The Hospitalist

Clinical question: Is hospital acquired anemia associated with increased postdischarge adverse outcomes?

Background: Hospital acquired anemia (HAA) is defined as the development of anemia during the course of a hospitalization when starting with a normal hemoglobin on admission. The incidence of HAA is at least 25% when using the last hemoglobin prior to discharge as the index value. HAA is felt to be potentially preventable and usually iatrogenic due to phlebotomy.

Dr. Newsom is a hospitalist at Ochsner Health System, New Orleans.

Clinical question: Is hospital acquired anemia associated with increased postdischarge adverse outcomes?

Background: Hospital acquired anemia (HAA) is defined as the development of anemia during the course of a hospitalization when starting with a normal hemoglobin on admission. The incidence of HAA is at least 25% when using the last hemoglobin prior to discharge as the index value. HAA is felt to be potentially preventable and usually iatrogenic due to phlebotomy.

Dr. Newsom is a hospitalist at Ochsner Health System, New Orleans.

Clinical question: Is hospital acquired anemia associated with increased postdischarge adverse outcomes?

Background: Hospital acquired anemia (HAA) is defined as the development of anemia during the course of a hospitalization when starting with a normal hemoglobin on admission. The incidence of HAA is at least 25% when using the last hemoglobin prior to discharge as the index value. HAA is felt to be potentially preventable and usually iatrogenic due to phlebotomy.

Dr. Newsom is a hospitalist at Ochsner Health System, New Orleans.

Routine use of low-dose oxygen supplementation in the first days after stroke doesn’t improve overall survival or reduce disability, according to a large new study.

The poststroke death and disability odds ratio was 0.97 for those receiving one of two continuous low-dose oxygen protocols, compared with the control group (95% confidence interval, 0.89-1.05; P = .47).

Photodisc/ThinkStock

[email protected]

On Twitter @karioakes

Routine use of low-dose oxygen supplementation in the first days after stroke doesn’t improve overall survival or reduce disability, according to a large new study.

The poststroke death and disability odds ratio was 0.97 for those receiving one of two continuous low-dose oxygen protocols, compared with the control group (95% confidence interval, 0.89-1.05; P = .47).

Photodisc/ThinkStock

[email protected]

On Twitter @karioakes

Routine use of low-dose oxygen supplementation in the first days after stroke doesn’t improve overall survival or reduce disability, according to a large new study.

The poststroke death and disability odds ratio was 0.97 for those receiving one of two continuous low-dose oxygen protocols, compared with the control group (95% confidence interval, 0.89-1.05; P = .47).

Photodisc/ThinkStock

[email protected]

On Twitter @karioakes

Wrongful Life

There have been recent discussions in the lay media about a growing trend of litigation cases focused not on the “right to live,” but rather on the “right to die.” These cases have involved patients who received aggressive treatment, despite having documentation of their wishes not to receive such aggressive treatment. Although unsettling, it is not surprising that this issue has arisen, given the national conversations about the exorbitant cost of care at the end of life in the United States, and the frequency with which patients do not receive end-of-life care that is concordant with their wishes.

These conversations have spurred providers and patients to discuss and document their wishes, via advanced care directives and/or POLST orders (Physicians Orders for Life Sustaining Treatment). There is now even a national day devoted to advanced care decision making (National Healthcare Decisions Day).

Also on The Hospital Leader…

Follow You, Follow Me by Tracy Cardin, ACNP-BC, SFHM

SHM Movers & Shakers, Hospital Silos & JHM Research in HM News by Felicia Steele
 

Wrongful Life

There have been recent discussions in the lay media about a growing trend of litigation cases focused not on the “right to live,” but rather on the “right to die.” These cases have involved patients who received aggressive treatment, despite having documentation of their wishes not to receive such aggressive treatment. Although unsettling, it is not surprising that this issue has arisen, given the national conversations about the exorbitant cost of care at the end of life in the United States, and the frequency with which patients do not receive end-of-life care that is concordant with their wishes.

These conversations have spurred providers and patients to discuss and document their wishes, via advanced care directives and/or POLST orders (Physicians Orders for Life Sustaining Treatment). There is now even a national day devoted to advanced care decision making (National Healthcare Decisions Day).

Also on The Hospital Leader…

Follow You, Follow Me by Tracy Cardin, ACNP-BC, SFHM

SHM Movers & Shakers, Hospital Silos & JHM Research in HM News by Felicia Steele
 

Wrongful Life

There have been recent discussions in the lay media about a growing trend of litigation cases focused not on the “right to live,” but rather on the “right to die.” These cases have involved patients who received aggressive treatment, despite having documentation of their wishes not to receive such aggressive treatment. Although unsettling, it is not surprising that this issue has arisen, given the national conversations about the exorbitant cost of care at the end of life in the United States, and the frequency with which patients do not receive end-of-life care that is concordant with their wishes.

These conversations have spurred providers and patients to discuss and document their wishes, via advanced care directives and/or POLST orders (Physicians Orders for Life Sustaining Treatment). There is now even a national day devoted to advanced care decision making (National Healthcare Decisions Day).

Also on The Hospital Leader…

Follow You, Follow Me by Tracy Cardin, ACNP-BC, SFHM

SHM Movers & Shakers, Hospital Silos & JHM Research in HM News by Felicia Steele
 

Rapid, targeted genomic sequencing shows promise in quickly diagnosing critically ill infants for whom standard clinical work-ups were unsuccessful, according to Cleo C. van Diemen, PhD, of the University of Groningen (the Netherlands), and associates.

Over the course of 1 year, 23 critically ill infants younger than 12 months who had no clear diagnosis after standard clinical work-ups underwent rapid, targeted genomics, with 7 receiving a genetic diagnosis. The median turnaround time was 12 days, falling from roughly 3 weeks at the beginning of the study to a maximum of 8 days by the end of the study.

Compound heterozygous mutations in the EPG5, RMND1, and EIF2B5 genes allowed for diagnoses of Vici syndrome, combined oxidative phosphorylation deficiency-11, and vanishing white matter, respectively. Homozygous mutations in the KLHL41, GFER, and GLB1 genes allowed for diagnoses of nemaline myopathy, progressive mitochondrial myopathy, and GM1-gangliosidosis, respectively. In addition, a 1p36.33p36.32 microdeletion was discovered in an infant with cardiomyopathy.

“The clinical relevance of rapid genome diagnostics lies in the fact that these results can be used in the clinical decisions made in caring for critically ill children in ICUs, in better genetic counseling of the parents, and in guiding their future reproductive choices,” the investigators noted.

Find the full study in Pediatrics (2017 Sep 22. doi: 10.1542/ peds.2016-2854).

[email protected]

Rapid, targeted genomic sequencing shows promise in quickly diagnosing critically ill infants for whom standard clinical work-ups were unsuccessful, according to Cleo C. van Diemen, PhD, of the University of Groningen (the Netherlands), and associates.

Over the course of 1 year, 23 critically ill infants younger than 12 months who had no clear diagnosis after standard clinical work-ups underwent rapid, targeted genomics, with 7 receiving a genetic diagnosis. The median turnaround time was 12 days, falling from roughly 3 weeks at the beginning of the study to a maximum of 8 days by the end of the study.

Compound heterozygous mutations in the EPG5, RMND1, and EIF2B5 genes allowed for diagnoses of Vici syndrome, combined oxidative phosphorylation deficiency-11, and vanishing white matter, respectively. Homozygous mutations in the KLHL41, GFER, and GLB1 genes allowed for diagnoses of nemaline myopathy, progressive mitochondrial myopathy, and GM1-gangliosidosis, respectively. In addition, a 1p36.33p36.32 microdeletion was discovered in an infant with cardiomyopathy.

“The clinical relevance of rapid genome diagnostics lies in the fact that these results can be used in the clinical decisions made in caring for critically ill children in ICUs, in better genetic counseling of the parents, and in guiding their future reproductive choices,” the investigators noted.

Find the full study in Pediatrics (2017 Sep 22. doi: 10.1542/ peds.2016-2854).

[email protected]

Rapid, targeted genomic sequencing shows promise in quickly diagnosing critically ill infants for whom standard clinical work-ups were unsuccessful, according to Cleo C. van Diemen, PhD, of the University of Groningen (the Netherlands), and associates.

Over the course of 1 year, 23 critically ill infants younger than 12 months who had no clear diagnosis after standard clinical work-ups underwent rapid, targeted genomics, with 7 receiving a genetic diagnosis. The median turnaround time was 12 days, falling from roughly 3 weeks at the beginning of the study to a maximum of 8 days by the end of the study.

Compound heterozygous mutations in the EPG5, RMND1, and EIF2B5 genes allowed for diagnoses of Vici syndrome, combined oxidative phosphorylation deficiency-11, and vanishing white matter, respectively. Homozygous mutations in the KLHL41, GFER, and GLB1 genes allowed for diagnoses of nemaline myopathy, progressive mitochondrial myopathy, and GM1-gangliosidosis, respectively. In addition, a 1p36.33p36.32 microdeletion was discovered in an infant with cardiomyopathy.

“The clinical relevance of rapid genome diagnostics lies in the fact that these results can be used in the clinical decisions made in caring for critically ill children in ICUs, in better genetic counseling of the parents, and in guiding their future reproductive choices,” the investigators noted.

Find the full study in Pediatrics (2017 Sep 22. doi: 10.1542/ peds.2016-2854).

[email protected]

Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their 1st, 2nd, and 3rd years of medical school. As a part of the program, recipients are required to write about their experience on a biweekly basis.

As a medical student, the summer is an excellent time to pursue extracurricular activities. While some people take these weeks to learn new skills in basic science laboratories or travel abroad for international electives, many will assume the role of a student researcher. But, with only 10 weeks of dedicated research time in the summer it can be challenging to see a project from start to finish.

Cole Hirschfeld is originally from Phoenix. He received undergraduate degrees in finance and entrepreneurship from the University of Arizona and went on to work in the finance industry for 2 years before deciding to change careers and attend medical school. He is now a 4th year medical student at Cornell University, New York, and plans to apply for residency in internal medicine.

Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their 1st, 2nd, and 3rd years of medical school. As a part of the program, recipients are required to write about their experience on a biweekly basis.

As a medical student, the summer is an excellent time to pursue extracurricular activities. While some people take these weeks to learn new skills in basic science laboratories or travel abroad for international electives, many will assume the role of a student researcher. But, with only 10 weeks of dedicated research time in the summer it can be challenging to see a project from start to finish.

