Anticoagulation Hub

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

After the American Academy of Pediatrics (AAP) began recommending vitamin K shots for newborns in 1961, infant bleeding as a result of vitamin K deficiency plummeted. The life-threatening disorder is so rare that some parents now question the need for injections to safeguard against it.

The situation amounts to “a failure of our success,” Ivan Hand, MD, a coauthor of a new AAP statement on vitamin K, told this news organization. Much like diseases that can be prevented with vaccines, vitamin K deficiency bleeding isn’t top of mind for parents. “It’s not something they’re aware of or afraid of,” he said.

In 2019, however, the AAP listed public education about the importance of the shots in its 10 most important priorities.

The policy update urges clinicians to bone up on the benefits and perceived risks of vitamin K deficiency, which is essential for clotting, and to “strongly advocate” for the shot in discussions with parents who may get competing messages from their social circles, the internet, and other health care professionals.

Dr. Hand, director of neonatology at NYC Health + Hospitals Kings County, Brooklyn, said clinicians walk a line between educating and alienating parents who favor natural birth processes. “We’re hoping that by talking to the families and answering their questions and explaining the risks, parents will accept vitamin K as a necessary treatment for their babies,” he said.

Vitamin K does not easily pass through the placenta and is not plentiful in breast milk, the preferred nutrition source for newborns. It takes months for babies to build their stores through food and gut bacteria.

Infants who do not receive vitamin K at birth are 81 times more likely to develop late-onset vitamin K deficiency bleeding, which occurs a week to 6 months after birth, according to the Centers for Disease Control and Prevention. One in five babies with the disorder dies, and about half have bleeding in the skull that can lead to brain damage.
 

New dosing for premature infants

The AAP’s new statement, published in the journal Pediatrics, reaffirms the administration of a 1-mg intramuscular dose for infants weighing more than 1,500 grams, or about 3 lb 5 oz, within 6 hours of birth. For premature infants who weigh less, the guidance recommends an intramuscular dose of 0.3 to 0.5 mg/kg.

The group notes that oral preparations of vitamin K have proven less effective because of malabsorption and challenges with adhering to dosing regimens.

The document also warns that breastfed babies can experience vitamin K deficiency bleeding even if they have received the shot, because concentration of vitamin K often wanes before a baby starts eating solid food. The disorder “should be considered when evaluating bleeding in the first 6 months of life, even in infants who received prophylaxis, and especially in exclusively breastfed infants,” it states.

Accounts of parental refusals date back to 2013, when the CDC reported four cases of deficiency bleeding in Tennessee. The infants’ parents said they declined vitamin K because they worried about increased risk of leukemia, thought the injection was unnecessary, or wanted to minimize the baby’s exposure to “toxins.” Leukemia concern stemmed from a 1992 report linking vitamin K to childhood cancer, an association that did not hold up in subsequent studies.

More recent research has documented parental concerns about preservatives and injection pain as well as distrust of medical and public health authorities. Some parents have been accused of neglect for refusing to allow their babies to receive the shots.  

Phoebe Danziger, MD, a pediatrician and writer in rural Michigan who has studied parental refusal of standard-of-care interventions, called the document a “welcome update” to the AAP’s last statement on the topic, in 2003. She told this news organization that lower dosing for premature infants may reassure some vitamin K–hesitant parents who worry about one-size-fits-all dosing.

But Dr. Danziger added that “evidence is lacking to support the claim that pediatricians can really move the needle on parental hesitancy and refusal simply through better listening and more persuasive counseling.” She said the AAP should do more to address “the broader social climate of mistrust and misinformation” that fuels refusal.

Dr. Hand and Dr. Danziger have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

After the American Academy of Pediatrics (AAP) began recommending vitamin K shots for newborns in 1961, infant bleeding as a result of vitamin K deficiency plummeted. The life-threatening disorder is so rare that some parents now question the need for injections to safeguard against it.

The situation amounts to “a failure of our success,” Ivan Hand, MD, a coauthor of a new AAP statement on vitamin K, told this news organization. Much like diseases that can be prevented with vaccines, vitamin K deficiency bleeding isn’t top of mind for parents. “It’s not something they’re aware of or afraid of,” he said.

In 2019, however, the AAP listed public education about the importance of the shots in its 10 most important priorities.

The policy update urges clinicians to bone up on the benefits and perceived risks of vitamin K deficiency, which is essential for clotting, and to “strongly advocate” for the shot in discussions with parents who may get competing messages from their social circles, the internet, and other health care professionals.

Dr. Hand, director of neonatology at NYC Health + Hospitals Kings County, Brooklyn, said clinicians walk a line between educating and alienating parents who favor natural birth processes. “We’re hoping that by talking to the families and answering their questions and explaining the risks, parents will accept vitamin K as a necessary treatment for their babies,” he said.

Vitamin K does not easily pass through the placenta and is not plentiful in breast milk, the preferred nutrition source for newborns. It takes months for babies to build their stores through food and gut bacteria.

Infants who do not receive vitamin K at birth are 81 times more likely to develop late-onset vitamin K deficiency bleeding, which occurs a week to 6 months after birth, according to the Centers for Disease Control and Prevention. One in five babies with the disorder dies, and about half have bleeding in the skull that can lead to brain damage.
 

New dosing for premature infants

The AAP’s new statement, published in the journal Pediatrics, reaffirms the administration of a 1-mg intramuscular dose for infants weighing more than 1,500 grams, or about 3 lb 5 oz, within 6 hours of birth. For premature infants who weigh less, the guidance recommends an intramuscular dose of 0.3 to 0.5 mg/kg.

The group notes that oral preparations of vitamin K have proven less effective because of malabsorption and challenges with adhering to dosing regimens.

The document also warns that breastfed babies can experience vitamin K deficiency bleeding even if they have received the shot, because concentration of vitamin K often wanes before a baby starts eating solid food. The disorder “should be considered when evaluating bleeding in the first 6 months of life, even in infants who received prophylaxis, and especially in exclusively breastfed infants,” it states.

Accounts of parental refusals date back to 2013, when the CDC reported four cases of deficiency bleeding in Tennessee. The infants’ parents said they declined vitamin K because they worried about increased risk of leukemia, thought the injection was unnecessary, or wanted to minimize the baby’s exposure to “toxins.” Leukemia concern stemmed from a 1992 report linking vitamin K to childhood cancer, an association that did not hold up in subsequent studies.

More recent research has documented parental concerns about preservatives and injection pain as well as distrust of medical and public health authorities. Some parents have been accused of neglect for refusing to allow their babies to receive the shots.  

Phoebe Danziger, MD, a pediatrician and writer in rural Michigan who has studied parental refusal of standard-of-care interventions, called the document a “welcome update” to the AAP’s last statement on the topic, in 2003. She told this news organization that lower dosing for premature infants may reassure some vitamin K–hesitant parents who worry about one-size-fits-all dosing.

But Dr. Danziger added that “evidence is lacking to support the claim that pediatricians can really move the needle on parental hesitancy and refusal simply through better listening and more persuasive counseling.” She said the AAP should do more to address “the broader social climate of mistrust and misinformation” that fuels refusal.

Dr. Hand and Dr. Danziger have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

After the American Academy of Pediatrics (AAP) began recommending vitamin K shots for newborns in 1961, infant bleeding as a result of vitamin K deficiency plummeted. The life-threatening disorder is so rare that some parents now question the need for injections to safeguard against it.

The situation amounts to “a failure of our success,” Ivan Hand, MD, a coauthor of a new AAP statement on vitamin K, told this news organization. Much like diseases that can be prevented with vaccines, vitamin K deficiency bleeding isn’t top of mind for parents. “It’s not something they’re aware of or afraid of,” he said.

In 2019, however, the AAP listed public education about the importance of the shots in its 10 most important priorities.

The policy update urges clinicians to bone up on the benefits and perceived risks of vitamin K deficiency, which is essential for clotting, and to “strongly advocate” for the shot in discussions with parents who may get competing messages from their social circles, the internet, and other health care professionals.

Dr. Hand, director of neonatology at NYC Health + Hospitals Kings County, Brooklyn, said clinicians walk a line between educating and alienating parents who favor natural birth processes. “We’re hoping that by talking to the families and answering their questions and explaining the risks, parents will accept vitamin K as a necessary treatment for their babies,” he said.

Vitamin K does not easily pass through the placenta and is not plentiful in breast milk, the preferred nutrition source for newborns. It takes months for babies to build their stores through food and gut bacteria.

Infants who do not receive vitamin K at birth are 81 times more likely to develop late-onset vitamin K deficiency bleeding, which occurs a week to 6 months after birth, according to the Centers for Disease Control and Prevention. One in five babies with the disorder dies, and about half have bleeding in the skull that can lead to brain damage.
 

New dosing for premature infants

The AAP’s new statement, published in the journal Pediatrics, reaffirms the administration of a 1-mg intramuscular dose for infants weighing more than 1,500 grams, or about 3 lb 5 oz, within 6 hours of birth. For premature infants who weigh less, the guidance recommends an intramuscular dose of 0.3 to 0.5 mg/kg.

The group notes that oral preparations of vitamin K have proven less effective because of malabsorption and challenges with adhering to dosing regimens.

The document also warns that breastfed babies can experience vitamin K deficiency bleeding even if they have received the shot, because concentration of vitamin K often wanes before a baby starts eating solid food. The disorder “should be considered when evaluating bleeding in the first 6 months of life, even in infants who received prophylaxis, and especially in exclusively breastfed infants,” it states.

Accounts of parental refusals date back to 2013, when the CDC reported four cases of deficiency bleeding in Tennessee. The infants’ parents said they declined vitamin K because they worried about increased risk of leukemia, thought the injection was unnecessary, or wanted to minimize the baby’s exposure to “toxins.” Leukemia concern stemmed from a 1992 report linking vitamin K to childhood cancer, an association that did not hold up in subsequent studies.

More recent research has documented parental concerns about preservatives and injection pain as well as distrust of medical and public health authorities. Some parents have been accused of neglect for refusing to allow their babies to receive the shots.  

Phoebe Danziger, MD, a pediatrician and writer in rural Michigan who has studied parental refusal of standard-of-care interventions, called the document a “welcome update” to the AAP’s last statement on the topic, in 2003. She told this news organization that lower dosing for premature infants may reassure some vitamin K–hesitant parents who worry about one-size-fits-all dosing.

