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.

The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.

The only adverse events observed in blinded assessment were minor injection site issues.

PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.

[email protected]

NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.

“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.

Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.

“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.

The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.

The only adverse events observed in blinded assessment were minor injection site issues.

PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.

[email protected]

NEW ORLEANS – The incidence of pulmonary embolism diagnosed in hospitalized U.S. patients nearly doubled during the period 2004-2015 based on data collected by the National Inpatient Sample.

During 2004-2015 the incidence of all diagnosed pulmonary embolism (PE), based on discharge diagnoses, rose from 5.4 cases/1,000 hospitalized patients in 2004 to 9.7 cases/1,000 hospitalized patients in 2015, an 80% increase, Joshua B. Goldberg, MD said at the annual meeting of the American College of Cardiology. The incidence of major PE – defined as a patient who needed vasopressor treatment, mechanical ventilation, or had nonseptic shock – rose from 7.9% of all hospitalized PE diagnoses in 2004 to 9.7% in 2015, a 23% relative increase.

Mitchel L. Zoler/MDedge News

The data also documented a shifting pattern of treatment for all hospitalized patients with PE, and especially among patients with major PE. During the study period, treatment with systemic thrombolysis for all PE rose nearly threefold, and catheter-directed therapy began to show a steady rise in use from 0.2% of all patients in 2011 (and before) to 1% of all patients by 2015. Surgical intervention remained lightly used throughout, with about 0.2% of all PE patients undergoing surgery annually.

Most of these intervention options focused on patients with major PE. Among patients in this subgroup with more severe disease, use of one of these three types of interventions rose from 6% in 2004 to 12% in 2015, mostly driven by a rise in systemic thrombolysis, which jumped from 3% of major PE in 2004 to 9% in 2015. However, the efficacy of systemic thrombolysis in patients with major PE remains suspect. In 2004, 39% of patients with major PE treated with systemic thrombolysis died in hospital; in 2015 the number was 47%. “The data don’t support using systemic thrombolysis to treat major PE; the mortality is high,” noted Dr. Goldberg, a cardiothoracic surgeon at Westchester Medical Center in Valhalla, N.Y.

Although catheter-directed therapy began to be much more widely used in U.S. practice starting in about 2015, during the period studied its use for major PE held fairly steady at roughly 2%-3%, but this approach also showed substantial shortcomings for the major PE population. These sicker patients treated with catheter-directed therapy had 37% mortality in 2004 and a 31% mortality in 2015, a difference that was not statistically significant. In general, PE patients enrolled in the catheter-directed therapy trials were not as sick as the major PE patients who get treated with surgery in routine practice, Dr. Goldberg said in an interview.

The data showed much better performance using surgery, although only 1,237 patients of the entire group of 713,083 PE patients studied in the database underwent surgical embolectomy. Overall, in-hospital mortality in these patients was 22%, but in a time trend analysis, mortality among all PE patients treated with surgery fell from 32% in 2004 to 14% in 2015; among patients with major PE treated with surgery, mortality fell from 52% in 2004 to 21% in 2015.

Dr. Goldberg attributed the success of surgery in severe PE patients to the definitive nature of embolectomy and the concurrent use of extracorporeal membrane oxygenation that helps stabilize acutely ill PE patients. He also cited refinements that surgery underwent during the 2004-2015 period based on the experience managing chronic thromboembolic pulmonary hypertension, including routine use of cardiopulmonary bypass during surgery. “Very high risk [PE] patients should go straight to surgery, unless the patient is at high risk for surgery because of conditions like prior sternotomy or very advanced age, in which case catheter-directed therapy may be a safer option, he said. He cited a recent 5% death rate after surgery at his center among patients with major PE who did not require cardiopulmonary resuscitation.

The database Dr. Goldberg and his collaborator reviewed included 12,735 patients treated by systemic thrombolysis, and 2,595 treated by catheter-directed therapy. Patients averaged 63 years old. The most common indicator of major PE was mechanical ventilation, used on 8% of all PE patients in the study. Non-septic shock occurred in 2%, and just under 1% needed vasopressor treatment.

Published guidelines on PE management from several medical groups are “vague and have numerous caveats,” Dr. Goldberg said. He is participating in an update to the 2011 PE management statement from the American College of Cardiology and American Heart Association (Circulation. 2011 April 26;123[16]:1788-1830).

The study received no commercial funding. Dr. Goldberg had no disclosures.

[email protected]

SOURCE: Haider A et al. J Amer Coll Cardiol. 2019 March;73:9[suppl 1]: doi: 10.1016/S0735-1097(19)32507-0

NEW ORLEANS – The incidence of pulmonary embolism diagnosed in hospitalized U.S. patients nearly doubled during the period 2004-2015 based on data collected by the National Inpatient Sample.