Cole Hirschfeld is originally from Phoenix. He received undergraduate degrees in finance and entrepreneurship from the University of Arizona and went on to work in the finance industry for 2 years before deciding to change careers and attend medical school. He is now a 4th year medical student at Cornell University, New York, and plans to apply for residency in internal medicine.

Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their 1st, 2nd, and 3rd years of medical school. As a part of the program, recipients are required to write about their experience on a biweekly basis.

As a medical student, the summer is an excellent time to pursue extracurricular activities. While some people take these weeks to learn new skills in basic science laboratories or travel abroad for international electives, many will assume the role of a student researcher. But, with only 10 weeks of dedicated research time in the summer it can be challenging to see a project from start to finish.

Cole Hirschfeld is originally from Phoenix. He received undergraduate degrees in finance and entrepreneurship from the University of Arizona and went on to work in the finance industry for 2 years before deciding to change careers and attend medical school. He is now a 4th year medical student at Cornell University, New York, and plans to apply for residency in internal medicine.

The financial impact of physician burnout can provide a guide to help organizations address the problem, according to a special communication published online in JAMA Internal Medicine.

Approximately half of U.S. physicians experience some degree of professional burnout, but health care organizations have done little to respond, wrote Tait Shanafelt, MD, of Stanford (Calif.) University, and colleagues (JAMA Intern Med. 2017 Sep 25. doi: 10.1001/jamainternmed.2017.4340).

The researchers cited “a lack of awareness regarding the economic costs of physician burnout” and a lack of confidence that anything can be done as key factors in why the organizational response to burnout has been so limited.

The business end of physician burnout includes the costs associated with physician turnover and decreased productivity, as well as “financial risks to the organization’s long-term viability due to the relationship between burnout and lower quality of care, decreased patient satisfaction, and problems with patient safety,” the researchers said.

Organizations can combat physician burnout, the authors noted, and the effort is financially worthwhile, as well as morally and ethically important. “Burnout is primarily a system-level problem driven by excess job demands and inadequate resources and support, not an individual problem triggered by personal limitations,” they wrote.

The researchers developed a model outlining “Typical Steps in an Organization’s Journey Toward Expertise in Physician Well-being.” The steps begin with strategies that have a minor impact, including awareness of the problem of physician burnout and a focus on individual interventions such as mindfulness training, exercise, and nutrition.

However, the “transformative” changes in an organization include developing a “culture of wellness,” strategic investment in physician well-being, the presence of a “chief well-being officer” at the executive level, and accountability for physician wellness shared among organizational leaders.

The cost of such strategies varies among institutions, and the researchers provided worksheets to calculate the organizational cost of burnout and the return on investment if intervention steps are taken.

For example, an organization employing 450 physicians could potentially spend $1 million per year on an intervention to reduce physician burnout from 50% to 40%. The intervention investment could yield organizational cost savings of $1.125 million per year, with a 12.5% return on investment, as well as the potential financial benefits of improved patient satisfaction and quality of care.

“Understanding the business case to reduce burnout and promote engagement, as well as overcoming the misperception that nothing meaningful can be done, are key steps for organizations to begin to take action,” the researchers concluded.

“Improvement is possible, investment is justified, and return on investment measurable,” they said.

Dr. Shanafelt is a coinventor of the Physician Well-Being Index, Medical Student Well-Being Index, and Well-Being Index; copyright and licensing rights for these tools belong to the Mayo Clinic, and Dr. Shanafelt receives part of the royalties. The researchers had no other financial conflicts to disclose.

The financial impact of physician burnout can provide a guide to help organizations address the problem, according to a special communication published online in JAMA Internal Medicine.

Approximately half of U.S. physicians experience some degree of professional burnout, but health care organizations have done little to respond, wrote Tait Shanafelt, MD, of Stanford (Calif.) University, and colleagues (JAMA Intern Med. 2017 Sep 25. doi: 10.1001/jamainternmed.2017.4340).

The researchers cited “a lack of awareness regarding the economic costs of physician burnout” and a lack of confidence that anything can be done as key factors in why the organizational response to burnout has been so limited.

The business end of physician burnout includes the costs associated with physician turnover and decreased productivity, as well as “financial risks to the organization’s long-term viability due to the relationship between burnout and lower quality of care, decreased patient satisfaction, and problems with patient safety,” the researchers said.

Organizations can combat physician burnout, the authors noted, and the effort is financially worthwhile, as well as morally and ethically important. “Burnout is primarily a system-level problem driven by excess job demands and inadequate resources and support, not an individual problem triggered by personal limitations,” they wrote.

The researchers developed a model outlining “Typical Steps in an Organization’s Journey Toward Expertise in Physician Well-being.” The steps begin with strategies that have a minor impact, including awareness of the problem of physician burnout and a focus on individual interventions such as mindfulness training, exercise, and nutrition.

However, the “transformative” changes in an organization include developing a “culture of wellness,” strategic investment in physician well-being, the presence of a “chief well-being officer” at the executive level, and accountability for physician wellness shared among organizational leaders.

The cost of such strategies varies among institutions, and the researchers provided worksheets to calculate the organizational cost of burnout and the return on investment if intervention steps are taken.

For example, an organization employing 450 physicians could potentially spend $1 million per year on an intervention to reduce physician burnout from 50% to 40%. The intervention investment could yield organizational cost savings of $1.125 million per year, with a 12.5% return on investment, as well as the potential financial benefits of improved patient satisfaction and quality of care.

“Understanding the business case to reduce burnout and promote engagement, as well as overcoming the misperception that nothing meaningful can be done, are key steps for organizations to begin to take action,” the researchers concluded.

“Improvement is possible, investment is justified, and return on investment measurable,” they said.

Dr. Shanafelt is a coinventor of the Physician Well-Being Index, Medical Student Well-Being Index, and Well-Being Index; copyright and licensing rights for these tools belong to the Mayo Clinic, and Dr. Shanafelt receives part of the royalties. The researchers had no other financial conflicts to disclose.

The financial impact of physician burnout can provide a guide to help organizations address the problem, according to a special communication published online in JAMA Internal Medicine.

Approximately half of U.S. physicians experience some degree of professional burnout, but health care organizations have done little to respond, wrote Tait Shanafelt, MD, of Stanford (Calif.) University, and colleagues (JAMA Intern Med. 2017 Sep 25. doi: 10.1001/jamainternmed.2017.4340).

The researchers cited “a lack of awareness regarding the economic costs of physician burnout” and a lack of confidence that anything can be done as key factors in why the organizational response to burnout has been so limited.

The business end of physician burnout includes the costs associated with physician turnover and decreased productivity, as well as “financial risks to the organization’s long-term viability due to the relationship between burnout and lower quality of care, decreased patient satisfaction, and problems with patient safety,” the researchers said.

Organizations can combat physician burnout, the authors noted, and the effort is financially worthwhile, as well as morally and ethically important. “Burnout is primarily a system-level problem driven by excess job demands and inadequate resources and support, not an individual problem triggered by personal limitations,” they wrote.

The researchers developed a model outlining “Typical Steps in an Organization’s Journey Toward Expertise in Physician Well-being.” The steps begin with strategies that have a minor impact, including awareness of the problem of physician burnout and a focus on individual interventions such as mindfulness training, exercise, and nutrition.

However, the “transformative” changes in an organization include developing a “culture of wellness,” strategic investment in physician well-being, the presence of a “chief well-being officer” at the executive level, and accountability for physician wellness shared among organizational leaders.

The cost of such strategies varies among institutions, and the researchers provided worksheets to calculate the organizational cost of burnout and the return on investment if intervention steps are taken.

For example, an organization employing 450 physicians could potentially spend $1 million per year on an intervention to reduce physician burnout from 50% to 40%. The intervention investment could yield organizational cost savings of $1.125 million per year, with a 12.5% return on investment, as well as the potential financial benefits of improved patient satisfaction and quality of care.

“Understanding the business case to reduce burnout and promote engagement, as well as overcoming the misperception that nothing meaningful can be done, are key steps for organizations to begin to take action,” the researchers concluded.

“Improvement is possible, investment is justified, and return on investment measurable,” they said.

Dr. Shanafelt is a coinventor of the Physician Well-Being Index, Medical Student Well-Being Index, and Well-Being Index; copyright and licensing rights for these tools belong to the Mayo Clinic, and Dr. Shanafelt receives part of the royalties. The researchers had no other financial conflicts to disclose.

Provider misconceptions about parental attitudes may be a more significant barrier to inpatient flu vaccination than the parents’ actual attitudes, reported Suchitra Rao, MD, of the University of Colorado, Aurora, and her colleagues.

Surveys assessing attitudes toward inpatient influenza vaccination were given to parents/caregivers of general pediatric inpatients and to inpatient physicians, residents, nurses, physician assistants, and nurse practitioners at Children’s Hospital Colorado in Aurora between October 2014 and March 2015. Response rates were 95% of the 1,053 parents/caregivers and 58% of the 339 providers.

luiscar/Thinkstock

[email protected]

Provider misconceptions about parental attitudes may be a more significant barrier to inpatient flu vaccination than the parents’ actual attitudes, reported Suchitra Rao, MD, of the University of Colorado, Aurora, and her colleagues.

Surveys assessing attitudes toward inpatient influenza vaccination were given to parents/caregivers of general pediatric inpatients and to inpatient physicians, residents, nurses, physician assistants, and nurse practitioners at Children’s Hospital Colorado in Aurora between October 2014 and March 2015. Response rates were 95% of the 1,053 parents/caregivers and 58% of the 339 providers.

luiscar/Thinkstock

[email protected]

Provider misconceptions about parental attitudes may be a more significant barrier to inpatient flu vaccination than the parents’ actual attitudes, reported Suchitra Rao, MD, of the University of Colorado, Aurora, and her colleagues.

Surveys assessing attitudes toward inpatient influenza vaccination were given to parents/caregivers of general pediatric inpatients and to inpatient physicians, residents, nurses, physician assistants, and nurse practitioners at Children’s Hospital Colorado in Aurora between October 2014 and March 2015. Response rates were 95% of the 1,053 parents/caregivers and 58% of the 339 providers.

luiscar/Thinkstock

[email protected]

It’s very unusual for hospitalists to achieve top quartile performance on the Physician Communication domain of the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. This is the story of a group that did just that for patients on one unit of a large hospital.

I’m not sure how reproducible this would be at other hospitals, or even on other units in the same hospital, and wonder whether performance will stay at this remarkably high level much longer than the current 5-month track record of success. Even so, five months of success suggests they’re on to something.

There is another hospitalist group at that hospital, but I’m discussing work done only by MedOne hospitalists, who together with hospital personnel, developed what they call the Comprehensive Medical Unit (CMU). Their goal was to involve multiple disciplines and use Lean principles to design a new approach to care on 5-Orange, a 20-bed unit in OhioHealth’s Riverside Methodist Hospital in Columbus. The CMU model went live in October 2016.