But Dr. Danziger added that “evidence is lacking to support the claim that pediatricians can really move the needle on parental hesitancy and refusal simply through better listening and more persuasive counseling.” She said the AAP should do more to address “the broader social climate of mistrust and misinformation” that fuels refusal.

Dr. Hand and Dr. Danziger have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

The incidence of venous thromboembolism (VTE) in nonhospitalized patients with COVID-19 was not significantly different from patients without the infectious disease, according to a new study published in JAMA Internal Medicine.

Design Cells/Getty Images

National Institutes of Health guidelines recommend blood thinners to prevent blood clots in patients hospitalized with COVID-19. However, the new study provides more insight on the best treatment approach for COVID-19 outpatients.

“[COVID-19’s] rapid global progression and impact has caused us to make and modify treatment decisions at a pace that we never have in modern medicine,” study author Nareg Roubinian, MD, an investigator at Kaiser Permanente, Oakland, Calif., said in an interview.

“As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes,” Dr. Roubinian added.

The increased risk of blood clots in patients hospitalized with COVID-19 has been a major issue throughout the pandemic. In fact, one study published in November 2020 found that more than half of patients hospitalized with the illness have prothrombotic antiphospholipid (aPL) autoantibodies in their blood, which could contribute to venous and arterial thromboembolism.

Although it was clear many hospitalized patients diagnosed with COVID-19 were developing more clots, researchers of the current study were not sure if this trend would also be seen in outpatients.

“Most people with COVID-19 do not need to be hospitalized, and we needed to know how often patients outside the hospital were having blood clots,” said Dr. Roubinian.

For the study, Dr. Roubinian and colleagues examined data on 220,588 patients who were members of Kaiser Permanente Northern California health plan and were tested for COVID-19 between Feb. 25 and Aug. 31, 2020. They then reported on the 30-day incidence of outpatient and hospital-associated blood clots following the COVID-19 diagnosis. Patients who were asymptomatic at the time of testing or had received anticoagulants within the last year were excluded.

“We knew from other studies that patients with COVID-19 often get sicker in the first few weeks after infection. What we didn’t know was whether COVID-19 patients were developing blood clots but not pneumonia or were developing blood clots at the same time as they developed pneumonia,” said Dr. Roubinian, an intensive care doctor with the Permanente Medical Group in Oakland, Calif. “Following the patients for 30 days allowed us to focus on the time period from infection to when blood clots were most likely to develop.”

Researchers found that of the cohort who took the COVID-19 test, 11.8% had a positive result. Within 30 days of the COVID-19 test, 0.8% of patients with a positive result were diagnosed with VTE compared to 0.5% of those who received a negative test result. They also found that viral testing took place in an outpatient setting for 59.1% of the patients with a positive viral test who later developed VTE. Of those patients, 76.1% had to be hospitalized.

Dr. Roubinian said he was surprised to see that the blood clotting in outpatients with COVID-19 was similar in frequency to what he saw in patients without the infection.

“Our findings suggest that blood clots do occur in COVID-19 patients but not on a scale where we need to put all or many COVID outpatients on blood thinners,” he said. “As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes.”

In December 2020, three trials investigating the risk and benefits of increased levels of anticoagulation in hospitalized COVID-19 patients were paused because of safety issues. The trials would have enrolled critically ill COVID-19 patients for whom therapeutic doses of anticoagulation drugs showed no benefit.

Anticoagulants are associated with bleeding risks, including prolonged nosebleeds and vomiting or coughing up blood.

Instead of prescribing the routine use of thromboprophylactic drugs to COVID-19 outpatients, Dr. Roubinian believes it would be helpful to learn how to determine whether a patient at risk of becoming sick or being hospitalized would benefit from being treated with such drugs.

Dr. Roubinian reported receiving grants from the National Institutes of Health and the National Heart, Lung, and Blood Institute during the conduct of the study.
 

The incidence of venous thromboembolism (VTE) in nonhospitalized patients with COVID-19 was not significantly different from patients without the infectious disease, according to a new study published in JAMA Internal Medicine.

Design Cells/Getty Images

National Institutes of Health guidelines recommend blood thinners to prevent blood clots in patients hospitalized with COVID-19. However, the new study provides more insight on the best treatment approach for COVID-19 outpatients.

“[COVID-19’s] rapid global progression and impact has caused us to make and modify treatment decisions at a pace that we never have in modern medicine,” study author Nareg Roubinian, MD, an investigator at Kaiser Permanente, Oakland, Calif., said in an interview.

“As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes,” Dr. Roubinian added.

The increased risk of blood clots in patients hospitalized with COVID-19 has been a major issue throughout the pandemic. In fact, one study published in November 2020 found that more than half of patients hospitalized with the illness have prothrombotic antiphospholipid (aPL) autoantibodies in their blood, which could contribute to venous and arterial thromboembolism.

Although it was clear many hospitalized patients diagnosed with COVID-19 were developing more clots, researchers of the current study were not sure if this trend would also be seen in outpatients.

“Most people with COVID-19 do not need to be hospitalized, and we needed to know how often patients outside the hospital were having blood clots,” said Dr. Roubinian.

For the study, Dr. Roubinian and colleagues examined data on 220,588 patients who were members of Kaiser Permanente Northern California health plan and were tested for COVID-19 between Feb. 25 and Aug. 31, 2020. They then reported on the 30-day incidence of outpatient and hospital-associated blood clots following the COVID-19 diagnosis. Patients who were asymptomatic at the time of testing or had received anticoagulants within the last year were excluded.

“We knew from other studies that patients with COVID-19 often get sicker in the first few weeks after infection. What we didn’t know was whether COVID-19 patients were developing blood clots but not pneumonia or were developing blood clots at the same time as they developed pneumonia,” said Dr. Roubinian, an intensive care doctor with the Permanente Medical Group in Oakland, Calif. “Following the patients for 30 days allowed us to focus on the time period from infection to when blood clots were most likely to develop.”

Researchers found that of the cohort who took the COVID-19 test, 11.8% had a positive result. Within 30 days of the COVID-19 test, 0.8% of patients with a positive result were diagnosed with VTE compared to 0.5% of those who received a negative test result. They also found that viral testing took place in an outpatient setting for 59.1% of the patients with a positive viral test who later developed VTE. Of those patients, 76.1% had to be hospitalized.

Dr. Roubinian said he was surprised to see that the blood clotting in outpatients with COVID-19 was similar in frequency to what he saw in patients without the infection.

“Our findings suggest that blood clots do occur in COVID-19 patients but not on a scale where we need to put all or many COVID outpatients on blood thinners,” he said. “As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes.”

In December 2020, three trials investigating the risk and benefits of increased levels of anticoagulation in hospitalized COVID-19 patients were paused because of safety issues. The trials would have enrolled critically ill COVID-19 patients for whom therapeutic doses of anticoagulation drugs showed no benefit.

Anticoagulants are associated with bleeding risks, including prolonged nosebleeds and vomiting or coughing up blood.

Instead of prescribing the routine use of thromboprophylactic drugs to COVID-19 outpatients, Dr. Roubinian believes it would be helpful to learn how to determine whether a patient at risk of becoming sick or being hospitalized would benefit from being treated with such drugs.

Dr. Roubinian reported receiving grants from the National Institutes of Health and the National Heart, Lung, and Blood Institute during the conduct of the study.
 

The incidence of venous thromboembolism (VTE) in nonhospitalized patients with COVID-19 was not significantly different from patients without the infectious disease, according to a new study published in JAMA Internal Medicine.

Design Cells/Getty Images

National Institutes of Health guidelines recommend blood thinners to prevent blood clots in patients hospitalized with COVID-19. However, the new study provides more insight on the best treatment approach for COVID-19 outpatients.

“[COVID-19’s] rapid global progression and impact has caused us to make and modify treatment decisions at a pace that we never have in modern medicine,” study author Nareg Roubinian, MD, an investigator at Kaiser Permanente, Oakland, Calif., said in an interview.

“As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes,” Dr. Roubinian added.

The increased risk of blood clots in patients hospitalized with COVID-19 has been a major issue throughout the pandemic. In fact, one study published in November 2020 found that more than half of patients hospitalized with the illness have prothrombotic antiphospholipid (aPL) autoantibodies in their blood, which could contribute to venous and arterial thromboembolism.

Although it was clear many hospitalized patients diagnosed with COVID-19 were developing more clots, researchers of the current study were not sure if this trend would also be seen in outpatients.

“Most people with COVID-19 do not need to be hospitalized, and we needed to know how often patients outside the hospital were having blood clots,” said Dr. Roubinian.

For the study, Dr. Roubinian and colleagues examined data on 220,588 patients who were members of Kaiser Permanente Northern California health plan and were tested for COVID-19 between Feb. 25 and Aug. 31, 2020. They then reported on the 30-day incidence of outpatient and hospital-associated blood clots following the COVID-19 diagnosis. Patients who were asymptomatic at the time of testing or had received anticoagulants within the last year were excluded.

“We knew from other studies that patients with COVID-19 often get sicker in the first few weeks after infection. What we didn’t know was whether COVID-19 patients were developing blood clots but not pneumonia or were developing blood clots at the same time as they developed pneumonia,” said Dr. Roubinian, an intensive care doctor with the Permanente Medical Group in Oakland, Calif. “Following the patients for 30 days allowed us to focus on the time period from infection to when blood clots were most likely to develop.”

Researchers found that of the cohort who took the COVID-19 test, 11.8% had a positive result. Within 30 days of the COVID-19 test, 0.8% of patients with a positive result were diagnosed with VTE compared to 0.5% of those who received a negative test result. They also found that viral testing took place in an outpatient setting for 59.1% of the patients with a positive viral test who later developed VTE. Of those patients, 76.1% had to be hospitalized.

Dr. Roubinian said he was surprised to see that the blood clotting in outpatients with COVID-19 was similar in frequency to what he saw in patients without the infection.

“Our findings suggest that blood clots do occur in COVID-19 patients but not on a scale where we need to put all or many COVID outpatients on blood thinners,” he said. “As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes.”

In December 2020, three trials investigating the risk and benefits of increased levels of anticoagulation in hospitalized COVID-19 patients were paused because of safety issues. The trials would have enrolled critically ill COVID-19 patients for whom therapeutic doses of anticoagulation drugs showed no benefit.