During 2004-2015 the incidence of all diagnosed pulmonary embolism (PE), based on discharge diagnoses, rose from 5.4 cases/1,000 hospitalized patients in 2004 to 9.7 cases/1,000 hospitalized patients in 2015, an 80% increase, Joshua B. Goldberg, MD said at the annual meeting of the American College of Cardiology. The incidence of major PE – defined as a patient who needed vasopressor treatment, mechanical ventilation, or had nonseptic shock – rose from 7.9% of all hospitalized PE diagnoses in 2004 to 9.7% in 2015, a 23% relative increase.

Mitchel L. Zoler/MDedge News

The data also documented a shifting pattern of treatment for all hospitalized patients with PE, and especially among patients with major PE. During the study period, treatment with systemic thrombolysis for all PE rose nearly threefold, and catheter-directed therapy began to show a steady rise in use from 0.2% of all patients in 2011 (and before) to 1% of all patients by 2015. Surgical intervention remained lightly used throughout, with about 0.2% of all PE patients undergoing surgery annually.

Most of these intervention options focused on patients with major PE. Among patients in this subgroup with more severe disease, use of one of these three types of interventions rose from 6% in 2004 to 12% in 2015, mostly driven by a rise in systemic thrombolysis, which jumped from 3% of major PE in 2004 to 9% in 2015. However, the efficacy of systemic thrombolysis in patients with major PE remains suspect. In 2004, 39% of patients with major PE treated with systemic thrombolysis died in hospital; in 2015 the number was 47%. “The data don’t support using systemic thrombolysis to treat major PE; the mortality is high,” noted Dr. Goldberg, a cardiothoracic surgeon at Westchester Medical Center in Valhalla, N.Y.

Although catheter-directed therapy began to be much more widely used in U.S. practice starting in about 2015, during the period studied its use for major PE held fairly steady at roughly 2%-3%, but this approach also showed substantial shortcomings for the major PE population. These sicker patients treated with catheter-directed therapy had 37% mortality in 2004 and a 31% mortality in 2015, a difference that was not statistically significant. In general, PE patients enrolled in the catheter-directed therapy trials were not as sick as the major PE patients who get treated with surgery in routine practice, Dr. Goldberg said in an interview.

The data showed much better performance using surgery, although only 1,237 patients of the entire group of 713,083 PE patients studied in the database underwent surgical embolectomy. Overall, in-hospital mortality in these patients was 22%, but in a time trend analysis, mortality among all PE patients treated with surgery fell from 32% in 2004 to 14% in 2015; among patients with major PE treated with surgery, mortality fell from 52% in 2004 to 21% in 2015.

Dr. Goldberg attributed the success of surgery in severe PE patients to the definitive nature of embolectomy and the concurrent use of extracorporeal membrane oxygenation that helps stabilize acutely ill PE patients. He also cited refinements that surgery underwent during the 2004-2015 period based on the experience managing chronic thromboembolic pulmonary hypertension, including routine use of cardiopulmonary bypass during surgery. “Very high risk [PE] patients should go straight to surgery, unless the patient is at high risk for surgery because of conditions like prior sternotomy or very advanced age, in which case catheter-directed therapy may be a safer option, he said. He cited a recent 5% death rate after surgery at his center among patients with major PE who did not require cardiopulmonary resuscitation.

The database Dr. Goldberg and his collaborator reviewed included 12,735 patients treated by systemic thrombolysis, and 2,595 treated by catheter-directed therapy. Patients averaged 63 years old. The most common indicator of major PE was mechanical ventilation, used on 8% of all PE patients in the study. Non-septic shock occurred in 2%, and just under 1% needed vasopressor treatment.

Published guidelines on PE management from several medical groups are “vague and have numerous caveats,” Dr. Goldberg said. He is participating in an update to the 2011 PE management statement from the American College of Cardiology and American Heart Association (Circulation. 2011 April 26;123[16]:1788-1830).

The study received no commercial funding. Dr. Goldberg had no disclosures.

[email protected]

SOURCE: Haider A et al. J Amer Coll Cardiol. 2019 March;73:9[suppl 1]: doi: 10.1016/S0735-1097(19)32507-0

NEW ORLEANS – The incidence of pulmonary embolism diagnosed in hospitalized U.S. patients nearly doubled during the period 2004-2015 based on data collected by the National Inpatient Sample.