MedOne Hospital Physicians is a private hospitalist group of 35 physicians and 12 advanced practice clinicians, which comprise nurse practitioners (NPs) and physician assistants (PAs), constituting 46 full-time–equivalent clinical staffing. The group contracts with Riverside, which has approximately 710 staffed beds. MedOne also works in area skilled nursing facilities, helps a long-term acute care and rehabilitation hospital, and provides support to two other hospitals that are not part of OhioHealth.
 

Features of the model

At its core, this model is a variation of the increasingly common combination of geographically assigned hospitalists (who in this case don’t have patients elsewhere in the hospital) and multidisciplinary rounds (that is, the physician and NP hospitalists make bedside rounds with a nurse and pharmacist). But their model also incorporates a few less-common features.

Only 4 of the 35 MedOne hospitalists are eligible to provide care on the CMU, and each still spends a significant portion of time in the regular hospitalist rotation working in the rest of the hospital. These doctors weren’t selected as the highest performers or because they had the best patient satisfaction track record. Instead, five MedOne doctors volunteered to work on the unit, and four were chosen. A MedOne hospitalist NP also works on the unit, since any NP in the group is eligible to work there.

This is a hospitalist-only unit; no non–hospitalist patients are placed on the unit. There is no deliberate attempt to assign patients to the unit based on how sick they are or complicated their cases are. All are general medicine patients, including up to six intermediate care patients (e.g., “ICU step-down” patients requiring mask ventilation, etc.). While configured for 20 patients, the unit can flex to as many as 24 patients and has done so numerous times. The hospitalists (physician and NP combined) have averaged 18.9 daily encounters since the CMU opened.

Nurse staffing on the unit was reconfigured to comprise bedside nurses – known as Clinical Nurses (CNs) – and more experienced RNs – in the role of Comprehensive Charge Nurses (CCNs), who attend rounds and coordinate the patients’ hospitalizations rather than doing bedside care. 5-Orange has one more Charge Nurse than is typical for other units in the hospital, so total RN-to-patient staffing levels and nurse staffing costs are higher. But the CNs care for the same number of patients as do their counterparts in other hospital units.

In order to try to discharge patients early in the day, the NP sees only the patients who are being discharged, while the physician makes all other visits. When possible, I think it’s best to minimize the incidence of a provider’s first visit with a patient being a discharge visit; this may increase the risk of misunderstandings and errors. Instead, in this model, the physician working on the CMU will already know the patient from the preceding days and will be on the unit and readily accessible to the NP all day, which might mitigate some of these concerns.
 

Outcomes

I think the most notable outcome is the top quartile patient satisfaction scores from the 37 patients cared for on the unit who returned a survey, some of whom have asked to return to the CMU if they’re hospitalized again. Specifically, 86% of responses were “top box,” which places the hospitalists at the 84th percentile of performance for all hospitals. Physician Communication scores on the HCAHPS survey for hospitalists on other units at this hospital are in the bottom deciles, which is more typical for hospitalists.

Length of stay is half a day shorter than comparable units with similar readmission rates, and more patients are discharged earlier in the day. The four hospitalists who work on the unit report higher satisfaction, in part because they get an average of only 1 page a day – compared with the typical 15-40 pages their colleagues get working elsewhere in the hospital.
 

Cautions

I’m not sure why the MedOne model has yielded such impressive patient satisfaction and other results. While there are some relatively unique features of their model – only four hospitalists are eligible to work there and nursing roles have been reconfigured – I wouldn’t expect these to yield such remarkable results. So far, they have roughly 5 months of data and just 37 returned patient satisfaction surveys, so it’s possible that random variation and/or the Hawthorne effect are playing a meaningful role. It will be really informative to see their outcomes a year or 2 from now and to gauge how they fare if and when they implement the same model in other units of the hospital.

I suspect MedOne’s precise configuration for staffing and roles of nurses, NPs, and physicians is important, but I’m guessing the most valuable thing they implemented was the creation of a powerful sense of teamwork and shared purpose among those working on the unit. The interpersonal bonding and feeling of shared purpose that likely occurred as they worked to devise and go live with the model, as well as the tremendous satisfaction at seeing their early results, have probably led to terrific enthusiasm within their team.

That enthusiasm may be the key ingredient contributing to their early success.
 

Dr. Nelson has been working in clinical practice as a hospitalist since 1988. He is a cofounder and past president of Society of Hospital Medicine and a principal in Nelson Flores Hospital Medicine Consultants. He is codirector for SHM’s practice-management courses. Contact him at [email protected]

It’s very unusual for hospitalists to achieve top quartile performance on the Physician Communication domain of the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. This is the story of a group that did just that for patients on one unit of a large hospital.

I’m not sure how reproducible this would be at other hospitals, or even on other units in the same hospital, and wonder whether performance will stay at this remarkably high level much longer than the current 5-month track record of success. Even so, five months of success suggests they’re on to something.

There is another hospitalist group at that hospital, but I’m discussing work done only by MedOne hospitalists, who together with hospital personnel, developed what they call the Comprehensive Medical Unit (CMU). Their goal was to involve multiple disciplines and use Lean principles to design a new approach to care on 5-Orange, a 20-bed unit in OhioHealth’s Riverside Methodist Hospital in Columbus. The CMU model went live in October 2016.

MedOne Hospital Physicians is a private hospitalist group of 35 physicians and 12 advanced practice clinicians, which comprise nurse practitioners (NPs) and physician assistants (PAs), constituting 46 full-time–equivalent clinical staffing. The group contracts with Riverside, which has approximately 710 staffed beds. MedOne also works in area skilled nursing facilities, helps a long-term acute care and rehabilitation hospital, and provides support to two other hospitals that are not part of OhioHealth.
 

Features of the model

At its core, this model is a variation of the increasingly common combination of geographically assigned hospitalists (who in this case don’t have patients elsewhere in the hospital) and multidisciplinary rounds (that is, the physician and NP hospitalists make bedside rounds with a nurse and pharmacist). But their model also incorporates a few less-common features.

Only 4 of the 35 MedOne hospitalists are eligible to provide care on the CMU, and each still spends a significant portion of time in the regular hospitalist rotation working in the rest of the hospital. These doctors weren’t selected as the highest performers or because they had the best patient satisfaction track record. Instead, five MedOne doctors volunteered to work on the unit, and four were chosen. A MedOne hospitalist NP also works on the unit, since any NP in the group is eligible to work there.

This is a hospitalist-only unit; no non–hospitalist patients are placed on the unit. There is no deliberate attempt to assign patients to the unit based on how sick they are or complicated their cases are. All are general medicine patients, including up to six intermediate care patients (e.g., “ICU step-down” patients requiring mask ventilation, etc.). While configured for 20 patients, the unit can flex to as many as 24 patients and has done so numerous times. The hospitalists (physician and NP combined) have averaged 18.9 daily encounters since the CMU opened.

Nurse staffing on the unit was reconfigured to comprise bedside nurses – known as Clinical Nurses (CNs) – and more experienced RNs – in the role of Comprehensive Charge Nurses (CCNs), who attend rounds and coordinate the patients’ hospitalizations rather than doing bedside care. 5-Orange has one more Charge Nurse than is typical for other units in the hospital, so total RN-to-patient staffing levels and nurse staffing costs are higher. But the CNs care for the same number of patients as do their counterparts in other hospital units.

In order to try to discharge patients early in the day, the NP sees only the patients who are being discharged, while the physician makes all other visits. When possible, I think it’s best to minimize the incidence of a provider’s first visit with a patient being a discharge visit; this may increase the risk of misunderstandings and errors. Instead, in this model, the physician working on the CMU will already know the patient from the preceding days and will be on the unit and readily accessible to the NP all day, which might mitigate some of these concerns.
 

Outcomes

I think the most notable outcome is the top quartile patient satisfaction scores from the 37 patients cared for on the unit who returned a survey, some of whom have asked to return to the CMU if they’re hospitalized again. Specifically, 86% of responses were “top box,” which places the hospitalists at the 84th percentile of performance for all hospitals. Physician Communication scores on the HCAHPS survey for hospitalists on other units at this hospital are in the bottom deciles, which is more typical for hospitalists.

Length of stay is half a day shorter than comparable units with similar readmission rates, and more patients are discharged earlier in the day. The four hospitalists who work on the unit report higher satisfaction, in part because they get an average of only 1 page a day – compared with the typical 15-40 pages their colleagues get working elsewhere in the hospital.
 

Cautions

I’m not sure why the MedOne model has yielded such impressive patient satisfaction and other results. While there are some relatively unique features of their model – only four hospitalists are eligible to work there and nursing roles have been reconfigured – I wouldn’t expect these to yield such remarkable results. So far, they have roughly 5 months of data and just 37 returned patient satisfaction surveys, so it’s possible that random variation and/or the Hawthorne effect are playing a meaningful role. It will be really informative to see their outcomes a year or 2 from now and to gauge how they fare if and when they implement the same model in other units of the hospital.

I suspect MedOne’s precise configuration for staffing and roles of nurses, NPs, and physicians is important, but I’m guessing the most valuable thing they implemented was the creation of a powerful sense of teamwork and shared purpose among those working on the unit. The interpersonal bonding and feeling of shared purpose that likely occurred as they worked to devise and go live with the model, as well as the tremendous satisfaction at seeing their early results, have probably led to terrific enthusiasm within their team.

That enthusiasm may be the key ingredient contributing to their early success.
 

Dr. Nelson has been working in clinical practice as a hospitalist since 1988. He is a cofounder and past president of Society of Hospital Medicine and a principal in Nelson Flores Hospital Medicine Consultants. He is codirector for SHM’s practice-management courses. Contact him at [email protected]

It’s very unusual for hospitalists to achieve top quartile performance on the Physician Communication domain of the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. This is the story of a group that did just that for patients on one unit of a large hospital.

I’m not sure how reproducible this would be at other hospitals, or even on other units in the same hospital, and wonder whether performance will stay at this remarkably high level much longer than the current 5-month track record of success. Even so, five months of success suggests they’re on to something.

There is another hospitalist group at that hospital, but I’m discussing work done only by MedOne hospitalists, who together with hospital personnel, developed what they call the Comprehensive Medical Unit (CMU). Their goal was to involve multiple disciplines and use Lean principles to design a new approach to care on 5-Orange, a 20-bed unit in OhioHealth’s Riverside Methodist Hospital in Columbus. The CMU model went live in October 2016.