Anticoagulants are associated with bleeding risks, including prolonged nosebleeds and vomiting or coughing up blood.

Instead of prescribing the routine use of thromboprophylactic drugs to COVID-19 outpatients, Dr. Roubinian believes it would be helpful to learn how to determine whether a patient at risk of becoming sick or being hospitalized would benefit from being treated with such drugs.

Dr. Roubinian reported receiving grants from the National Institutes of Health and the National Heart, Lung, and Blood Institute during the conduct of the study.
 

MADRID – The risks of specific manifestations of antiphospholipid syndrome and systemic lupus erythematosus are linked to the types and levels of antiphospholipid antibodies, according to study findings presented at the European Congress of Rheumatology.

Sara Freeman/MDedge News

Spanish researchers found that the number of antiphospholipid (aPL) antibodies present was important for the development of antiphospholipid syndrome (APS) and that lupus anticoagulant (LA) was the major aPL antibody linked to systemic lupus erythematosus (SLE)–related organ involvement.

“aPL [antibodies] has been extensively associated with an increased risk of thrombosis and poor pregnancy outcomes, mainly in patients with primary APS,” study investigator Leyre Riancho-Zarrabeitia, MD, PhD, explained in an interview ahead of the congress.

“Moreover, aPL [antibody] positivity in SLE has been proposed to be associated with higher damage accrual and with certain manifestations such as valvular heart disease, pulmonary hypertension, and neuropsychiatric manifestations,” she added.

Anticardiolipin antibodies – notably IgG rather than IgM isotypes – also seemed to play an important role in APS and SLE manifestations, Dr. Riancho-Zarrabeitia, of Hospital Sierrallana, Instituto De Investigación Marqués De Valdecilla, and the University of Cantabria (Spain), noted during her oral presentation.

She reported data on 3,651 patients included in the RELESSER registry between October 2011 and August 2012. This large, multicenter, hospital-based registry retrospectively collects immunologic, clinical and demographic data from unselected adult patients with SLE who are attending 45 Spanish rheumatology services within the country’s national health system.

Over one-third (37.5%) of patients, who had a mean age of 47 years and were mostly (90%) women, were positive for aPL. The most frequent aPL detected was IgG anticardiolipin (aCL) antibodies, seen in 25% of patients, followed by LA in 24%, and IgM aCL in 20%.

Of the aPL-positive patients, 20.6% were positive for only one antibody, 12.1% were positive for two antibodies, and 4.8% were positive for three antibodies.

“All types of aPL were associated with classic APS manifestations,” Dr. Riancho-Zarrabeitia said. The associations were strongest for thrombotic events, such as arterial and venous small-vessel thrombosis and recurrent early pregnancy losses.

aCL antibodies conferred the highest risk for arterial thrombosis, she noted (odds ratio, 5.7), whereas LA conferred the highest risk for venous thrombosis (OR, 4.7). Both IgG and IgM isotypes were associated with thrombotic events, fetal death and recurrent pregnancy loss, but the association was stronger with the IgG isotypes.

Having more than one aPL was particularly associated with a higher risk of these APS manifestations. For example, when one antibody was present the OR for arterial thrombosis was 4.45, but when two or more aPL were detected, the ORs rose to 9.23 and 15.6, respectively.

aCL and LA also were associated with thrombocytopenia and hemolytic anemia, with ORs of around 1-2 and 2-3 respectively. There also were antibody associations with cognitive impairments.

Similar results were seen in patients with SLE. “aPL [antibody] positivity in SLE patients influenced the risk for thrombotic and obstetric manifestations,” Dr. Riancho-Zarrabeitia said. LA and aCL were associated with an increased risk of neuropsychiatric manifestations, and LA was linked to an increased risk for renal disease.

The risk for specific SLE manifestations was again higher with IgG isotypes of aCL, notably an increased risk for cardiac and respiratory events.

While increased antibody numbers generally led to a higher risk of complications, the risk for cutaneous manifestations decreased.

“The load of aPL [antibodies] confers a higher risk for APS,” Dr. Riancho-Zarrabeitia said during her conclusion. “Regarding systemic lupus erythematosus, the number of positive antibodies is directly associated with neurological and ophthalmological manifestations, and inversely associated with cutaneous manifestations.”

What these findings show, said Dr. Riancho-Zarrabeitia in the precongress interview, is that individuals who test positive for aPL antibodies need careful monitoring to prevent and treat severe manifestations. “The next step would be to confirm our findings with a prospective study.”

Dr. Riancho-Zarrabeitia has received travel grants from AbbVie, Pfizer, UCB, Merck, GlaxoSmithKline, Amgen, and Roche.

SOURCE: Riancho-Zarrabeitia L et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):136-7. Abstract OP0124. doi: 10.1136/annrheumdis-2019-eular.2485.

MADRID – The risks of specific manifestations of antiphospholipid syndrome and systemic lupus erythematosus are linked to the types and levels of antiphospholipid antibodies, according to study findings presented at the European Congress of Rheumatology.

Sara Freeman/MDedge News

Spanish researchers found that the number of antiphospholipid (aPL) antibodies present was important for the development of antiphospholipid syndrome (APS) and that lupus anticoagulant (LA) was the major aPL antibody linked to systemic lupus erythematosus (SLE)–related organ involvement.

“aPL [antibodies] has been extensively associated with an increased risk of thrombosis and poor pregnancy outcomes, mainly in patients with primary APS,” study investigator Leyre Riancho-Zarrabeitia, MD, PhD, explained in an interview ahead of the congress.

“Moreover, aPL [antibody] positivity in SLE has been proposed to be associated with higher damage accrual and with certain manifestations such as valvular heart disease, pulmonary hypertension, and neuropsychiatric manifestations,” she added.

Anticardiolipin antibodies – notably IgG rather than IgM isotypes – also seemed to play an important role in APS and SLE manifestations, Dr. Riancho-Zarrabeitia, of Hospital Sierrallana, Instituto De Investigación Marqués De Valdecilla, and the University of Cantabria (Spain), noted during her oral presentation.

She reported data on 3,651 patients included in the RELESSER registry between October 2011 and August 2012. This large, multicenter, hospital-based registry retrospectively collects immunologic, clinical and demographic data from unselected adult patients with SLE who are attending 45 Spanish rheumatology services within the country’s national health system.

Over one-third (37.5%) of patients, who had a mean age of 47 years and were mostly (90%) women, were positive for aPL. The most frequent aPL detected was IgG anticardiolipin (aCL) antibodies, seen in 25% of patients, followed by LA in 24%, and IgM aCL in 20%.

Of the aPL-positive patients, 20.6% were positive for only one antibody, 12.1% were positive for two antibodies, and 4.8% were positive for three antibodies.

“All types of aPL were associated with classic APS manifestations,” Dr. Riancho-Zarrabeitia said. The associations were strongest for thrombotic events, such as arterial and venous small-vessel thrombosis and recurrent early pregnancy losses.

aCL antibodies conferred the highest risk for arterial thrombosis, she noted (odds ratio, 5.7), whereas LA conferred the highest risk for venous thrombosis (OR, 4.7). Both IgG and IgM isotypes were associated with thrombotic events, fetal death and recurrent pregnancy loss, but the association was stronger with the IgG isotypes.

Having more than one aPL was particularly associated with a higher risk of these APS manifestations. For example, when one antibody was present the OR for arterial thrombosis was 4.45, but when two or more aPL were detected, the ORs rose to 9.23 and 15.6, respectively.

aCL and LA also were associated with thrombocytopenia and hemolytic anemia, with ORs of around 1-2 and 2-3 respectively. There also were antibody associations with cognitive impairments.

Similar results were seen in patients with SLE. “aPL [antibody] positivity in SLE patients influenced the risk for thrombotic and obstetric manifestations,” Dr. Riancho-Zarrabeitia said. LA and aCL were associated with an increased risk of neuropsychiatric manifestations, and LA was linked to an increased risk for renal disease.

The risk for specific SLE manifestations was again higher with IgG isotypes of aCL, notably an increased risk for cardiac and respiratory events.

While increased antibody numbers generally led to a higher risk of complications, the risk for cutaneous manifestations decreased.

“The load of aPL [antibodies] confers a higher risk for APS,” Dr. Riancho-Zarrabeitia said during her conclusion. “Regarding systemic lupus erythematosus, the number of positive antibodies is directly associated with neurological and ophthalmological manifestations, and inversely associated with cutaneous manifestations.”

What these findings show, said Dr. Riancho-Zarrabeitia in the precongress interview, is that individuals who test positive for aPL antibodies need careful monitoring to prevent and treat severe manifestations. “The next step would be to confirm our findings with a prospective study.”

Dr. Riancho-Zarrabeitia has received travel grants from AbbVie, Pfizer, UCB, Merck, GlaxoSmithKline, Amgen, and Roche.

SOURCE: Riancho-Zarrabeitia L et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):136-7. Abstract OP0124. doi: 10.1136/annrheumdis-2019-eular.2485.

MADRID – The risks of specific manifestations of antiphospholipid syndrome and systemic lupus erythematosus are linked to the types and levels of antiphospholipid antibodies, according to study findings presented at the European Congress of Rheumatology.

Sara Freeman/MDedge News

Spanish researchers found that the number of antiphospholipid (aPL) antibodies present was important for the development of antiphospholipid syndrome (APS) and that lupus anticoagulant (LA) was the major aPL antibody linked to systemic lupus erythematosus (SLE)–related organ involvement.

“aPL [antibodies] has been extensively associated with an increased risk of thrombosis and poor pregnancy outcomes, mainly in patients with primary APS,” study investigator Leyre Riancho-Zarrabeitia, MD, PhD, explained in an interview ahead of the congress.

“Moreover, aPL [antibody] positivity in SLE has been proposed to be associated with higher damage accrual and with certain manifestations such as valvular heart disease, pulmonary hypertension, and neuropsychiatric manifestations,” she added.

Anticardiolipin antibodies – notably IgG rather than IgM isotypes – also seemed to play an important role in APS and SLE manifestations, Dr. Riancho-Zarrabeitia, of Hospital Sierrallana, Instituto De Investigación Marqués De Valdecilla, and the University of Cantabria (Spain), noted during her oral presentation.