During 2004-2015 the incidence of all diagnosed pulmonary embolism (PE), based on discharge diagnoses, rose from 5.4 cases/1,000 hospitalized patients in 2004 to 9.7 cases/1,000 hospitalized patients in 2015, an 80% increase, Joshua B. Goldberg, MD said at the annual meeting of the American College of Cardiology. The incidence of major PE – defined as a patient who needed vasopressor treatment, mechanical ventilation, or had nonseptic shock – rose from 7.9% of all hospitalized PE diagnoses in 2004 to 9.7% in 2015, a 23% relative increase.

Mitchel L. Zoler/MDedge News

The data also documented a shifting pattern of treatment for all hospitalized patients with PE, and especially among patients with major PE. During the study period, treatment with systemic thrombolysis for all PE rose nearly threefold, and catheter-directed therapy began to show a steady rise in use from 0.2% of all patients in 2011 (and before) to 1% of all patients by 2015. Surgical intervention remained lightly used throughout, with about 0.2% of all PE patients undergoing surgery annually.

Most of these intervention options focused on patients with major PE. Among patients in this subgroup with more severe disease, use of one of these three types of interventions rose from 6% in 2004 to 12% in 2015, mostly driven by a rise in systemic thrombolysis, which jumped from 3% of major PE in 2004 to 9% in 2015. However, the efficacy of systemic thrombolysis in patients with major PE remains suspect. In 2004, 39% of patients with major PE treated with systemic thrombolysis died in hospital; in 2015 the number was 47%. “The data don’t support using systemic thrombolysis to treat major PE; the mortality is high,” noted Dr. Goldberg, a cardiothoracic surgeon at Westchester Medical Center in Valhalla, N.Y.

Although catheter-directed therapy began to be much more widely used in U.S. practice starting in about 2015, during the period studied its use for major PE held fairly steady at roughly 2%-3%, but this approach also showed substantial shortcomings for the major PE population. These sicker patients treated with catheter-directed therapy had 37% mortality in 2004 and a 31% mortality in 2015, a difference that was not statistically significant. In general, PE patients enrolled in the catheter-directed therapy trials were not as sick as the major PE patients who get treated with surgery in routine practice, Dr. Goldberg said in an interview.

The data showed much better performance using surgery, although only 1,237 patients of the entire group of 713,083 PE patients studied in the database underwent surgical embolectomy. Overall, in-hospital mortality in these patients was 22%, but in a time trend analysis, mortality among all PE patients treated with surgery fell from 32% in 2004 to 14% in 2015; among patients with major PE treated with surgery, mortality fell from 52% in 2004 to 21% in 2015.

Dr. Goldberg attributed the success of surgery in severe PE patients to the definitive nature of embolectomy and the concurrent use of extracorporeal membrane oxygenation that helps stabilize acutely ill PE patients. He also cited refinements that surgery underwent during the 2004-2015 period based on the experience managing chronic thromboembolic pulmonary hypertension, including routine use of cardiopulmonary bypass during surgery. “Very high risk [PE] patients should go straight to surgery, unless the patient is at high risk for surgery because of conditions like prior sternotomy or very advanced age, in which case catheter-directed therapy may be a safer option, he said. He cited a recent 5% death rate after surgery at his center among patients with major PE who did not require cardiopulmonary resuscitation.

The database Dr. Goldberg and his collaborator reviewed included 12,735 patients treated by systemic thrombolysis, and 2,595 treated by catheter-directed therapy. Patients averaged 63 years old. The most common indicator of major PE was mechanical ventilation, used on 8% of all PE patients in the study. Non-septic shock occurred in 2%, and just under 1% needed vasopressor treatment.

Published guidelines on PE management from several medical groups are “vague and have numerous caveats,” Dr. Goldberg said. He is participating in an update to the 2011 PE management statement from the American College of Cardiology and American Heart Association (Circulation. 2011 April 26;123[16]:1788-1830).

The study received no commercial funding. Dr. Goldberg had no disclosures.

[email protected]

SOURCE: Haider A et al. J Amer Coll Cardiol. 2019 March;73:9[suppl 1]: doi: 10.1016/S0735-1097(19)32507-0

Antithrombotic therapy with low-dose rivaroxaban plus aspirin should be considered in low–bleeding risk patients with peripheral arterial disease who are at increased risk for ischemic and/or limb events, according to an analysis of the COMPASS trial published in Current Opinion in Cardiology.

Patrice Wendling/MDedge News

Mohamad A. Hussain, MD, of the University of Toronto and his colleagues assessed the ramifications of COMPASS to vascular surgeons. They used two clinical case studies of patients with peripheral arterial disease (PAD) to illustrate differing considerations in care.