MedOne Hospital Physicians is a private hospitalist group of 35 physicians and 12 advanced practice clinicians, which comprise nurse practitioners (NPs) and physician assistants (PAs), constituting 46 full-time–equivalent clinical staffing. The group contracts with Riverside, which has approximately 710 staffed beds. MedOne also works in area skilled nursing facilities, helps a long-term acute care and rehabilitation hospital, and provides support to two other hospitals that are not part of OhioHealth.
 

Features of the model

At its core, this model is a variation of the increasingly common combination of geographically assigned hospitalists (who in this case don’t have patients elsewhere in the hospital) and multidisciplinary rounds (that is, the physician and NP hospitalists make bedside rounds with a nurse and pharmacist). But their model also incorporates a few less-common features.

Only 4 of the 35 MedOne hospitalists are eligible to provide care on the CMU, and each still spends a significant portion of time in the regular hospitalist rotation working in the rest of the hospital. These doctors weren’t selected as the highest performers or because they had the best patient satisfaction track record. Instead, five MedOne doctors volunteered to work on the unit, and four were chosen. A MedOne hospitalist NP also works on the unit, since any NP in the group is eligible to work there.

This is a hospitalist-only unit; no non–hospitalist patients are placed on the unit. There is no deliberate attempt to assign patients to the unit based on how sick they are or complicated their cases are. All are general medicine patients, including up to six intermediate care patients (e.g., “ICU step-down” patients requiring mask ventilation, etc.). While configured for 20 patients, the unit can flex to as many as 24 patients and has done so numerous times. The hospitalists (physician and NP combined) have averaged 18.9 daily encounters since the CMU opened.

Nurse staffing on the unit was reconfigured to comprise bedside nurses – known as Clinical Nurses (CNs) – and more experienced RNs – in the role of Comprehensive Charge Nurses (CCNs), who attend rounds and coordinate the patients’ hospitalizations rather than doing bedside care. 5-Orange has one more Charge Nurse than is typical for other units in the hospital, so total RN-to-patient staffing levels and nurse staffing costs are higher. But the CNs care for the same number of patients as do their counterparts in other hospital units.

In order to try to discharge patients early in the day, the NP sees only the patients who are being discharged, while the physician makes all other visits. When possible, I think it’s best to minimize the incidence of a provider’s first visit with a patient being a discharge visit; this may increase the risk of misunderstandings and errors. Instead, in this model, the physician working on the CMU will already know the patient from the preceding days and will be on the unit and readily accessible to the NP all day, which might mitigate some of these concerns.
 

Outcomes

I think the most notable outcome is the top quartile patient satisfaction scores from the 37 patients cared for on the unit who returned a survey, some of whom have asked to return to the CMU if they’re hospitalized again. Specifically, 86% of responses were “top box,” which places the hospitalists at the 84th percentile of performance for all hospitals. Physician Communication scores on the HCAHPS survey for hospitalists on other units at this hospital are in the bottom deciles, which is more typical for hospitalists.

Length of stay is half a day shorter than comparable units with similar readmission rates, and more patients are discharged earlier in the day. The four hospitalists who work on the unit report higher satisfaction, in part because they get an average of only 1 page a day – compared with the typical 15-40 pages their colleagues get working elsewhere in the hospital.
 

Cautions

I’m not sure why the MedOne model has yielded such impressive patient satisfaction and other results. While there are some relatively unique features of their model – only four hospitalists are eligible to work there and nursing roles have been reconfigured – I wouldn’t expect these to yield such remarkable results. So far, they have roughly 5 months of data and just 37 returned patient satisfaction surveys, so it’s possible that random variation and/or the Hawthorne effect are playing a meaningful role. It will be really informative to see their outcomes a year or 2 from now and to gauge how they fare if and when they implement the same model in other units of the hospital.

I suspect MedOne’s precise configuration for staffing and roles of nurses, NPs, and physicians is important, but I’m guessing the most valuable thing they implemented was the creation of a powerful sense of teamwork and shared purpose among those working on the unit. The interpersonal bonding and feeling of shared purpose that likely occurred as they worked to devise and go live with the model, as well as the tremendous satisfaction at seeing their early results, have probably led to terrific enthusiasm within their team.

That enthusiasm may be the key ingredient contributing to their early success.
 

Dr. Nelson has been working in clinical practice as a hospitalist since 1988. He is a cofounder and past president of Society of Hospital Medicine and a principal in Nelson Flores Hospital Medicine Consultants. He is codirector for SHM’s practice-management courses. Contact him at [email protected]

Case

A 72-year-old man with a history of nonvalvular atrial fibrillation (AF) and hypertension presents to the ER after an episode of hematochezia. He is prescribed dabigatran 150 mg twice daily for his AF and took his evening dose 2 hours prior to presentation. His initial exam reveals vital signs of BP 120/55, HR 105, RR 14 and bright red stool on rectal exam. His hemoglobin is 8.1 g/dL, down from 12.0 g/dL one month ago. He has normal renal function. How should you manage his gastrointestinal bleeding?

Background

Direct oral anticoagulants (DOACs) consist of two classes of drugs: oral factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) and direct thrombin inhibitors (dabigatran). They have gained substantial popularity since their commercial introduction in 2010, and are now Food and Drug Administration approved for the treatment of atrial fibrillation (AF) and venous thromboembolism (VTE) in noncancer patients. DOAC use will likely increase given favorable safety profiles, reliable pharmacokinetics, and recent guidelines recommending their use over vitamin K antagonists (VKAs) for treatment of VTE in noncancer patients.¹

A primary concern about the routine use of DOACs has been the lack of commercially available direct reversal agents. Unlike warfarin, which has an effective rapid antidote, no direct reversal agent is available for Xa inhibitors, and only recently has there been FDA approval for idarucizumab, a direct thrombin inhibitor reversal drug. Therefore, clinicians are often left wondering how to manage bleeding episodes in patients receiving DOACs.
 

Literature review

What is the risk of bleeding for patients taking DOACs?

DOACs carry a low but significant risk of bleeding, including life-threatening bleeding. There is now robust data from over 100,000 patients in randomized clinical trials of nonvalvular AF and VTE comparing the risk of major and fatal bleeding between DOACs and VKAs.² These trials reveal an annual major bleeding rate of 2%-4% in patients with AF and 1%-2% in patients with VTE taking DOACs.

Importantly, DOACs were found to carry a statistically lower risk of major and fatal bleeding than VKAs. Patients taking DOACs have a relative risk of major bleeding of 0.72, compared with VKAs, and a RR of fatal bleeding of 0.53. Additionally, the case fatality rate for major bleeding episodes was 7.6% for DOACs versus 11.0% for warfarin, despite not having an available antidote for DOACs in these trials.³ Although there is an increased risk of bleeding from DOACs, the rates of major bleeding and of serious complications from bleeding are lower than with warfarin.
 

How long does the effect of a DOAC last?

A significant advantage of DOACs over VKAs in the setting of bleeding is their shorter half-lives, which range from a low estimate of 5 hours for rivaroxaban to a high estimate of 17 hours for dabigatran^4-8 (Table 1). Given that it takes 4-5 half-lives for a drug to be functionally eliminated, coagulation typically normalizes in patients taking DOACs within 1-3 days, compared with 3-5 days for warfarin. All DOACs have significant renal clearance, and renal failure will prolong the duration of anticoagulation. For patients who are taking DOACs and present with bleeding, it is important to assess their renal function.

Are coagulation tests helpful when assessing the effect of DOACs?

Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) should be measured in all patients presenting with significant bleeding, whether or not the patient is taking a DOAC. PT and aPTT are commonly elevated for patients taking direct thrombin inhibitors and Xa inhibitors. Although a prolonged PT and/or aPTT can be useful in determining if the anticoagulant effect from DOACs is still present, normal values of these tests do not rule out an anticoagulant effect in patients taking DOACs.^9,10 Thrombin Time (TT) is a widely available test with quick results, and a normal value rules out the therapeutic effect of dabigatran. Finally, the anti–factor Xa assay is a sensitive test for Xa inhibitors, but requires calibration to the DOAC of interest in order to be reliable. Clinicians should consult with their institution’s laboratory prior to using an anti–factor Xa level to test the anticoagulant effect of a specific DOAC. Repeat coagulation testing may be useful in some clinical circumstances, especially if a patient has renal impairment.

Are there reversal agents for DOACs?

In October 2015, the FDA approved idarucizumab, a monoclonal antibody fragment that binds dabigatran with much greater affinity than thrombin, thus quickly reversing the effect of the direct thrombin inhibitor. FDA approval came in response to an interim analysis of an ongoing open-label trial, RE-VERSE AD.¹¹ This study enrolled 90 adults with major bleeding or need for an emergency procedure taking dabigatran to receive idarucizumab (2.5 g in 50 mL rapid infusion dose given twice less than 15 minutes apart for a total of 5 g). Idarucizumab immediately reversed the effect of dabigatran on clotting tests in 88%-98% of the patients. For patients with major bleeding, the median time for bleeding cessation was 11.4 hours. One thrombotic event was reported within 72 hours of drug administration. Therefore, in patients taking dabigatran with an elevated TT, idarucizumab may be used if the bleeding is life threatening and refractory to initial supportive measures.

There are no FDA-approved antidotes for the factor Xa inhibitors. One promising agent is andexanet-alfa, an inactivated form of factor Xa that irreversibly binds Xa inhibitors. The ongoing, open-label ANNEXA-4 trial¹² reported a decrease in anti–factor Xa activity of ~90% after bolus administration of the drug followed by 2-hour infusion in 67 patients with life-threatening bleeding, with clinical hemostasis achieved in 79% in patients by 12 hours. However, thrombotic events occurred in 18% of the patients at 1 month. Additional safety and efficacy data, along with plans for postmarket surveillance, will be needed prior to approval for clinical use.
 

Are there other options to obtain hemostasis?

Clotting factor products, specifically fresh frozen plasma (FFP) and prothrombin complex concentrates (PCCs), are often used to attempt to reverse anticoagulation from DOACs. While FFP alone has no evidence to support its use in reversing the effect of DOACs, PCCs might reverse anticoagulation for both Xa inhibitors and direct thrombin inhibitors.¹³ Some experts recommend unactivated PCC over activated PCC because of a theoretically increased thrombotic risk of activated PCC.¹⁴ For patients taking Xa inhibitors or dabigatran (if idarucizumab is unavailable) with life-threatening bleeding, PCC should be used in an attempt to reverse the bleeding.