She reported data on 3,651 patients included in the RELESSER registry between October 2011 and August 2012. This large, multicenter, hospital-based registry retrospectively collects immunologic, clinical and demographic data from unselected adult patients with SLE who are attending 45 Spanish rheumatology services within the country’s national health system.

Over one-third (37.5%) of patients, who had a mean age of 47 years and were mostly (90%) women, were positive for aPL. The most frequent aPL detected was IgG anticardiolipin (aCL) antibodies, seen in 25% of patients, followed by LA in 24%, and IgM aCL in 20%.

Of the aPL-positive patients, 20.6% were positive for only one antibody, 12.1% were positive for two antibodies, and 4.8% were positive for three antibodies.

“All types of aPL were associated with classic APS manifestations,” Dr. Riancho-Zarrabeitia said. The associations were strongest for thrombotic events, such as arterial and venous small-vessel thrombosis and recurrent early pregnancy losses.

aCL antibodies conferred the highest risk for arterial thrombosis, she noted (odds ratio, 5.7), whereas LA conferred the highest risk for venous thrombosis (OR, 4.7). Both IgG and IgM isotypes were associated with thrombotic events, fetal death and recurrent pregnancy loss, but the association was stronger with the IgG isotypes.

Having more than one aPL was particularly associated with a higher risk of these APS manifestations. For example, when one antibody was present the OR for arterial thrombosis was 4.45, but when two or more aPL were detected, the ORs rose to 9.23 and 15.6, respectively.

aCL and LA also were associated with thrombocytopenia and hemolytic anemia, with ORs of around 1-2 and 2-3 respectively. There also were antibody associations with cognitive impairments.

Similar results were seen in patients with SLE. “aPL [antibody] positivity in SLE patients influenced the risk for thrombotic and obstetric manifestations,” Dr. Riancho-Zarrabeitia said. LA and aCL were associated with an increased risk of neuropsychiatric manifestations, and LA was linked to an increased risk for renal disease.

The risk for specific SLE manifestations was again higher with IgG isotypes of aCL, notably an increased risk for cardiac and respiratory events.

While increased antibody numbers generally led to a higher risk of complications, the risk for cutaneous manifestations decreased.

“The load of aPL [antibodies] confers a higher risk for APS,” Dr. Riancho-Zarrabeitia said during her conclusion. “Regarding systemic lupus erythematosus, the number of positive antibodies is directly associated with neurological and ophthalmological manifestations, and inversely associated with cutaneous manifestations.”

What these findings show, said Dr. Riancho-Zarrabeitia in the precongress interview, is that individuals who test positive for aPL antibodies need careful monitoring to prevent and treat severe manifestations. “The next step would be to confirm our findings with a prospective study.”

Dr. Riancho-Zarrabeitia has received travel grants from AbbVie, Pfizer, UCB, Merck, GlaxoSmithKline, Amgen, and Roche.

SOURCE: Riancho-Zarrabeitia L et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):136-7. Abstract OP0124. doi: 10.1136/annrheumdis-2019-eular.2485.

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.

mzoler@mdedge.com

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.

mzoler@mdedge.com

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.

mzoler@mdedge.com

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

A diagnostic algorithm adapted for use in pregnancy safely ruled out acute pulmonary embolism in nearly 500 women with suspected pulmonary embolism enrolled in a recent prospective study, investigators are reporting.

Using the adapted algorithm, there was only one deep-vein thrombosis (DVT) and no pulmonary embolism (PE) in follow-up among those women, according to the investigators, including senior author Menno V. Huisman, MD, PhD, of the department of thrombosis and hemostasis at Leiden (Netherlands) University Medical Center and his coauthors.

Courtesy Wikimedia Commons/Walter Serra, Giuseppe De Iaco, Claudio Reverberi, and Tiziano Gherli/Creative Commons License

The main advantage of the algorithm is that it averted CT pulmonary angiography in nearly 40% of patients, thus sparing radiation exposure to mother and fetus in many cases, the investigators added.

“Our algorithm provides solid evidence for the safe management of suspected PE in pregnant women, with selective use of CT pulmonary angiography,” Dr. Huisman and colleagues said in their March 21 report in the New England Journal of Medicine.

In a previous clinical trial, known as the YEARS study, a specialized diagnostic algorithm had a low incidence of failure in men and women with clinically suspected PE, as shown by a venous thromboembolism (VTE) rate of just 0.61% at 3 months and by use of CT pulmonary angiography that was 14 percentage points lower than with a conventional algorithmic approach.

For the current study, Dr. Huisman and his coinvestigators took the YEARS algorithm and adapted it for use in pregnant women with suspected PE presenting at 1 of 18 centers in the Netherlands, France, and Ireland.

Their adapted algorithm was based on the three criteria investigators said were most predictive in the YEARS trial, namely, clinical signs of symptoms of DVT, hemoptysis, and PE as the most likely diagnosis. Patients also underwent D-dimer testing, and if they had clinical signs and symptoms of DVT, underwent compression utrasonography of the symptomatic leg.

Pulmonary embolism was considered ruled out in patients who met none of the three YEARS criteria and had a D-dimer under 1,000 ng/mL, or if they met one to three YEARS criteria and had a D-dimer under 500 ng/mL. Otherwise, patients underwent CT pulmonary angiography and started anticoagulant treatment if results of that test indicated PE.

The primary endpoint of the study was the cumulative 3-month incidence of symptomatic VTE among patients with PE ruled out by this algorithm.

Of 498 patients participating in the study, 477 (96%) had a negative result on the adapted YEARS algorithm at baseline, while 20 (4.0%) received a diagnosis of PE, according to results of the study. One patient was lost to follow-up.

Of the 477 patients with negative results, 1 patient (0.21%) had a diagnosis of symptomatic DVT over the 3 months of follow-up, investigators reported, adding that there were no PE diagnoses over the follow-up period.

That patient with the DVT diagnosis met none of the three YEARS criteria and had a D-dimer level of 480 ng/mL, and so did not undergo CT pulmonary angiography, investigators said.

In the worst-case scenario, the VTE incidence would have been 0.42%, assuming the one patient lost to follow-up would have had a VTE diagnosis over the 3-month follow-up period, they added.

“These data meet the proposed criteria for assessing the safety of diagnostic methods in VTE, even in the context of a low baseline prevalence of disease,” Dr. Huisman and his colleagues wrote.

Overall, CT pulmonary angiography was avoided – avoiding potential radiation exposure-related harms– in 39% of the patients, the investigators said, noting that the proportion of women avoiding the diagnostic test decreased from 65% for those evaluated in the third trimester, 46% in the second trimester, and 32% in the third.

“This decreasing specificity can be explained by the physiological rise in the D-dimer level that commonly occurs during pregnancy,” said Dr. Huisman and his coauthors.

The study was supported by unrestricted grants from Leiden University Medical Center and 17 other participating hospitals. Many authors reported financial ties to the pharmaceutical industry.

SOURCE: van der Pol LM et al. N Engl J Med. 2019;380:1139-49

A diagnostic algorithm adapted for use in pregnancy safely ruled out acute pulmonary embolism in nearly 500 women with suspected pulmonary embolism enrolled in a recent prospective study, investigators are reporting.

Using the adapted algorithm, there was only one deep-vein thrombosis (DVT) and no pulmonary embolism (PE) in follow-up among those women, according to the investigators, including senior author Menno V. Huisman, MD, PhD, of the department of thrombosis and hemostasis at Leiden (Netherlands) University Medical Center and his coauthors.

Courtesy Wikimedia Commons/Walter Serra, Giuseppe De Iaco, Claudio Reverberi, and Tiziano Gherli/Creative Commons License

The main advantage of the algorithm is that it averted CT pulmonary angiography in nearly 40% of patients, thus sparing radiation exposure to mother and fetus in many cases, the investigators added.

“Our algorithm provides solid evidence for the safe management of suspected PE in pregnant women, with selective use of CT pulmonary angiography,” Dr. Huisman and colleagues said in their March 21 report in the New England Journal of Medicine.

In a previous clinical trial, known as the YEARS study, a specialized diagnostic algorithm had a low incidence of failure in men and women with clinically suspected PE, as shown by a venous thromboembolism (VTE) rate of just 0.61% at 3 months and by use of CT pulmonary angiography that was 14 percentage points lower than with a conventional algorithmic approach.

For the current study, Dr. Huisman and his coinvestigators took the YEARS algorithm and adapted it for use in pregnant women with suspected PE presenting at 1 of 18 centers in the Netherlands, France, and Ireland.

Their adapted algorithm was based on the three criteria investigators said were most predictive in the YEARS trial, namely, clinical signs of symptoms of DVT, hemoptysis, and PE as the most likely diagnosis. Patients also underwent D-dimer testing, and if they had clinical signs and symptoms of DVT, underwent compression utrasonography of the symptomatic leg.

Pulmonary embolism was considered ruled out in patients who met none of the three YEARS criteria and had a D-dimer under 1,000 ng/mL, or if they met one to three YEARS criteria and had a D-dimer under 500 ng/mL. Otherwise, patients underwent CT pulmonary angiography and started anticoagulant treatment if results of that test indicated PE.

The primary endpoint of the study was the cumulative 3-month incidence of symptomatic VTE among patients with PE ruled out by this algorithm.

Of 498 patients participating in the study, 477 (96%) had a negative result on the adapted YEARS algorithm at baseline, while 20 (4.0%) received a diagnosis of PE, according to results of the study. One patient was lost to follow-up.

Of the 477 patients with negative results, 1 patient (0.21%) had a diagnosis of symptomatic DVT over the 3 months of follow-up, investigators reported, adding that there were no PE diagnoses over the follow-up period.

That patient with the DVT diagnosis met none of the three YEARS criteria and had a D-dimer level of 480 ng/mL, and so did not undergo CT pulmonary angiography, investigators said.

In the worst-case scenario, the VTE incidence would have been 0.42%, assuming the one patient lost to follow-up would have had a VTE diagnosis over the 3-month follow-up period, they added.

“These data meet the proposed criteria for assessing the safety of diagnostic methods in VTE, even in the context of a low baseline prevalence of disease,” Dr. Huisman and his colleagues wrote.