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that low-dose rivaroxaban at 2.5 mg twice daily plus daily aspirin was superior to aspirin alone in reducing major adverse cardiovascular and cerebrovascular events, as well as major adverse limb events, among patients with stable atherosclerotic vascular disease, including those with PAD. However, the risk for major bleeding was higher with rivaroxaban plus aspirin and is a serious consideration for patient treatment.

In clinical case 1, used to illustrate the pertinence of COMPASS to patient care, Dr. Hussain and his colleagues detailed a 68-year-old man presenting with a 3-month history of intermittent claudication of bilateral calves at 10 minutes of brisk walking. His comorbidities include a MI with percutaneous coronary stenting 2 years ago, diabetes mellitus, hypertension, hyperlipidemia, and chronic obstructive pulmonary disease on the basis of prior smoking.

Clinical case 2 was a 70-year-old woman with a small gangrenous ulcer on the dorsal part of her first toe on the left foot. She has history of coronary artery disease with coronary artery bypass graft surgery 5 years prior, diabetes mellitus, mild chronic kidney disease, and hypertension. She underwent an uneventful lower extremity bypass using a prosthetic graft and had an uncomplicated postoperative course.

Both patients were on daily 81 mg aspirin.

In order to determine the appropriate care for these patients, the authors presented a flowchart of considerations regarding risk and benefits. Patients with symptomatic PAD who had no recent major bleeds, history of stroke, congestive heart failure, chronic kidney disease, frailty, or anemia were considered for rivaroxaban treatment, otherwise they were put on single antiplatelet therapy.

The investigators recommended that, if the patients were at high limb risk or high ischemic risk, they should be treated with either rivaroxaban plus aspirin or dual antiplatelet therapy (the latter if there was a recent MI or peripheral stenting). If the patients were not at risk, they were deemed eligible for either the rivaroxaban plus aspirin therapy or single antiplatelet therapy.

With regard to the clinical case studies, the authors discussed the rationale for putting both patients on the rivaroxaban plus aspirin therapy after an assessment of the risk/benefit profile for each patient based upon the above considerations. In both cases the bleeding risk was considered low; the ischemic risk in the first patient and the limb risk in the second patient was considered high. Although the second patient had chronic kidney disease, it was not considered severe enough to preclude such treatment.

“Future data from trials such as Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization For Peripheral Artery Disease [VOYAGER PAD] will provide data with regards to the role of low-dose rivaroxaban plus aspirin following peripheral artery revascularization for PAD,” the researchers concluded.

Dr. Hussain reported having no conflicts; his coauthors reported receiving funding from various pharmaceutical companies, including Bayer, which was a sponsor of the original COMPASS trial.

[email protected]

SOURCE: Hussain MA et al. Curr Opin Cardiol. 2019;34:178-84.

Antithrombotic therapy with low-dose rivaroxaban plus aspirin should be considered in low–bleeding risk patients with peripheral arterial disease who are at increased risk for ischemic and/or limb events, according to an analysis of the COMPASS trial published in Current Opinion in Cardiology.

Patrice Wendling/MDedge News

Mohamad A. Hussain, MD, of the University of Toronto and his colleagues assessed the ramifications of COMPASS to vascular surgeons. They used two clinical case studies of patients with peripheral arterial disease (PAD) to illustrate differing considerations in care.

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that low-dose rivaroxaban at 2.5 mg twice daily plus daily aspirin was superior to aspirin alone in reducing major adverse cardiovascular and cerebrovascular events, as well as major adverse limb events, among patients with stable atherosclerotic vascular disease, including those with PAD. However, the risk for major bleeding was higher with rivaroxaban plus aspirin and is a serious consideration for patient treatment.

In clinical case 1, used to illustrate the pertinence of COMPASS to patient care, Dr. Hussain and his colleagues detailed a 68-year-old man presenting with a 3-month history of intermittent claudication of bilateral calves at 10 minutes of brisk walking. His comorbidities include a MI with percutaneous coronary stenting 2 years ago, diabetes mellitus, hypertension, hyperlipidemia, and chronic obstructive pulmonary disease on the basis of prior smoking.

Clinical case 2 was a 70-year-old woman with a small gangrenous ulcer on the dorsal part of her first toe on the left foot. She has history of coronary artery disease with coronary artery bypass graft surgery 5 years prior, diabetes mellitus, mild chronic kidney disease, and hypertension. She underwent an uneventful lower extremity bypass using a prosthetic graft and had an uncomplicated postoperative course.

Both patients were on daily 81 mg aspirin.

In order to determine the appropriate care for these patients, the authors presented a flowchart of considerations regarding risk and benefits. Patients with symptomatic PAD who had no recent major bleeds, history of stroke, congestive heart failure, chronic kidney disease, frailty, or anemia were considered for rivaroxaban treatment, otherwise they were put on single antiplatelet therapy.