Another strategy to promote hemostasis in bleeding patients taking DOACs is to use antifibrinolytics. Effective for control of bleeding in trauma and surgical patients, tranexamic acid has not been widely studied in nonsurgical bleeding, much less DOAC-related nonsurgical bleeding. A 2014 Cochrane review of a small number of trials suggested a possible mortality benefit from its use in upper GI bleeding, but the quality of included trials was poor.¹⁵ The ongoing HALT-IT trial, enrolling 8,000 patients with gastrointestinal bleeding, aims to clarify the mortality benefit of tranexamic acid.¹⁶ Despite effectively promoting hemostasis in many populations of bleeding patients, tranexamic acid carries no discernible thrombotic risk.^17,18 By preventing clot degradation through a downstream mechanism at low cost and risk, antifibrinolytics are a practical adjunctive therapy to control major bleeding in patients on DOACs.
 

Can charcoal or dialysis reduce the systemic concentration of DOACs?

In addition to discontinuing the DOAC, both charcoal and dialysis can reduce the systemic concentration of DOACs. If the ingestion was recent, oral activated charcoal can reduce the systemic absorption of DOACs. To date there are no data on the efficacy of charcoal in bleeding patients taking DOACs. However, in two recent trials, administration of a single dose of charcoal in healthy patients led to significantly decreased area under concentration-time curves (AUC) when given at 6 and 8 hours after ingestion of a therapeutic dose of apixaban and rivaroxaban, respectively.^19,20 While further studies are needed to confirm its clinical benefit, charcoal is recommended for major bleeding when given within 2 hours of ingestion of a DOAC and may be useful within 8 hours.

Unlike charcoal, which can be used for patients on Xa inhibitors or dabigatran, hemodialysis is only effective for reducing serum concentrations of dabigatran because of its low plasma protein binding (~35%). A review of 35 patients (10 with normal renal function) with severe bleeding showed significant reductions in coagulation tests (aPTT, PT, TT) and dabigatran levels after hemodialysis.²¹ For severe bleeding episodes particularly in patients with impaired renal function, providers should consider the use of continuous renal replacement therapy until clinical hemostasis is achieved.
 

What is the expert’s opinion?

We asked one of our hematologists with expertise in DOACs for his opinion on this topic. Most patients with DOAC-associated bleeding can be managed with supportive care because of the short half-life of these agents in patients with reasonably preserved renal function. The main scenario for escalating therapy to PCC or idarucizumab is life-threatening bleeding, such as intracranial hemorrhage and gastrointestinal hemorrhage with hemodynamic instability. The threshold for use of idarucizumab for patients taking dabigatran with bleeding should be lower than PCCs because there is better evidence for clinical benefit with less risk.

Developing reversal agents continues to be costly, requiring extensive preclinical work and clinical trials that are difficult to do. Assuming that reversal agents become more affordable in the longer term, and safety profiles are better established, clinicians may eventually have a lower threshold for their use in a wider variety of bleeding episodes. Lastly, adverse outcomes often occur, not during the acute bleeding episode, but several weeks later in patients whose providers delay restarting anticoagulation. Thus, it is important to resume anticoagulant therapy as soon as it is safe to do so.
 

Back to the case

Our patient was given a 50-g suspension of oral activated charcoal, along with two doses of 1 g intravenous tranexamic acid 8 hours apart. He was typed and crossed for blood, and ultimately received 1 unit of packed red blood cells before stabilizing without other measures. His colonoscopy subsequently revealed a diverticular bleed with a visible vessel that was coagulated. He was discharged 2 days later after remaining clinically stable after colonoscopy.

Bottom line

For the majority of bleeding patients on DOACs, supportive care with transfusions and local hemostatic interventions to control bleeding will likely be sufficient. Because of the short half-lives of DOACs, most patients do not require additional therapy (Table 2), and these patients actually have better outcomes from major bleeding episodes than patients taking VKAs. Antifibrinolytics should be a first-line prohemostatic therapy in major bleeding. Oral activated charcoal may be effective within 2-8 hours after ingestion for reduction of serum DOAC concentrations. Finally, in cases of life-threatening bleeding, idarucizumab can be used to reverse anticoagulation for patients taking dabigatran. When idarucizumab is unavailable, or for patients taking Xa inhibitors, PCC can be used.

Dr. Hagan is chief medical resident at the University of Washington Medical Center in Seattle. Dr. Albert is clinical instructor of medicine at UWMC. Dr. Garcia is professor of medicine and associate medical director of antithrombotic therapy at UWMC. Dr. Huang is an attending with the UWMC Medicine Consult Service and assistant clinical professor in the division of general internal medicine at UW.

Key Points

• The risk of major bleeding, and the case fatality rate of major bleeding, is significantly lower in patients taking DOACs versus VKAs

• For the majority of patients with bleeding on DOACs, withholding anticoagulation and supportive care is sufficient

• Idarucizumab is a novel and effective antidote to dabigatran, but should be reserved for patients with life-threatening bleeding

• Patients with DOAC-associated bleeding should be restarted on anticoagulation as soon as it is safe to do so

Additional Reading

Management of bleeding in patients receiving direct oral anticoagulants. UpToDate 2016.

How do I treat target-specific oral anticoagulant-associated bleeding? Blood 2014.

References

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-52.

2. Chai-adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450-8.

3. Chai-adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost. 2015;13(11):2012-20.

4. Savaysa (edoxaban) [package insert]. Daiichi Sankyo, Inc, Tokyo, Japan; 2015. www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf. Accessed January 8th, 2016.

5. Xarelto (rivaroxaban) [package insert]. Janssen Pharmaceuticals, Inc. Titusville, NJ; 2011. www.accessdata.fda.gov/drugsatfda_docs/label/2011/202439s001lbl.pdf. Accessed January 8th, 2016.

6. Pradaxa (dabigatran) [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT; 2011. www.accessdata.fda.gov/drugsatfda_docs/label/2011/022512s007lbl.pdf. Accessed January 8th, 2016.

7. Eliquis (apixaban) [package insert]. Bristol-Myers Squibb Company, Princeton, NJ; 2012. www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf. Accessed January 8th, 2016.

8. Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013;52(2):69-82.

9. Tripodi A. The laboratory and the direct oral anticoagulants. Blood.

2013;121(20):4032-5.

10. Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA. Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants (DOACs): A Systematic Review. Chest. 2016;

11. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511-20.

12. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016.

13. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?. Thromb Haemost. 2014;111(2):189-98.

14. Sørensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: Prothrombin complex concentrates--evaluation of safety and thrombogenicity. Crit Care. 2011;15(1):201.

15. Bennett C, Klingenberg S, Langholz E, Gluud L. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD006640.

16. Roberts I, Coats T, Edwards P, et al. HALT-IT – tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomised controlled trial. Trials. 2014 Nov 19;15:450.

17. Dyba J, Chan F, Lau K, Chan A, Chan H. Tranexamic Acid is a Weak Provoking Factor for Thromboembolic Events: A Systematic Review of the Literature. Blood. 2013; 122(21): 3629.

18. Myles PS, Smith JA, Forbes A, et al. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. N Engl J Med. 2016; 376(2):136-148.

19. Wang X, Mondal S, Wang J, et al. Effect of Activated Charcoal on Apixaban Pharmacokinetics in Healthy Subjects. American Journal of Cardiovascular Drugs. 2014;14(2):147-154.

20. Ollier E, Hodin S, Lanoiselée J, et al. Effect of Activated Charcoal on Rivaroxaban Complex Absorption. Clin Pharmacokinet. 2016 Dec 2.

21. Chai-adisaksopha C, Hillis C, Lim W, Boonyawat K, Moffat K, Crowther M. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thromb Haemost. 2015;13(10):1790-8.

22. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-4.

23. UW Anticoagulation Services. UW Medicine Pharmacy Services Web site. 2014. Available at https://depts.washington.edu/anticoag, Accessed March 8, 2017.

________________________________________________________________________
 

Table 1: Pharmacologic Profiles of Xa and Direct Thrombin Inhibitors^{4-8, 23}

t_max t_1/2, CrCl 50-80 t_1/2 CrCl < 30 Dialyzable?

Apixaban 3-4 h 15 h 17 h No

Dabigatran 1-3 h 17 h 28 h Yes

Edoxaban 1-2 h 10-14 h no data No

Rivaroxaban 2-4 h 9 h 10 h No



t_max = time to peak serum concentration after ingestion, t_1/2= serum half-life, CrCl= creatinine clearance in mL/min

*Average values assuming normal hepatic function. Aside from dabigatran, which has minimal hepatic clearance, all other DOACs can have prolonged half-lives in hepatic impairment.
 

Table 2: Management of Bleeding Patients Taking DOACs

Direct Thrombin Inhibitors (dabigatran)

Xa inhibitors (apixaban, edoxaban, rivaroxaban)Minor Bleeding

• Withhold DOAC

• Local hemostatic measures

Major Bleeding*

All of the above, AND

• Antifibrinolytic if bleeding persists

• Restore physiologic perfusion

• Charcoal if last dose within 2-8 hours

• Transfusion indications:

o Red blood cells: anemia

o Platelets: antiplatelet agents or thrombocytopenia

o Plasma: coagulopathy (dilution, DIC, liver failure), not for DOAC reversal

Life-threatening Bleeding**

All of the above, AND:

• Idarucizumab (confirm anticoagulant effect with thrombin time first)

• If idarucizumab is unavailable, use PCC

• Consider hemodialysis until hemostasis achieved, especially if patient in renal failure

All of the above, AND:

• Unactivated PCC (if available and calibrated to specific Xa inhibitor, confirm anticoagulant effect with anti-Xa level)



* Adapted from the International Society on Thrombosis and Hemostasis: bleeding with a fall in hemoglobin level ≥ 2 g/dL, OR bleeding leading to ≥ 2 units of PRBC transfused.²¹ Clinicians should perform risk stratification of bleeding episodes using vital signs, laboratory results, the area of bleeding, and patient comorbidities.

**Uncontrolled bleeding, OR symptomatic bleeding in a critical area or organ (such as intracranial, intraocular, intraspinal, retroperitoneal, pericardial, or intramuscular with compartment syndrome).

Case

A 72-year-old man with a history of nonvalvular atrial fibrillation (AF) and hypertension presents to the ER after an episode of hematochezia. He is prescribed dabigatran 150 mg twice daily for his AF and took his evening dose 2 hours prior to presentation. His initial exam reveals vital signs of BP 120/55, HR 105, RR 14 and bright red stool on rectal exam. His hemoglobin is 8.1 g/dL, down from 12.0 g/dL one month ago. He has normal renal function. How should you manage his gastrointestinal bleeding?