Overall, CT pulmonary angiography was avoided – avoiding potential radiation exposure-related harms– in 39% of the patients, the investigators said, noting that the proportion of women avoiding the diagnostic test decreased from 65% for those evaluated in the third trimester, 46% in the second trimester, and 32% in the third.

“This decreasing specificity can be explained by the physiological rise in the D-dimer level that commonly occurs during pregnancy,” said Dr. Huisman and his coauthors.

The study was supported by unrestricted grants from Leiden University Medical Center and 17 other participating hospitals. Many authors reported financial ties to the pharmaceutical industry.

SOURCE: van der Pol LM et al. N Engl J Med. 2019;380:1139-49

A diagnostic algorithm adapted for use in pregnancy safely ruled out acute pulmonary embolism in nearly 500 women with suspected pulmonary embolism enrolled in a recent prospective study, investigators are reporting.

Using the adapted algorithm, there was only one deep-vein thrombosis (DVT) and no pulmonary embolism (PE) in follow-up among those women, according to the investigators, including senior author Menno V. Huisman, MD, PhD, of the department of thrombosis and hemostasis at Leiden (Netherlands) University Medical Center and his coauthors.

Courtesy Wikimedia Commons/Walter Serra, Giuseppe De Iaco, Claudio Reverberi, and Tiziano Gherli/Creative Commons License

The main advantage of the algorithm is that it averted CT pulmonary angiography in nearly 40% of patients, thus sparing radiation exposure to mother and fetus in many cases, the investigators added.

“Our algorithm provides solid evidence for the safe management of suspected PE in pregnant women, with selective use of CT pulmonary angiography,” Dr. Huisman and colleagues said in their March 21 report in the New England Journal of Medicine.

In a previous clinical trial, known as the YEARS study, a specialized diagnostic algorithm had a low incidence of failure in men and women with clinically suspected PE, as shown by a venous thromboembolism (VTE) rate of just 0.61% at 3 months and by use of CT pulmonary angiography that was 14 percentage points lower than with a conventional algorithmic approach.

For the current study, Dr. Huisman and his coinvestigators took the YEARS algorithm and adapted it for use in pregnant women with suspected PE presenting at 1 of 18 centers in the Netherlands, France, and Ireland.

Their adapted algorithm was based on the three criteria investigators said were most predictive in the YEARS trial, namely, clinical signs of symptoms of DVT, hemoptysis, and PE as the most likely diagnosis. Patients also underwent D-dimer testing, and if they had clinical signs and symptoms of DVT, underwent compression utrasonography of the symptomatic leg.

Pulmonary embolism was considered ruled out in patients who met none of the three YEARS criteria and had a D-dimer under 1,000 ng/mL, or if they met one to three YEARS criteria and had a D-dimer under 500 ng/mL. Otherwise, patients underwent CT pulmonary angiography and started anticoagulant treatment if results of that test indicated PE.

The primary endpoint of the study was the cumulative 3-month incidence of symptomatic VTE among patients with PE ruled out by this algorithm.

Of 498 patients participating in the study, 477 (96%) had a negative result on the adapted YEARS algorithm at baseline, while 20 (4.0%) received a diagnosis of PE, according to results of the study. One patient was lost to follow-up.

Of the 477 patients with negative results, 1 patient (0.21%) had a diagnosis of symptomatic DVT over the 3 months of follow-up, investigators reported, adding that there were no PE diagnoses over the follow-up period.

That patient with the DVT diagnosis met none of the three YEARS criteria and had a D-dimer level of 480 ng/mL, and so did not undergo CT pulmonary angiography, investigators said.

In the worst-case scenario, the VTE incidence would have been 0.42%, assuming the one patient lost to follow-up would have had a VTE diagnosis over the 3-month follow-up period, they added.

“These data meet the proposed criteria for assessing the safety of diagnostic methods in VTE, even in the context of a low baseline prevalence of disease,” Dr. Huisman and his colleagues wrote.

Overall, CT pulmonary angiography was avoided – avoiding potential radiation exposure-related harms– in 39% of the patients, the investigators said, noting that the proportion of women avoiding the diagnostic test decreased from 65% for those evaluated in the third trimester, 46% in the second trimester, and 32% in the third.

“This decreasing specificity can be explained by the physiological rise in the D-dimer level that commonly occurs during pregnancy,” said Dr. Huisman and his coauthors.

The study was supported by unrestricted grants from Leiden University Medical Center and 17 other participating hospitals. Many authors reported financial ties to the pharmaceutical industry.

SOURCE: van der Pol LM et al. N Engl J Med. 2019;380:1139-49

SEATTLE – HIV infection is associated with increased risk of recurrent venous thromboembolism, especially within 1 year of the initial episode. The finding, presented during a poster session at the Conference on Retroviruses & Opportunistic Infections, follows up on an earlier study that found that first-time VTE risk also is higher among HIV-positive individuals than in the general population.

Jim Kling/MDedge News

The conclusion about first-time VTE risk, published earlier this year in Lancet HIV, came from a comparison between the ATHENA (AIDS Therapy Evaluation in the Netherlands) cohort and European population-level of studies of VTE. It found a crude incidence of 2.33 VTE events per 1,000 person-years In HIV patients, with heightened odds when CD4 cell counts were below 200 cells/mcL (adjusted hazard ratio, 3.40).

The new work represents a follow-up and compared results from ATHENA (153 patients with HIV and first VTE) and the Dutch MEGA cohort (4,005 patients without HIV, with first VTE), which includes the general population. Overall, 26% of patients in the ATHENA cohort experienced a second VTE event, compared with 16% of the general population. At 1 year after anticoagulation withdrawal, HIV-positive individuals were at 67% increased risk (HR, 1.67). At 6-years after withdrawal, the relationship was not statistically significant (HR, 1.22).

Researchers also found that CD4 cell-count recovery was associated with lowered risk, with every 100 cell-count increase between initial VTE diagnosis and anticoagulant withdrawal linked to a 20% reduction in risk (HR, 0.80).

“The clinical question is: If it’s true you have an increased risk of recurrence, should you be continuing anticoagulant therapy longer in people with HIV? This poster doesn’t answer that question and you probably need a randomized, controlled trial to look at that,” Peter Reiss, MD, professor of medicine at Amsterdam University Medical Center, said in an interview during the conference.

In the absence of a clear answer, it’s sensible for clinicians to be aware of the potential increased risk, much as clinicians have internalized the increased risk of atherosclerotic vascular disease in HIV patients. “I think the publication [in Lancet HIV] as well as this poster suggest that on the venous side of things there may also be an accentuated risk,” said Dr. Reiss.

Heidi Crane, MD, a professor of medicine at the University of Washington, Seattle, presented a poster examining the underlying factors that may predispose HIV patients to first-time VTE events. Her team performed an adjudicated review of VTE cases among HIV patients at six institutions and found that the risk factors appeared to be distinct from those seen in the general population.

The traditional long plane ride was less common in this population, while factors such as injected drug use and pneumonia were more common. The VTE events occurred at a median age of 49 years; 30% of the patients had a detectable viral load. “We’re seeing a little more (VTE) than you might expect, and in a younger population than you might have guessed,” said Dr. Crane in an interview.

The most frequent predisposing risk factors were recent hospitalization (40%), infection (40%), or immobilization/bed rest (24%) within the past 90 days, and injectable drug use (22%). “It’s not just the traditional risk factors. Some HIV-specific risk factors are driving this,” said Dr. Crane.

She also aims to learn more about the specifics of risk factors, such as catheter-associated thromboses. The team is working to increase the sample size in order to parse out the relationships with specific outcomes.

In the meantime, the data further characterize the health challenges facing people living with HIV. “This is another example demonstrating that comorbid conditions among patients with HIV that are often considered age related occur at much younger ages in our population,” said Dr. Crane.

SOURCE: Rokx C et al. CROI 2019, Abstract 636; and Tenforde MW et al. CROI 2019, Abstract 637.

.

SEATTLE – HIV infection is associated with increased risk of recurrent venous thromboembolism, especially within 1 year of the initial episode. The finding, presented during a poster session at the Conference on Retroviruses & Opportunistic Infections, follows up on an earlier study that found that first-time VTE risk also is higher among HIV-positive individuals than in the general population.

Jim Kling/MDedge News

The conclusion about first-time VTE risk, published earlier this year in Lancet HIV, came from a comparison between the ATHENA (AIDS Therapy Evaluation in the Netherlands) cohort and European population-level of studies of VTE. It found a crude incidence of 2.33 VTE events per 1,000 person-years In HIV patients, with heightened odds when CD4 cell counts were below 200 cells/mcL (adjusted hazard ratio, 3.40).

The new work represents a follow-up and compared results from ATHENA (153 patients with HIV and first VTE) and the Dutch MEGA cohort (4,005 patients without HIV, with first VTE), which includes the general population. Overall, 26% of patients in the ATHENA cohort experienced a second VTE event, compared with 16% of the general population. At 1 year after anticoagulation withdrawal, HIV-positive individuals were at 67% increased risk (HR, 1.67). At 6-years after withdrawal, the relationship was not statistically significant (HR, 1.22).

Researchers also found that CD4 cell-count recovery was associated with lowered risk, with every 100 cell-count increase between initial VTE diagnosis and anticoagulant withdrawal linked to a 20% reduction in risk (HR, 0.80).

“The clinical question is: If it’s true you have an increased risk of recurrence, should you be continuing anticoagulant therapy longer in people with HIV? This poster doesn’t answer that question and you probably need a randomized, controlled trial to look at that,” Peter Reiss, MD, professor of medicine at Amsterdam University Medical Center, said in an interview during the conference.

In the absence of a clear answer, it’s sensible for clinicians to be aware of the potential increased risk, much as clinicians have internalized the increased risk of atherosclerotic vascular disease in HIV patients. “I think the publication [in Lancet HIV] as well as this poster suggest that on the venous side of things there may also be an accentuated risk,” said Dr. Reiss.

Heidi Crane, MD, a professor of medicine at the University of Washington, Seattle, presented a poster examining the underlying factors that may predispose HIV patients to first-time VTE events. Her team performed an adjudicated review of VTE cases among HIV patients at six institutions and found that the risk factors appeared to be distinct from those seen in the general population.