The investigators recommended that, if the patients were at high limb risk or high ischemic risk, they should be treated with either rivaroxaban plus aspirin or dual antiplatelet therapy (the latter if there was a recent MI or peripheral stenting). If the patients were not at risk, they were deemed eligible for either the rivaroxaban plus aspirin therapy or single antiplatelet therapy.

With regard to the clinical case studies, the authors discussed the rationale for putting both patients on the rivaroxaban plus aspirin therapy after an assessment of the risk/benefit profile for each patient based upon the above considerations. In both cases the bleeding risk was considered low; the ischemic risk in the first patient and the limb risk in the second patient was considered high. Although the second patient had chronic kidney disease, it was not considered severe enough to preclude such treatment.

“Future data from trials such as Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization For Peripheral Artery Disease [VOYAGER PAD] will provide data with regards to the role of low-dose rivaroxaban plus aspirin following peripheral artery revascularization for PAD,” the researchers concluded.

Dr. Hussain reported having no conflicts; his coauthors reported receiving funding from various pharmaceutical companies, including Bayer, which was a sponsor of the original COMPASS trial.

[email protected]

SOURCE: Hussain MA et al. Curr Opin Cardiol. 2019;34:178-84.

Antithrombotic therapy with low-dose rivaroxaban plus aspirin should be considered in low–bleeding risk patients with peripheral arterial disease who are at increased risk for ischemic and/or limb events, according to an analysis of the COMPASS trial published in Current Opinion in Cardiology.

Patrice Wendling/MDedge News

Mohamad A. Hussain, MD, of the University of Toronto and his colleagues assessed the ramifications of COMPASS to vascular surgeons. They used two clinical case studies of patients with peripheral arterial disease (PAD) to illustrate differing considerations in care.

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that low-dose rivaroxaban at 2.5 mg twice daily plus daily aspirin was superior to aspirin alone in reducing major adverse cardiovascular and cerebrovascular events, as well as major adverse limb events, among patients with stable atherosclerotic vascular disease, including those with PAD. However, the risk for major bleeding was higher with rivaroxaban plus aspirin and is a serious consideration for patient treatment.

In clinical case 1, used to illustrate the pertinence of COMPASS to patient care, Dr. Hussain and his colleagues detailed a 68-year-old man presenting with a 3-month history of intermittent claudication of bilateral calves at 10 minutes of brisk walking. His comorbidities include a MI with percutaneous coronary stenting 2 years ago, diabetes mellitus, hypertension, hyperlipidemia, and chronic obstructive pulmonary disease on the basis of prior smoking.

Clinical case 2 was a 70-year-old woman with a small gangrenous ulcer on the dorsal part of her first toe on the left foot. She has history of coronary artery disease with coronary artery bypass graft surgery 5 years prior, diabetes mellitus, mild chronic kidney disease, and hypertension. She underwent an uneventful lower extremity bypass using a prosthetic graft and had an uncomplicated postoperative course.

Both patients were on daily 81 mg aspirin.

In order to determine the appropriate care for these patients, the authors presented a flowchart of considerations regarding risk and benefits. Patients with symptomatic PAD who had no recent major bleeds, history of stroke, congestive heart failure, chronic kidney disease, frailty, or anemia were considered for rivaroxaban treatment, otherwise they were put on single antiplatelet therapy.

The investigators recommended that, if the patients were at high limb risk or high ischemic risk, they should be treated with either rivaroxaban plus aspirin or dual antiplatelet therapy (the latter if there was a recent MI or peripheral stenting). If the patients were not at risk, they were deemed eligible for either the rivaroxaban plus aspirin therapy or single antiplatelet therapy.

With regard to the clinical case studies, the authors discussed the rationale for putting both patients on the rivaroxaban plus aspirin therapy after an assessment of the risk/benefit profile for each patient based upon the above considerations. In both cases the bleeding risk was considered low; the ischemic risk in the first patient and the limb risk in the second patient was considered high. Although the second patient had chronic kidney disease, it was not considered severe enough to preclude such treatment.

“Future data from trials such as Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization For Peripheral Artery Disease [VOYAGER PAD] will provide data with regards to the role of low-dose rivaroxaban plus aspirin following peripheral artery revascularization for PAD,” the researchers concluded.

Dr. Hussain reported having no conflicts; his coauthors reported receiving funding from various pharmaceutical companies, including Bayer, which was a sponsor of the original COMPASS trial.

[email protected]

SOURCE: Hussain MA et al. Curr Opin Cardiol. 2019;34:178-84.