Background

Direct oral anticoagulants (DOACs) consist of two classes of drugs: oral factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) and direct thrombin inhibitors (dabigatran). They have gained substantial popularity since their commercial introduction in 2010, and are now Food and Drug Administration approved for the treatment of atrial fibrillation (AF) and venous thromboembolism (VTE) in noncancer patients. DOAC use will likely increase given favorable safety profiles, reliable pharmacokinetics, and recent guidelines recommending their use over vitamin K antagonists (VKAs) for treatment of VTE in noncancer patients.¹

A primary concern about the routine use of DOACs has been the lack of commercially available direct reversal agents. Unlike warfarin, which has an effective rapid antidote, no direct reversal agent is available for Xa inhibitors, and only recently has there been FDA approval for idarucizumab, a direct thrombin inhibitor reversal drug. Therefore, clinicians are often left wondering how to manage bleeding episodes in patients receiving DOACs.
 

Literature review

What is the risk of bleeding for patients taking DOACs?

DOACs carry a low but significant risk of bleeding, including life-threatening bleeding. There is now robust data from over 100,000 patients in randomized clinical trials of nonvalvular AF and VTE comparing the risk of major and fatal bleeding between DOACs and VKAs.² These trials reveal an annual major bleeding rate of 2%-4% in patients with AF and 1%-2% in patients with VTE taking DOACs.

Importantly, DOACs were found to carry a statistically lower risk of major and fatal bleeding than VKAs. Patients taking DOACs have a relative risk of major bleeding of 0.72, compared with VKAs, and a RR of fatal bleeding of 0.53. Additionally, the case fatality rate for major bleeding episodes was 7.6% for DOACs versus 11.0% for warfarin, despite not having an available antidote for DOACs in these trials.³ Although there is an increased risk of bleeding from DOACs, the rates of major bleeding and of serious complications from bleeding are lower than with warfarin.
 

How long does the effect of a DOAC last?

A significant advantage of DOACs over VKAs in the setting of bleeding is their shorter half-lives, which range from a low estimate of 5 hours for rivaroxaban to a high estimate of 17 hours for dabigatran^4-8 (Table 1). Given that it takes 4-5 half-lives for a drug to be functionally eliminated, coagulation typically normalizes in patients taking DOACs within 1-3 days, compared with 3-5 days for warfarin. All DOACs have significant renal clearance, and renal failure will prolong the duration of anticoagulation. For patients who are taking DOACs and present with bleeding, it is important to assess their renal function.

Are coagulation tests helpful when assessing the effect of DOACs?

Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) should be measured in all patients presenting with significant bleeding, whether or not the patient is taking a DOAC. PT and aPTT are commonly elevated for patients taking direct thrombin inhibitors and Xa inhibitors. Although a prolonged PT and/or aPTT can be useful in determining if the anticoagulant effect from DOACs is still present, normal values of these tests do not rule out an anticoagulant effect in patients taking DOACs.^9,10 Thrombin Time (TT) is a widely available test with quick results, and a normal value rules out the therapeutic effect of dabigatran. Finally, the anti–factor Xa assay is a sensitive test for Xa inhibitors, but requires calibration to the DOAC of interest in order to be reliable. Clinicians should consult with their institution’s laboratory prior to using an anti–factor Xa level to test the anticoagulant effect of a specific DOAC. Repeat coagulation testing may be useful in some clinical circumstances, especially if a patient has renal impairment.

Are there reversal agents for DOACs?

In October 2015, the FDA approved idarucizumab, a monoclonal antibody fragment that binds dabigatran with much greater affinity than thrombin, thus quickly reversing the effect of the direct thrombin inhibitor. FDA approval came in response to an interim analysis of an ongoing open-label trial, RE-VERSE AD.¹¹ This study enrolled 90 adults with major bleeding or need for an emergency procedure taking dabigatran to receive idarucizumab (2.5 g in 50 mL rapid infusion dose given twice less than 15 minutes apart for a total of 5 g). Idarucizumab immediately reversed the effect of dabigatran on clotting tests in 88%-98% of the patients. For patients with major bleeding, the median time for bleeding cessation was 11.4 hours. One thrombotic event was reported within 72 hours of drug administration. Therefore, in patients taking dabigatran with an elevated TT, idarucizumab may be used if the bleeding is life threatening and refractory to initial supportive measures.

There are no FDA-approved antidotes for the factor Xa inhibitors. One promising agent is andexanet-alfa, an inactivated form of factor Xa that irreversibly binds Xa inhibitors. The ongoing, open-label ANNEXA-4 trial¹² reported a decrease in anti–factor Xa activity of ~90% after bolus administration of the drug followed by 2-hour infusion in 67 patients with life-threatening bleeding, with clinical hemostasis achieved in 79% in patients by 12 hours. However, thrombotic events occurred in 18% of the patients at 1 month. Additional safety and efficacy data, along with plans for postmarket surveillance, will be needed prior to approval for clinical use.
 

Are there other options to obtain hemostasis?

Clotting factor products, specifically fresh frozen plasma (FFP) and prothrombin complex concentrates (PCCs), are often used to attempt to reverse anticoagulation from DOACs. While FFP alone has no evidence to support its use in reversing the effect of DOACs, PCCs might reverse anticoagulation for both Xa inhibitors and direct thrombin inhibitors.¹³ Some experts recommend unactivated PCC over activated PCC because of a theoretically increased thrombotic risk of activated PCC.¹⁴ For patients taking Xa inhibitors or dabigatran (if idarucizumab is unavailable) with life-threatening bleeding, PCC should be used in an attempt to reverse the bleeding.

Another strategy to promote hemostasis in bleeding patients taking DOACs is to use antifibrinolytics. Effective for control of bleeding in trauma and surgical patients, tranexamic acid has not been widely studied in nonsurgical bleeding, much less DOAC-related nonsurgical bleeding. A 2014 Cochrane review of a small number of trials suggested a possible mortality benefit from its use in upper GI bleeding, but the quality of included trials was poor.¹⁵ The ongoing HALT-IT trial, enrolling 8,000 patients with gastrointestinal bleeding, aims to clarify the mortality benefit of tranexamic acid.¹⁶ Despite effectively promoting hemostasis in many populations of bleeding patients, tranexamic acid carries no discernible thrombotic risk.^17,18 By preventing clot degradation through a downstream mechanism at low cost and risk, antifibrinolytics are a practical adjunctive therapy to control major bleeding in patients on DOACs.
 

Can charcoal or dialysis reduce the systemic concentration of DOACs?

In addition to discontinuing the DOAC, both charcoal and dialysis can reduce the systemic concentration of DOACs. If the ingestion was recent, oral activated charcoal can reduce the systemic absorption of DOACs. To date there are no data on the efficacy of charcoal in bleeding patients taking DOACs. However, in two recent trials, administration of a single dose of charcoal in healthy patients led to significantly decreased area under concentration-time curves (AUC) when given at 6 and 8 hours after ingestion of a therapeutic dose of apixaban and rivaroxaban, respectively.^19,20 While further studies are needed to confirm its clinical benefit, charcoal is recommended for major bleeding when given within 2 hours of ingestion of a DOAC and may be useful within 8 hours.

Unlike charcoal, which can be used for patients on Xa inhibitors or dabigatran, hemodialysis is only effective for reducing serum concentrations of dabigatran because of its low plasma protein binding (~35%). A review of 35 patients (10 with normal renal function) with severe bleeding showed significant reductions in coagulation tests (aPTT, PT, TT) and dabigatran levels after hemodialysis.²¹ For severe bleeding episodes particularly in patients with impaired renal function, providers should consider the use of continuous renal replacement therapy until clinical hemostasis is achieved.
 

What is the expert’s opinion?

We asked one of our hematologists with expertise in DOACs for his opinion on this topic. Most patients with DOAC-associated bleeding can be managed with supportive care because of the short half-life of these agents in patients with reasonably preserved renal function. The main scenario for escalating therapy to PCC or idarucizumab is life-threatening bleeding, such as intracranial hemorrhage and gastrointestinal hemorrhage with hemodynamic instability. The threshold for use of idarucizumab for patients taking dabigatran with bleeding should be lower than PCCs because there is better evidence for clinical benefit with less risk.

Developing reversal agents continues to be costly, requiring extensive preclinical work and clinical trials that are difficult to do. Assuming that reversal agents become more affordable in the longer term, and safety profiles are better established, clinicians may eventually have a lower threshold for their use in a wider variety of bleeding episodes. Lastly, adverse outcomes often occur, not during the acute bleeding episode, but several weeks later in patients whose providers delay restarting anticoagulation. Thus, it is important to resume anticoagulant therapy as soon as it is safe to do so.
 

Back to the case

Our patient was given a 50-g suspension of oral activated charcoal, along with two doses of 1 g intravenous tranexamic acid 8 hours apart. He was typed and crossed for blood, and ultimately received 1 unit of packed red blood cells before stabilizing without other measures. His colonoscopy subsequently revealed a diverticular bleed with a visible vessel that was coagulated. He was discharged 2 days later after remaining clinically stable after colonoscopy.

Bottom line

For the majority of bleeding patients on DOACs, supportive care with transfusions and local hemostatic interventions to control bleeding will likely be sufficient. Because of the short half-lives of DOACs, most patients do not require additional therapy (Table 2), and these patients actually have better outcomes from major bleeding episodes than patients taking VKAs. Antifibrinolytics should be a first-line prohemostatic therapy in major bleeding. Oral activated charcoal may be effective within 2-8 hours after ingestion for reduction of serum DOAC concentrations. Finally, in cases of life-threatening bleeding, idarucizumab can be used to reverse anticoagulation for patients taking dabigatran. When idarucizumab is unavailable, or for patients taking Xa inhibitors, PCC can be used.

Dr. Hagan is chief medical resident at the University of Washington Medical Center in Seattle. Dr. Albert is clinical instructor of medicine at UWMC. Dr. Garcia is professor of medicine and associate medical director of antithrombotic therapy at UWMC. Dr. Huang is an attending with the UWMC Medicine Consult Service and assistant clinical professor in the division of general internal medicine at UW.

Key Points

• The risk of major bleeding, and the case fatality rate of major bleeding, is significantly lower in patients taking DOACs versus VKAs

• For the majority of patients with bleeding on DOACs, withholding anticoagulation and supportive care is sufficient

• Idarucizumab is a novel and effective antidote to dabigatran, but should be reserved for patients with life-threatening bleeding

• Patients with DOAC-associated bleeding should be restarted on anticoagulation as soon as it is safe to do so

Additional Reading

Management of bleeding in patients receiving direct oral anticoagulants. UpToDate 2016.

How do I treat target-specific oral anticoagulant-associated bleeding? Blood 2014.