The traditional long plane ride was less common in this population, while factors such as injected drug use and pneumonia were more common. The VTE events occurred at a median age of 49 years; 30% of the patients had a detectable viral load. “We’re seeing a little more (VTE) than you might expect, and in a younger population than you might have guessed,” said Dr. Crane in an interview.

The most frequent predisposing risk factors were recent hospitalization (40%), infection (40%), or immobilization/bed rest (24%) within the past 90 days, and injectable drug use (22%). “It’s not just the traditional risk factors. Some HIV-specific risk factors are driving this,” said Dr. Crane.

She also aims to learn more about the specifics of risk factors, such as catheter-associated thromboses. The team is working to increase the sample size in order to parse out the relationships with specific outcomes.

In the meantime, the data further characterize the health challenges facing people living with HIV. “This is another example demonstrating that comorbid conditions among patients with HIV that are often considered age related occur at much younger ages in our population,” said Dr. Crane.

SOURCE: Rokx C et al. CROI 2019, Abstract 636; and Tenforde MW et al. CROI 2019, Abstract 637.

.

SEATTLE – HIV infection is associated with increased risk of recurrent venous thromboembolism, especially within 1 year of the initial episode. The finding, presented during a poster session at the Conference on Retroviruses & Opportunistic Infections, follows up on an earlier study that found that first-time VTE risk also is higher among HIV-positive individuals than in the general population.

Jim Kling/MDedge News

The conclusion about first-time VTE risk, published earlier this year in Lancet HIV, came from a comparison between the ATHENA (AIDS Therapy Evaluation in the Netherlands) cohort and European population-level of studies of VTE. It found a crude incidence of 2.33 VTE events per 1,000 person-years In HIV patients, with heightened odds when CD4 cell counts were below 200 cells/mcL (adjusted hazard ratio, 3.40).

The new work represents a follow-up and compared results from ATHENA (153 patients with HIV and first VTE) and the Dutch MEGA cohort (4,005 patients without HIV, with first VTE), which includes the general population. Overall, 26% of patients in the ATHENA cohort experienced a second VTE event, compared with 16% of the general population. At 1 year after anticoagulation withdrawal, HIV-positive individuals were at 67% increased risk (HR, 1.67). At 6-years after withdrawal, the relationship was not statistically significant (HR, 1.22).

Researchers also found that CD4 cell-count recovery was associated with lowered risk, with every 100 cell-count increase between initial VTE diagnosis and anticoagulant withdrawal linked to a 20% reduction in risk (HR, 0.80).

“The clinical question is: If it’s true you have an increased risk of recurrence, should you be continuing anticoagulant therapy longer in people with HIV? This poster doesn’t answer that question and you probably need a randomized, controlled trial to look at that,” Peter Reiss, MD, professor of medicine at Amsterdam University Medical Center, said in an interview during the conference.

In the absence of a clear answer, it’s sensible for clinicians to be aware of the potential increased risk, much as clinicians have internalized the increased risk of atherosclerotic vascular disease in HIV patients. “I think the publication [in Lancet HIV] as well as this poster suggest that on the venous side of things there may also be an accentuated risk,” said Dr. Reiss.

Heidi Crane, MD, a professor of medicine at the University of Washington, Seattle, presented a poster examining the underlying factors that may predispose HIV patients to first-time VTE events. Her team performed an adjudicated review of VTE cases among HIV patients at six institutions and found that the risk factors appeared to be distinct from those seen in the general population.

The traditional long plane ride was less common in this population, while factors such as injected drug use and pneumonia were more common. The VTE events occurred at a median age of 49 years; 30% of the patients had a detectable viral load. “We’re seeing a little more (VTE) than you might expect, and in a younger population than you might have guessed,” said Dr. Crane in an interview.

The most frequent predisposing risk factors were recent hospitalization (40%), infection (40%), or immobilization/bed rest (24%) within the past 90 days, and injectable drug use (22%). “It’s not just the traditional risk factors. Some HIV-specific risk factors are driving this,” said Dr. Crane.

She also aims to learn more about the specifics of risk factors, such as catheter-associated thromboses. The team is working to increase the sample size in order to parse out the relationships with specific outcomes.

In the meantime, the data further characterize the health challenges facing people living with HIV. “This is another example demonstrating that comorbid conditions among patients with HIV that are often considered age related occur at much younger ages in our population,” said Dr. Crane.

SOURCE: Rokx C et al. CROI 2019, Abstract 636; and Tenforde MW et al. CROI 2019, Abstract 637.

.

CHICAGO – High-risk hospitalized patients with atrial fibrillation (AF) whose doctors monitored them with a computerized alert system were more than twice as likely to be on anticoagulation and had significantly lower rates of death and other cardiovascular events, compared with patients on a standard admissions protocol, according to results of a randomized, controlled trial presented at the American Heart Association Scientific Sessions.

“Alert-based computerized decision support [CDS] increased the prescription of anticoagulation for stroke prevention in atrial fibrillation during hospitalization, at discharge, and at 90 days after randomization in high-risk patients,” said Gregory Piazza, MD, of Brigham and Women’s Hospital, Boston, in presenting results of the AF-ALERT trial. “The reductions in major cardiovascular events was attributable to reductions in MI and stroke/transient ischemic attack at 90 days in patients whose physicians received the alert.”

The trial evaluated 458 patients hospitalized for AF or flutter and with CHA2DS2-VASc scores of 1-8 randomly assigned to the alert (n = 258) or no-alert (n = 210) groups.

Dr. Piazza explained that for those in the alert group, the CDS system notified physicians when the patient’s CHA₂DS₂-VASc score increased. From there, the physician could choose to open an order template to prescribe evidence-based medications to prevent stroke, to elect to review evidence-based clinical practice guidelines, or to continue with the admissions order with an acknowledged reason for omitting anticoagulation (such as high bleeding risk, low stroke risk, high risk for falls, or patient refusal of anticoagulation).

“In patients for whom their providers were alerted, 35% elected to open the stroke-prevention order set, a very tiny percentage elected to read the AF guidelines, and about 64% exited but provided a rationale for omitting anticoagulation,” Dr. Piazza noted.

The alert group was far more likely to be prescribed anticoagulation during the hospitalization (25.8% vs. 9.5%; P less than .0001), at discharge (23.8% vs. 12.9%; P = .003), and at 90 days (27.7% vs. 17.1%; P = .007) than the control group. The alert resulted in a 55% relative risk reduction in a composite outcome of death, MI, cerebrovascular event, and systemic embolic event at 90 days (11.3% vs. 21.9%; P = .002). The alert group had an 87% lower incidence of MI at 90 days (1.2% vs. 8.6%, P = .0002) and 88% lower incidence of cerebrovascular events or systemic embolism at 90 days (0% vs. 2.4%; P = .02). Death at 90 days occurred in 10.1% in the alert group and 14.8% in the control group (P = .13).

One of the limitations of the study, Dr. Piazza noted, was that the most dramatic finding – reduction of major cardiovascular events – was a secondary, not a primary, endpoint. “CDS has the potential to be a powerful tool in prevention of cardiovascular events in patients with atrial fibrillation.”

Moderator Mintu Turakhia, MD, of Stanford (Calif.) University, questioned the low rate of anticoagulation in the study’s control arm – 9.5% – much lower than medians reported in many registries. He also asked Dr. Piazza to describe the mechanism of action for prescribing anticoagulation in these patients.

Dr. Piazza noted the study population was hospitalized patients whose providers had decided prior to their admissions not to prescribe anticoagulation; hence, the rate of anticoagulation in these patients was actually higher than expected.

Regarding the mechanism of action, “the electronic alert seems to preferentially increase the prescription of [direct oral anticoagulants] over warfarin, and that may have been one of the mechanisms,” Dr. Piazza said. Another explanation he offered were “off-target” effects whereby, if providers have a better idea of a patient’s risk for a stroke or MI, they’ll be more aggressive about managing other risk factors.

“There are a number of interventions that could be triggered if the alert prompted the provider to have a conversation with patients about their risk of stroke from AF,” he said. “This may have impact beyond what we can tell from this simple [Best Practice Advisory in the Epic EHR system]. I think we don’t have a great understanding of the full mechanisms of CDS.”

Dr. Piazza reported financial relationships with BTG, Janssen, Bristol-Myers Squibb, Daiichi Sankyo, Portola, and Bayer. Daiichi Sankyo funded the trial. Dr. Turakhia reported relationships with Apple, Janssen, AstraZeneca, VA, Boehringer Ingelheim, Cardiva Medical, Medtronic, Abbott, Precision Health Economics, iBeat, iRhythm, MyoKardia, Biotronik, and an ownership Interest in AliveCor.

CHICAGO – High-risk hospitalized patients with atrial fibrillation (AF) whose doctors monitored them with a computerized alert system were more than twice as likely to be on anticoagulation and had significantly lower rates of death and other cardiovascular events, compared with patients on a standard admissions protocol, according to results of a randomized, controlled trial presented at the American Heart Association Scientific Sessions.

“Alert-based computerized decision support [CDS] increased the prescription of anticoagulation for stroke prevention in atrial fibrillation during hospitalization, at discharge, and at 90 days after randomization in high-risk patients,” said Gregory Piazza, MD, of Brigham and Women’s Hospital, Boston, in presenting results of the AF-ALERT trial. “The reductions in major cardiovascular events was attributable to reductions in MI and stroke/transient ischemic attack at 90 days in patients whose physicians received the alert.”

The trial evaluated 458 patients hospitalized for AF or flutter and with CHA2DS2-VASc scores of 1-8 randomly assigned to the alert (n = 258) or no-alert (n = 210) groups.

Dr. Piazza explained that for those in the alert group, the CDS system notified physicians when the patient’s CHA₂DS₂-VASc score increased. From there, the physician could choose to open an order template to prescribe evidence-based medications to prevent stroke, to elect to review evidence-based clinical practice guidelines, or to continue with the admissions order with an acknowledged reason for omitting anticoagulation (such as high bleeding risk, low stroke risk, high risk for falls, or patient refusal of anticoagulation).

“In patients for whom their providers were alerted, 35% elected to open the stroke-prevention order set, a very tiny percentage elected to read the AF guidelines, and about 64% exited but provided a rationale for omitting anticoagulation,” Dr. Piazza noted.

The alert group was far more likely to be prescribed anticoagulation during the hospitalization (25.8% vs. 9.5%; P less than .0001), at discharge (23.8% vs. 12.9%; P = .003), and at 90 days (27.7% vs. 17.1%; P = .007) than the control group. The alert resulted in a 55% relative risk reduction in a composite outcome of death, MI, cerebrovascular event, and systemic embolic event at 90 days (11.3% vs. 21.9%; P = .002). The alert group had an 87% lower incidence of MI at 90 days (1.2% vs. 8.6%, P = .0002) and 88% lower incidence of cerebrovascular events or systemic embolism at 90 days (0% vs. 2.4%; P = .02). Death at 90 days occurred in 10.1% in the alert group and 14.8% in the control group (P = .13).

One of the limitations of the study, Dr. Piazza noted, was that the most dramatic finding – reduction of major cardiovascular events – was a secondary, not a primary, endpoint. “CDS has the potential to be a powerful tool in prevention of cardiovascular events in patients with atrial fibrillation.”

Moderator Mintu Turakhia, MD, of Stanford (Calif.) University, questioned the low rate of anticoagulation in the study’s control arm – 9.5% – much lower than medians reported in many registries. He also asked Dr. Piazza to describe the mechanism of action for prescribing anticoagulation in these patients.

Dr. Piazza noted the study population was hospitalized patients whose providers had decided prior to their admissions not to prescribe anticoagulation; hence, the rate of anticoagulation in these patients was actually higher than expected.

Regarding the mechanism of action, “the electronic alert seems to preferentially increase the prescription of [direct oral anticoagulants] over warfarin, and that may have been one of the mechanisms,” Dr. Piazza said. Another explanation he offered were “off-target” effects whereby, if providers have a better idea of a patient’s risk for a stroke or MI, they’ll be more aggressive about managing other risk factors.

“There are a number of interventions that could be triggered if the alert prompted the provider to have a conversation with patients about their risk of stroke from AF,” he said. “This may have impact beyond what we can tell from this simple [Best Practice Advisory in the Epic EHR system]. I think we don’t have a great understanding of the full mechanisms of CDS.”

Dr. Piazza reported financial relationships with BTG, Janssen, Bristol-Myers Squibb, Daiichi Sankyo, Portola, and Bayer. Daiichi Sankyo funded the trial. Dr. Turakhia reported relationships with Apple, Janssen, AstraZeneca, VA, Boehringer Ingelheim, Cardiva Medical, Medtronic, Abbott, Precision Health Economics, iBeat, iRhythm, MyoKardia, Biotronik, and an ownership Interest in AliveCor.

CHICAGO – High-risk hospitalized patients with atrial fibrillation (AF) whose doctors monitored them with a computerized alert system were more than twice as likely to be on anticoagulation and had significantly lower rates of death and other cardiovascular events, compared with patients on a standard admissions protocol, according to results of a randomized, controlled trial presented at the American Heart Association Scientific Sessions.

“Alert-based computerized decision support [CDS] increased the prescription of anticoagulation for stroke prevention in atrial fibrillation during hospitalization, at discharge, and at 90 days after randomization in high-risk patients,” said Gregory Piazza, MD, of Brigham and Women’s Hospital, Boston, in presenting results of the AF-ALERT trial. “The reductions in major cardiovascular events was attributable to reductions in MI and stroke/transient ischemic attack at 90 days in patients whose physicians received the alert.”

The trial evaluated 458 patients hospitalized for AF or flutter and with CHA2DS2-VASc scores of 1-8 randomly assigned to the alert (n = 258) or no-alert (n = 210) groups.

Dr. Piazza explained that for those in the alert group, the CDS system notified physicians when the patient’s CHA₂DS₂-VASc score increased. From there, the physician could choose to open an order template to prescribe evidence-based medications to prevent stroke, to elect to review evidence-based clinical practice guidelines, or to continue with the admissions order with an acknowledged reason for omitting anticoagulation (such as high bleeding risk, low stroke risk, high risk for falls, or patient refusal of anticoagulation).

“In patients for whom their providers were alerted, 35% elected to open the stroke-prevention order set, a very tiny percentage elected to read the AF guidelines, and about 64% exited but provided a rationale for omitting anticoagulation,” Dr. Piazza noted.

The alert group was far more likely to be prescribed anticoagulation during the hospitalization (25.8% vs. 9.5%; P less than .0001), at discharge (23.8% vs. 12.9%; P = .003), and at 90 days (27.7% vs. 17.1%; P = .007) than the control group. The alert resulted in a 55% relative risk reduction in a composite outcome of death, MI, cerebrovascular event, and systemic embolic event at 90 days (11.3% vs. 21.9%; P = .002). The alert group had an 87% lower incidence of MI at 90 days (1.2% vs. 8.6%, P = .0002) and 88% lower incidence of cerebrovascular events or systemic embolism at 90 days (0% vs. 2.4%; P = .02). Death at 90 days occurred in 10.1% in the alert group and 14.8% in the control group (P = .13).

One of the limitations of the study, Dr. Piazza noted, was that the most dramatic finding – reduction of major cardiovascular events – was a secondary, not a primary, endpoint. “CDS has the potential to be a powerful tool in prevention of cardiovascular events in patients with atrial fibrillation.”

Moderator Mintu Turakhia, MD, of Stanford (Calif.) University, questioned the low rate of anticoagulation in the study’s control arm – 9.5% – much lower than medians reported in many registries. He also asked Dr. Piazza to describe the mechanism of action for prescribing anticoagulation in these patients.

Dr. Piazza noted the study population was hospitalized patients whose providers had decided prior to their admissions not to prescribe anticoagulation; hence, the rate of anticoagulation in these patients was actually higher than expected.

Regarding the mechanism of action, “the electronic alert seems to preferentially increase the prescription of [direct oral anticoagulants] over warfarin, and that may have been one of the mechanisms,” Dr. Piazza said. Another explanation he offered were “off-target” effects whereby, if providers have a better idea of a patient’s risk for a stroke or MI, they’ll be more aggressive about managing other risk factors.

“There are a number of interventions that could be triggered if the alert prompted the provider to have a conversation with patients about their risk of stroke from AF,” he said. “This may have impact beyond what we can tell from this simple [Best Practice Advisory in the Epic EHR system]. I think we don’t have a great understanding of the full mechanisms of CDS.”

Dr. Piazza reported financial relationships with BTG, Janssen, Bristol-Myers Squibb, Daiichi Sankyo, Portola, and Bayer. Daiichi Sankyo funded the trial. Dr. Turakhia reported relationships with Apple, Janssen, AstraZeneca, VA, Boehringer Ingelheim, Cardiva Medical, Medtronic, Abbott, Precision Health Economics, iBeat, iRhythm, MyoKardia, Biotronik, and an ownership Interest in AliveCor.

SAN DIEGO – Apixaban is as safe as, and more effective than, dalteparin for patients with cancer-associated venous thromboembolism (VTE), according to the Phase 3 ADAM VTE trial.

The rates of major bleeding and clinically relevant nonmajor bleeding in patients who received apixaban were similar to those in patients who received dalteparin. However, the rate of VTE recurrence was significantly lower with apixaban than it was with dalteparin.

“[A]pixaban was associated with very low bleeding rates and venous thrombosis recurrence rates compared to dalteparin,” said Robert D. McBane II, MD, of the Mayo Clinic in Rochester, Minn., at the annual meeting of the American Society of Hematology.

The trial included 300 adults (aged 18 years and older) with active cancer and acute VTE who were randomized to receive apixaban (n = 150) or dalteparin (n = 150). The dose and schedule for oral apixaban was 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months. Dalteparin was given subcutaneously at 200 IU/kg per day for 1 month followed by 150 IU/kg daily for 6 months. Among the patients in the study, 145 patients in the apixaban arm and 142 in the dalteparin arm ultimately received their assigned treatment.

Every month, patients completed an anticoagulation satisfaction survey and bruise survey (a modification of the Duke Anticoagulation Satisfaction Scale). They also underwent lab testing (complete blood count, liver and renal function testing) and were assessed for outcomes, medication reconciliation, drug compliance, and ECOG status on a monthly basis.
 

Patient characteristics

Baseline characteristics were similar between the treatment arms. The mean age was 64 years in both arms, and roughly half of patients in both arms were female. Hematologic malignancies were present in 9% of patients in the apixaban arm and 11% in the dalteparin arm. Others included lung, colorectal,

pancreatic/hepatobiliary, gynecologic, breast, genitourinary, upper gastrointestinal, and brain cancers.

Of patients in the study, 65% of those in the apixaban arm and 66% in the dalteparin arm had distant metastasis, and 74% of patients in both arms were receiving chemotherapy while on study.

Patients had the following qualifying thrombotic events:

• Any pulmonary embolism (PE) – 55% of patients in the apixaban arm and 51% in the dalteparin arm
• Any deep vein thrombosis (DVT) – 48% and 47%, respectively
• PE only – 44% and 39%, respectively
• PE with DVT – 12% in both arms
• DVT only – 37% and 35%, respectively
• Lower extremity DVT – 31% and 34%, respectively
• Upper extremity DVT – 17% and 14%, respectively
• Cerebral venous thrombosis (VT) – 1% and 0%, respectively
• Splanchnic VT – 8% and 18%, respectively.

Bleeding, thrombosis, and death

The study’s primary endpoint was major bleeding, which did not occur in any of the apixaban-treated patients. However, major bleeding did occur in two (1.4%) patients in the dalteparin arm (P = .14).

A secondary endpoint was major bleeding plus clinically relevant nonmajor bleeding. This occurred in nine (6.2%) patients in the apixaban arm and nine (6.3%) in the dalteparin arm (P = .88).

The researchers also assessed VTE recurrence. One patient in the apixaban arm (0.7%) and nine in the dalteparin arm (6.3%) had VTE recurrence (P = .03).

The patient in the apixaban arm experienced cerebral VT, and the patients with recurrence in the dalteparin arm had leg (n = 4) or arm (n = 2) VTE, PE (n = 1), or splanchnic VT (n = 2).

One patient in each arm (0.7%) had arterial thrombosis.

There was no significant difference in cumulative mortality between the treatment arms (hazard ratio, 1.40; P = .3078).
 