References

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-52.

2. Chai-adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450-8.

3. Chai-adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost. 2015;13(11):2012-20.

4. Savaysa (edoxaban) [package insert]. Daiichi Sankyo, Inc, Tokyo, Japan; 2015. www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf. Accessed January 8th, 2016.

5. Xarelto (rivaroxaban) [package insert]. Janssen Pharmaceuticals, Inc. Titusville, NJ; 2011. www.accessdata.fda.gov/drugsatfda_docs/label/2011/202439s001lbl.pdf. Accessed January 8th, 2016.

6. Pradaxa (dabigatran) [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT; 2011. www.accessdata.fda.gov/drugsatfda_docs/label/2011/022512s007lbl.pdf. Accessed January 8th, 2016.

7. Eliquis (apixaban) [package insert]. Bristol-Myers Squibb Company, Princeton, NJ; 2012. www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf. Accessed January 8th, 2016.

8. Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013;52(2):69-82.

9. Tripodi A. The laboratory and the direct oral anticoagulants. Blood.

2013;121(20):4032-5.

10. Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA. Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants (DOACs): A Systematic Review. Chest. 2016;

11. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511-20.

12. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016.

13. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?. Thromb Haemost. 2014;111(2):189-98.

14. Sørensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: Prothrombin complex concentrates--evaluation of safety and thrombogenicity. Crit Care. 2011;15(1):201.

15. Bennett C, Klingenberg S, Langholz E, Gluud L. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD006640.

16. Roberts I, Coats T, Edwards P, et al. HALT-IT – tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomised controlled trial. Trials. 2014 Nov 19;15:450.

17. Dyba J, Chan F, Lau K, Chan A, Chan H. Tranexamic Acid is a Weak Provoking Factor for Thromboembolic Events: A Systematic Review of the Literature. Blood. 2013; 122(21): 3629.

18. Myles PS, Smith JA, Forbes A, et al. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. N Engl J Med. 2016; 376(2):136-148.

19. Wang X, Mondal S, Wang J, et al. Effect of Activated Charcoal on Apixaban Pharmacokinetics in Healthy Subjects. American Journal of Cardiovascular Drugs. 2014;14(2):147-154.

20. Ollier E, Hodin S, Lanoiselée J, et al. Effect of Activated Charcoal on Rivaroxaban Complex Absorption. Clin Pharmacokinet. 2016 Dec 2.

21. Chai-adisaksopha C, Hillis C, Lim W, Boonyawat K, Moffat K, Crowther M. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thromb Haemost. 2015;13(10):1790-8.

22. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-4.

23. UW Anticoagulation Services. UW Medicine Pharmacy Services Web site. 2014. Available at https://depts.washington.edu/anticoag, Accessed March 8, 2017.

________________________________________________________________________
 

Table 1: Pharmacologic Profiles of Xa and Direct Thrombin Inhibitors^{4-8, 23}

t_max t_1/2, CrCl 50-80 t_1/2 CrCl < 30 Dialyzable?

Apixaban 3-4 h 15 h 17 h No

Dabigatran 1-3 h 17 h 28 h Yes

Edoxaban 1-2 h 10-14 h no data No

Rivaroxaban 2-4 h 9 h 10 h No



t_max = time to peak serum concentration after ingestion, t_1/2= serum half-life, CrCl= creatinine clearance in mL/min

*Average values assuming normal hepatic function. Aside from dabigatran, which has minimal hepatic clearance, all other DOACs can have prolonged half-lives in hepatic impairment.
 

Table 2: Management of Bleeding Patients Taking DOACs

Direct Thrombin Inhibitors (dabigatran)

Xa inhibitors (apixaban, edoxaban, rivaroxaban)Minor Bleeding

• Withhold DOAC

• Local hemostatic measures

Major Bleeding*

All of the above, AND

• Antifibrinolytic if bleeding persists

• Restore physiologic perfusion

• Charcoal if last dose within 2-8 hours

• Transfusion indications:

o Red blood cells: anemia

o Platelets: antiplatelet agents or thrombocytopenia

o Plasma: coagulopathy (dilution, DIC, liver failure), not for DOAC reversal

Life-threatening Bleeding**

All of the above, AND:

• Idarucizumab (confirm anticoagulant effect with thrombin time first)

• If idarucizumab is unavailable, use PCC

• Consider hemodialysis until hemostasis achieved, especially if patient in renal failure

All of the above, AND:

• Unactivated PCC (if available and calibrated to specific Xa inhibitor, confirm anticoagulant effect with anti-Xa level)



* Adapted from the International Society on Thrombosis and Hemostasis: bleeding with a fall in hemoglobin level ≥ 2 g/dL, OR bleeding leading to ≥ 2 units of PRBC transfused.²¹ Clinicians should perform risk stratification of bleeding episodes using vital signs, laboratory results, the area of bleeding, and patient comorbidities.

**Uncontrolled bleeding, OR symptomatic bleeding in a critical area or organ (such as intracranial, intraocular, intraspinal, retroperitoneal, pericardial, or intramuscular with compartment syndrome).

Case

A 72-year-old man with a history of nonvalvular atrial fibrillation (AF) and hypertension presents to the ER after an episode of hematochezia. He is prescribed dabigatran 150 mg twice daily for his AF and took his evening dose 2 hours prior to presentation. His initial exam reveals vital signs of BP 120/55, HR 105, RR 14 and bright red stool on rectal exam. His hemoglobin is 8.1 g/dL, down from 12.0 g/dL one month ago. He has normal renal function. How should you manage his gastrointestinal bleeding?

Background

Direct oral anticoagulants (DOACs) consist of two classes of drugs: oral factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) and direct thrombin inhibitors (dabigatran). They have gained substantial popularity since their commercial introduction in 2010, and are now Food and Drug Administration approved for the treatment of atrial fibrillation (AF) and venous thromboembolism (VTE) in noncancer patients. DOAC use will likely increase given favorable safety profiles, reliable pharmacokinetics, and recent guidelines recommending their use over vitamin K antagonists (VKAs) for treatment of VTE in noncancer patients.¹

A primary concern about the routine use of DOACs has been the lack of commercially available direct reversal agents. Unlike warfarin, which has an effective rapid antidote, no direct reversal agent is available for Xa inhibitors, and only recently has there been FDA approval for idarucizumab, a direct thrombin inhibitor reversal drug. Therefore, clinicians are often left wondering how to manage bleeding episodes in patients receiving DOACs.
 

Literature review

What is the risk of bleeding for patients taking DOACs?

DOACs carry a low but significant risk of bleeding, including life-threatening bleeding. There is now robust data from over 100,000 patients in randomized clinical trials of nonvalvular AF and VTE comparing the risk of major and fatal bleeding between DOACs and VKAs.² These trials reveal an annual major bleeding rate of 2%-4% in patients with AF and 1%-2% in patients with VTE taking DOACs.

Importantly, DOACs were found to carry a statistically lower risk of major and fatal bleeding than VKAs. Patients taking DOACs have a relative risk of major bleeding of 0.72, compared with VKAs, and a RR of fatal bleeding of 0.53. Additionally, the case fatality rate for major bleeding episodes was 7.6% for DOACs versus 11.0% for warfarin, despite not having an available antidote for DOACs in these trials.³ Although there is an increased risk of bleeding from DOACs, the rates of major bleeding and of serious complications from bleeding are lower than with warfarin.
 

How long does the effect of a DOAC last?

A significant advantage of DOACs over VKAs in the setting of bleeding is their shorter half-lives, which range from a low estimate of 5 hours for rivaroxaban to a high estimate of 17 hours for dabigatran^4-8 (Table 1). Given that it takes 4-5 half-lives for a drug to be functionally eliminated, coagulation typically normalizes in patients taking DOACs within 1-3 days, compared with 3-5 days for warfarin. All DOACs have significant renal clearance, and renal failure will prolong the duration of anticoagulation. For patients who are taking DOACs and present with bleeding, it is important to assess their renal function.

Are coagulation tests helpful when assessing the effect of DOACs?

Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) should be measured in all patients presenting with significant bleeding, whether or not the patient is taking a DOAC. PT and aPTT are commonly elevated for patients taking direct thrombin inhibitors and Xa inhibitors. Although a prolonged PT and/or aPTT can be useful in determining if the anticoagulant effect from DOACs is still present, normal values of these tests do not rule out an anticoagulant effect in patients taking DOACs.^9,10 Thrombin Time (TT) is a widely available test with quick results, and a normal value rules out the therapeutic effect of dabigatran. Finally, the anti–factor Xa assay is a sensitive test for Xa inhibitors, but requires calibration to the DOAC of interest in order to be reliable. Clinicians should consult with their institution’s laboratory prior to using an anti–factor Xa level to test the anticoagulant effect of a specific DOAC. Repeat coagulation testing may be useful in some clinical circumstances, especially if a patient has renal impairment.

Are there reversal agents for DOACs?

In October 2015, the FDA approved idarucizumab, a monoclonal antibody fragment that binds dabigatran with much greater affinity than thrombin, thus quickly reversing the effect of the direct thrombin inhibitor. FDA approval came in response to an interim analysis of an ongoing open-label trial, RE-VERSE AD.¹¹ This study enrolled 90 adults with major bleeding or need for an emergency procedure taking dabigatran to receive idarucizumab (2.5 g in 50 mL rapid infusion dose given twice less than 15 minutes apart for a total of 5 g). Idarucizumab immediately reversed the effect of dabigatran on clotting tests in 88%-98% of the patients. For patients with major bleeding, the median time for bleeding cessation was 11.4 hours. One thrombotic event was reported within 72 hours of drug administration. Therefore, in patients taking dabigatran with an elevated TT, idarucizumab may be used if the bleeding is life threatening and refractory to initial supportive measures.

There are no FDA-approved antidotes for the factor Xa inhibitors. One promising agent is andexanet-alfa, an inactivated form of factor Xa that irreversibly binds Xa inhibitors. The ongoing, open-label ANNEXA-4 trial¹² reported a decrease in anti–factor Xa activity of ~90% after bolus administration of the drug followed by 2-hour infusion in 67 patients with life-threatening bleeding, with clinical hemostasis achieved in 79% in patients by 12 hours. However, thrombotic events occurred in 18% of the patients at 1 month. Additional safety and efficacy data, along with plans for postmarket surveillance, will be needed prior to approval for clinical use.
 

Are there other options to obtain hemostasis?