Satisfaction and discontinuation

Overall, apixaban fared better than dalteparin in the monthly patient satisfaction surveys. At various time points, apixaban-treated patients were significantly less likely to be concerned about excessive bruising, find anticoagulant treatment a burden or difficult to carry out, or say anticoagulant treatment added stress to their lives, negatively impacted their quality of life, or caused them “a great deal” of worry, irritation, or frustration.

However, apixaban-treated patients were less likely than dalteparin recipients to have confidence that their drug protected them from VTE recurrence, while the apixaban recipients were more likely than the dalteparin group to report overall satisfaction with their treatment.

In addition, premature treatment discontinuation was more common in the dalteparin group than in the apixaban group – 15% and 4%, respectively (P = .0012).

“Apixaban was well tolerated with superior patient safety satisfaction, as well as significantly fewer study drug discontinuations compared to dalteparin,” Dr. McBane said. “I believe that these data support the use of apixaban for the acute treatment of cancer-associated venous thromboembolism.”

This study was funded by BMS/Pfizer Alliance. Dr. McBane declared no other conflicts of interest.

jensmith@mdedge.com

SOURCE: McBane RD et al. ASH 2018, Abstract 421.

SAN DIEGO – Apixaban is as safe as, and more effective than, dalteparin for patients with cancer-associated venous thromboembolism (VTE), according to the Phase 3 ADAM VTE trial.

The rates of major bleeding and clinically relevant nonmajor bleeding in patients who received apixaban were similar to those in patients who received dalteparin. However, the rate of VTE recurrence was significantly lower with apixaban than it was with dalteparin.

“[A]pixaban was associated with very low bleeding rates and venous thrombosis recurrence rates compared to dalteparin,” said Robert D. McBane II, MD, of the Mayo Clinic in Rochester, Minn., at the annual meeting of the American Society of Hematology.

The trial included 300 adults (aged 18 years and older) with active cancer and acute VTE who were randomized to receive apixaban (n = 150) or dalteparin (n = 150). The dose and schedule for oral apixaban was 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months. Dalteparin was given subcutaneously at 200 IU/kg per day for 1 month followed by 150 IU/kg daily for 6 months. Among the patients in the study, 145 patients in the apixaban arm and 142 in the dalteparin arm ultimately received their assigned treatment.

Every month, patients completed an anticoagulation satisfaction survey and bruise survey (a modification of the Duke Anticoagulation Satisfaction Scale). They also underwent lab testing (complete blood count, liver and renal function testing) and were assessed for outcomes, medication reconciliation, drug compliance, and ECOG status on a monthly basis.
 

Patient characteristics

Baseline characteristics were similar between the treatment arms. The mean age was 64 years in both arms, and roughly half of patients in both arms were female. Hematologic malignancies were present in 9% of patients in the apixaban arm and 11% in the dalteparin arm. Others included lung, colorectal,

pancreatic/hepatobiliary, gynecologic, breast, genitourinary, upper gastrointestinal, and brain cancers.

Of patients in the study, 65% of those in the apixaban arm and 66% in the dalteparin arm had distant metastasis, and 74% of patients in both arms were receiving chemotherapy while on study.

Patients had the following qualifying thrombotic events:

• Any pulmonary embolism (PE) – 55% of patients in the apixaban arm and 51% in the dalteparin arm
• Any deep vein thrombosis (DVT) – 48% and 47%, respectively
• PE only – 44% and 39%, respectively
• PE with DVT – 12% in both arms
• DVT only – 37% and 35%, respectively
• Lower extremity DVT – 31% and 34%, respectively
• Upper extremity DVT – 17% and 14%, respectively
• Cerebral venous thrombosis (VT) – 1% and 0%, respectively
• Splanchnic VT – 8% and 18%, respectively.

Bleeding, thrombosis, and death

The study’s primary endpoint was major bleeding, which did not occur in any of the apixaban-treated patients. However, major bleeding did occur in two (1.4%) patients in the dalteparin arm (P = .14).

A secondary endpoint was major bleeding plus clinically relevant nonmajor bleeding. This occurred in nine (6.2%) patients in the apixaban arm and nine (6.3%) in the dalteparin arm (P = .88).

The researchers also assessed VTE recurrence. One patient in the apixaban arm (0.7%) and nine in the dalteparin arm (6.3%) had VTE recurrence (P = .03).

The patient in the apixaban arm experienced cerebral VT, and the patients with recurrence in the dalteparin arm had leg (n = 4) or arm (n = 2) VTE, PE (n = 1), or splanchnic VT (n = 2).

One patient in each arm (0.7%) had arterial thrombosis.

There was no significant difference in cumulative mortality between the treatment arms (hazard ratio, 1.40; P = .3078).
 

Satisfaction and discontinuation

Overall, apixaban fared better than dalteparin in the monthly patient satisfaction surveys. At various time points, apixaban-treated patients were significantly less likely to be concerned about excessive bruising, find anticoagulant treatment a burden or difficult to carry out, or say anticoagulant treatment added stress to their lives, negatively impacted their quality of life, or caused them “a great deal” of worry, irritation, or frustration.

However, apixaban-treated patients were less likely than dalteparin recipients to have confidence that their drug protected them from VTE recurrence, while the apixaban recipients were more likely than the dalteparin group to report overall satisfaction with their treatment.

In addition, premature treatment discontinuation was more common in the dalteparin group than in the apixaban group – 15% and 4%, respectively (P = .0012).

“Apixaban was well tolerated with superior patient safety satisfaction, as well as significantly fewer study drug discontinuations compared to dalteparin,” Dr. McBane said. “I believe that these data support the use of apixaban for the acute treatment of cancer-associated venous thromboembolism.”

This study was funded by BMS/Pfizer Alliance. Dr. McBane declared no other conflicts of interest.

jensmith@mdedge.com

SOURCE: McBane RD et al. ASH 2018, Abstract 421.

SAN DIEGO – Apixaban is as safe as, and more effective than, dalteparin for patients with cancer-associated venous thromboembolism (VTE), according to the Phase 3 ADAM VTE trial.

The rates of major bleeding and clinically relevant nonmajor bleeding in patients who received apixaban were similar to those in patients who received dalteparin. However, the rate of VTE recurrence was significantly lower with apixaban than it was with dalteparin.

“[A]pixaban was associated with very low bleeding rates and venous thrombosis recurrence rates compared to dalteparin,” said Robert D. McBane II, MD, of the Mayo Clinic in Rochester, Minn., at the annual meeting of the American Society of Hematology.

The trial included 300 adults (aged 18 years and older) with active cancer and acute VTE who were randomized to receive apixaban (n = 150) or dalteparin (n = 150). The dose and schedule for oral apixaban was 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months. Dalteparin was given subcutaneously at 200 IU/kg per day for 1 month followed by 150 IU/kg daily for 6 months. Among the patients in the study, 145 patients in the apixaban arm and 142 in the dalteparin arm ultimately received their assigned treatment.

Every month, patients completed an anticoagulation satisfaction survey and bruise survey (a modification of the Duke Anticoagulation Satisfaction Scale). They also underwent lab testing (complete blood count, liver and renal function testing) and were assessed for outcomes, medication reconciliation, drug compliance, and ECOG status on a monthly basis.
 

Patient characteristics

Baseline characteristics were similar between the treatment arms. The mean age was 64 years in both arms, and roughly half of patients in both arms were female. Hematologic malignancies were present in 9% of patients in the apixaban arm and 11% in the dalteparin arm. Others included lung, colorectal,

pancreatic/hepatobiliary, gynecologic, breast, genitourinary, upper gastrointestinal, and brain cancers.

Of patients in the study, 65% of those in the apixaban arm and 66% in the dalteparin arm had distant metastasis, and 74% of patients in both arms were receiving chemotherapy while on study.

Patients had the following qualifying thrombotic events:

• Any pulmonary embolism (PE) – 55% of patients in the apixaban arm and 51% in the dalteparin arm
• Any deep vein thrombosis (DVT) – 48% and 47%, respectively
• PE only – 44% and 39%, respectively
• PE with DVT – 12% in both arms
• DVT only – 37% and 35%, respectively
• Lower extremity DVT – 31% and 34%, respectively
• Upper extremity DVT – 17% and 14%, respectively
• Cerebral venous thrombosis (VT) – 1% and 0%, respectively
• Splanchnic VT – 8% and 18%, respectively.

Bleeding, thrombosis, and death

The study’s primary endpoint was major bleeding, which did not occur in any of the apixaban-treated patients. However, major bleeding did occur in two (1.4%) patients in the dalteparin arm (P = .14).

A secondary endpoint was major bleeding plus clinically relevant nonmajor bleeding. This occurred in nine (6.2%) patients in the apixaban arm and nine (6.3%) in the dalteparin arm (P = .88).

The researchers also assessed VTE recurrence. One patient in the apixaban arm (0.7%) and nine in the dalteparin arm (6.3%) had VTE recurrence (P = .03).

The patient in the apixaban arm experienced cerebral VT, and the patients with recurrence in the dalteparin arm had leg (n = 4) or arm (n = 2) VTE, PE (n = 1), or splanchnic VT (n = 2).

One patient in each arm (0.7%) had arterial thrombosis.

There was no significant difference in cumulative mortality between the treatment arms (hazard ratio, 1.40; P = .3078).
 

Satisfaction and discontinuation

Overall, apixaban fared better than dalteparin in the monthly patient satisfaction surveys. At various time points, apixaban-treated patients were significantly less likely to be concerned about excessive bruising, find anticoagulant treatment a burden or difficult to carry out, or say anticoagulant treatment added stress to their lives, negatively impacted their quality of life, or caused them “a great deal” of worry, irritation, or frustration.

However, apixaban-treated patients were less likely than dalteparin recipients to have confidence that their drug protected them from VTE recurrence, while the apixaban recipients were more likely than the dalteparin group to report overall satisfaction with their treatment.

In addition, premature treatment discontinuation was more common in the dalteparin group than in the apixaban group – 15% and 4%, respectively (P = .0012).

“Apixaban was well tolerated with superior patient safety satisfaction, as well as significantly fewer study drug discontinuations compared to dalteparin,” Dr. McBane said. “I believe that these data support the use of apixaban for the acute treatment of cancer-associated venous thromboembolism.”

This study was funded by BMS/Pfizer Alliance. Dr. McBane declared no other conflicts of interest.

jensmith@mdedge.com

SOURCE: McBane RD et al. ASH 2018, Abstract 421.