Clotting factor products, specifically fresh frozen plasma (FFP) and prothrombin complex concentrates (PCCs), are often used to attempt to reverse anticoagulation from DOACs. While FFP alone has no evidence to support its use in reversing the effect of DOACs, PCCs might reverse anticoagulation for both Xa inhibitors and direct thrombin inhibitors.¹³ Some experts recommend unactivated PCC over activated PCC because of a theoretically increased thrombotic risk of activated PCC.¹⁴ For patients taking Xa inhibitors or dabigatran (if idarucizumab is unavailable) with life-threatening bleeding, PCC should be used in an attempt to reverse the bleeding.

Another strategy to promote hemostasis in bleeding patients taking DOACs is to use antifibrinolytics. Effective for control of bleeding in trauma and surgical patients, tranexamic acid has not been widely studied in nonsurgical bleeding, much less DOAC-related nonsurgical bleeding. A 2014 Cochrane review of a small number of trials suggested a possible mortality benefit from its use in upper GI bleeding, but the quality of included trials was poor.¹⁵ The ongoing HALT-IT trial, enrolling 8,000 patients with gastrointestinal bleeding, aims to clarify the mortality benefit of tranexamic acid.¹⁶ Despite effectively promoting hemostasis in many populations of bleeding patients, tranexamic acid carries no discernible thrombotic risk.^17,18 By preventing clot degradation through a downstream mechanism at low cost and risk, antifibrinolytics are a practical adjunctive therapy to control major bleeding in patients on DOACs.
 

Can charcoal or dialysis reduce the systemic concentration of DOACs?

In addition to discontinuing the DOAC, both charcoal and dialysis can reduce the systemic concentration of DOACs. If the ingestion was recent, oral activated charcoal can reduce the systemic absorption of DOACs. To date there are no data on the efficacy of charcoal in bleeding patients taking DOACs. However, in two recent trials, administration of a single dose of charcoal in healthy patients led to significantly decreased area under concentration-time curves (AUC) when given at 6 and 8 hours after ingestion of a therapeutic dose of apixaban and rivaroxaban, respectively.^19,20 While further studies are needed to confirm its clinical benefit, charcoal is recommended for major bleeding when given within 2 hours of ingestion of a DOAC and may be useful within 8 hours.

Unlike charcoal, which can be used for patients on Xa inhibitors or dabigatran, hemodialysis is only effective for reducing serum concentrations of dabigatran because of its low plasma protein binding (~35%). A review of 35 patients (10 with normal renal function) with severe bleeding showed significant reductions in coagulation tests (aPTT, PT, TT) and dabigatran levels after hemodialysis.²¹ For severe bleeding episodes particularly in patients with impaired renal function, providers should consider the use of continuous renal replacement therapy until clinical hemostasis is achieved.
 

What is the expert’s opinion?

We asked one of our hematologists with expertise in DOACs for his opinion on this topic. Most patients with DOAC-associated bleeding can be managed with supportive care because of the short half-life of these agents in patients with reasonably preserved renal function. The main scenario for escalating therapy to PCC or idarucizumab is life-threatening bleeding, such as intracranial hemorrhage and gastrointestinal hemorrhage with hemodynamic instability. The threshold for use of idarucizumab for patients taking dabigatran with bleeding should be lower than PCCs because there is better evidence for clinical benefit with less risk.

Developing reversal agents continues to be costly, requiring extensive preclinical work and clinical trials that are difficult to do. Assuming that reversal agents become more affordable in the longer term, and safety profiles are better established, clinicians may eventually have a lower threshold for their use in a wider variety of bleeding episodes. Lastly, adverse outcomes often occur, not during the acute bleeding episode, but several weeks later in patients whose providers delay restarting anticoagulation. Thus, it is important to resume anticoagulant therapy as soon as it is safe to do so.
 

Back to the case

Our patient was given a 50-g suspension of oral activated charcoal, along with two doses of 1 g intravenous tranexamic acid 8 hours apart. He was typed and crossed for blood, and ultimately received 1 unit of packed red blood cells before stabilizing without other measures. His colonoscopy subsequently revealed a diverticular bleed with a visible vessel that was coagulated. He was discharged 2 days later after remaining clinically stable after colonoscopy.

Bottom line

For the majority of bleeding patients on DOACs, supportive care with transfusions and local hemostatic interventions to control bleeding will likely be sufficient. Because of the short half-lives of DOACs, most patients do not require additional therapy (Table 2), and these patients actually have better outcomes from major bleeding episodes than patients taking VKAs. Antifibrinolytics should be a first-line prohemostatic therapy in major bleeding. Oral activated charcoal may be effective within 2-8 hours after ingestion for reduction of serum DOAC concentrations. Finally, in cases of life-threatening bleeding, idarucizumab can be used to reverse anticoagulation for patients taking dabigatran. When idarucizumab is unavailable, or for patients taking Xa inhibitors, PCC can be used.

Dr. Hagan is chief medical resident at the University of Washington Medical Center in Seattle. Dr. Albert is clinical instructor of medicine at UWMC. Dr. Garcia is professor of medicine and associate medical director of antithrombotic therapy at UWMC. Dr. Huang is an attending with the UWMC Medicine Consult Service and assistant clinical professor in the division of general internal medicine at UW.

Key Points

• The risk of major bleeding, and the case fatality rate of major bleeding, is significantly lower in patients taking DOACs versus VKAs

• For the majority of patients with bleeding on DOACs, withholding anticoagulation and supportive care is sufficient

• Idarucizumab is a novel and effective antidote to dabigatran, but should be reserved for patients with life-threatening bleeding

• Patients with DOAC-associated bleeding should be restarted on anticoagulation as soon as it is safe to do so

Additional Reading

Management of bleeding in patients receiving direct oral anticoagulants. UpToDate 2016.

How do I treat target-specific oral anticoagulant-associated bleeding? Blood 2014.

References

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-52.

2. Chai-adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450-8.

3. Chai-adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost. 2015;13(11):2012-20.

4. Savaysa (edoxaban) [package insert]. Daiichi Sankyo, Inc, Tokyo, Japan; 2015. www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf. Accessed January 8th, 2016.

5. Xarelto (rivaroxaban) [package insert]. Janssen Pharmaceuticals, Inc. Titusville, NJ; 2011. www.accessdata.fda.gov/drugsatfda_docs/label/2011/202439s001lbl.pdf. Accessed January 8th, 2016.

6. Pradaxa (dabigatran) [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT; 2011. www.accessdata.fda.gov/drugsatfda_docs/label/2011/022512s007lbl.pdf. Accessed January 8th, 2016.

7. Eliquis (apixaban) [package insert]. Bristol-Myers Squibb Company, Princeton, NJ; 2012. www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf. Accessed January 8th, 2016.

8. Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013;52(2):69-82.

9. Tripodi A. The laboratory and the direct oral anticoagulants. Blood.

2013;121(20):4032-5.

10. Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA. Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants (DOACs): A Systematic Review. Chest. 2016;

11. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511-20.

12. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016.

13. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?. Thromb Haemost. 2014;111(2):189-98.

14. Sørensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: Prothrombin complex concentrates--evaluation of safety and thrombogenicity. Crit Care. 2011;15(1):201.

15. Bennett C, Klingenberg S, Langholz E, Gluud L. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD006640.

16. Roberts I, Coats T, Edwards P, et al. HALT-IT – tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomised controlled trial. Trials. 2014 Nov 19;15:450.

17. Dyba J, Chan F, Lau K, Chan A, Chan H. Tranexamic Acid is a Weak Provoking Factor for Thromboembolic Events: A Systematic Review of the Literature. Blood. 2013; 122(21): 3629.

18. Myles PS, Smith JA, Forbes A, et al. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. N Engl J Med. 2016; 376(2):136-148.

19. Wang X, Mondal S, Wang J, et al. Effect of Activated Charcoal on Apixaban Pharmacokinetics in Healthy Subjects. American Journal of Cardiovascular Drugs. 2014;14(2):147-154.

20. Ollier E, Hodin S, Lanoiselée J, et al. Effect of Activated Charcoal on Rivaroxaban Complex Absorption. Clin Pharmacokinet. 2016 Dec 2.

21. Chai-adisaksopha C, Hillis C, Lim W, Boonyawat K, Moffat K, Crowther M. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thromb Haemost. 2015;13(10):1790-8.

22. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-4.

23. UW Anticoagulation Services. UW Medicine Pharmacy Services Web site. 2014. Available at https://depts.washington.edu/anticoag, Accessed March 8, 2017.

________________________________________________________________________
 

Table 1: Pharmacologic Profiles of Xa and Direct Thrombin Inhibitors^{4-8, 23}

t_max t_1/2, CrCl 50-80 t_1/2 CrCl < 30 Dialyzable?

Apixaban 3-4 h 15 h 17 h No

Dabigatran 1-3 h 17 h 28 h Yes

Edoxaban 1-2 h 10-14 h no data No

Rivaroxaban 2-4 h 9 h 10 h No



t_max = time to peak serum concentration after ingestion, t_1/2= serum half-life, CrCl= creatinine clearance in mL/min

*Average values assuming normal hepatic function. Aside from dabigatran, which has minimal hepatic clearance, all other DOACs can have prolonged half-lives in hepatic impairment.
 

Table 2: Management of Bleeding Patients Taking DOACs

Direct Thrombin Inhibitors (dabigatran)

Xa inhibitors (apixaban, edoxaban, rivaroxaban)Minor Bleeding

• Withhold DOAC

• Local hemostatic measures

Major Bleeding*

All of the above, AND

• Antifibrinolytic if bleeding persists

• Restore physiologic perfusion

• Charcoal if last dose within 2-8 hours

• Transfusion indications:

o Red blood cells: anemia

o Platelets: antiplatelet agents or thrombocytopenia

o Plasma: coagulopathy (dilution, DIC, liver failure), not for DOAC reversal

Life-threatening Bleeding**

All of the above, AND:

• Idarucizumab (confirm anticoagulant effect with thrombin time first)

• If idarucizumab is unavailable, use PCC

• Consider hemodialysis until hemostasis achieved, especially if patient in renal failure

All of the above, AND:

• Unactivated PCC (if available and calibrated to specific Xa inhibitor, confirm anticoagulant effect with anti-Xa level)



* Adapted from the International Society on Thrombosis and Hemostasis: bleeding with a fall in hemoglobin level ≥ 2 g/dL, OR bleeding leading to ≥ 2 units of PRBC transfused.²¹ Clinicians should perform risk stratification of bleeding episodes using vital signs, laboratory results, the area of bleeding, and patient comorbidities.

**Uncontrolled bleeding, OR symptomatic bleeding in a critical area or organ (such as intracranial, intraocular, intraspinal, retroperitoneal, pericardial, or intramuscular with compartment syndrome).