Clinical

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

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]

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]

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).

The opioid addiction medications buprenorphine and methadone should not be withheld from patients who are taking benzodiazepines or other drugs that depress the central nervous system, the Food and Drug Administration advised in a safety alert posted Sept. 20.

The combined use of these medication-assisted treatment (MAT) drugs and central nervous system (CNS) depressants can lead to serious side effects. But the harm associated with opioid addiction that remains untreated usually outweighs those risks, the agency said. After reviewing this issue, the FDA said, it is requiring that this information be added to the drug labels of buprenorphine and methadone in addition to “recommendations for minimizing the use of [MAT] drugs and benzodiazepines together.”

[email protected]

The opioid addiction medications buprenorphine and methadone should not be withheld from patients who are taking benzodiazepines or other drugs that depress the central nervous system, the Food and Drug Administration advised in a safety alert posted Sept. 20.

The combined use of these medication-assisted treatment (MAT) drugs and central nervous system (CNS) depressants can lead to serious side effects. But the harm associated with opioid addiction that remains untreated usually outweighs those risks, the agency said. After reviewing this issue, the FDA said, it is requiring that this information be added to the drug labels of buprenorphine and methadone in addition to “recommendations for minimizing the use of [MAT] drugs and benzodiazepines together.”

[email protected]

The opioid addiction medications buprenorphine and methadone should not be withheld from patients who are taking benzodiazepines or other drugs that depress the central nervous system, the Food and Drug Administration advised in a safety alert posted Sept. 20.

The combined use of these medication-assisted treatment (MAT) drugs and central nervous system (CNS) depressants can lead to serious side effects. But the harm associated with opioid addiction that remains untreated usually outweighs those risks, the agency said. After reviewing this issue, the FDA said, it is requiring that this information be added to the drug labels of buprenorphine and methadone in addition to “recommendations for minimizing the use of [MAT] drugs and benzodiazepines together.”

[email protected]

DALLAS – U.S. hospitals have recently shown a consistent and disturbing disconnect between reductions in their heart failure hospital readmission rates and heart failure mortality. Readmissions have dropped while mortality has risen.

“Despite reductions in 30-day heart failure readmissions in 89% of U.S. hospitals” during 2009-2016, “30-day heart failure mortality rates increased at 73%* of these ‘successful’ hospitals” during the same period,” Ahmad A. Abdul-Aziz, MD, said at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

*This article was updated October 5, 2017

DALLAS – U.S. hospitals have recently shown a consistent and disturbing disconnect between reductions in their heart failure hospital readmission rates and heart failure mortality. Readmissions have dropped while mortality has risen.

“Despite reductions in 30-day heart failure readmissions in 89% of U.S. hospitals” during 2009-2016, “30-day heart failure mortality rates increased at 73%* of these ‘successful’ hospitals” during the same period,” Ahmad A. Abdul-Aziz, MD, said at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

*This article was updated October 5, 2017

DALLAS – U.S. hospitals have recently shown a consistent and disturbing disconnect between reductions in their heart failure hospital readmission rates and heart failure mortality. Readmissions have dropped while mortality has risen.

“Despite reductions in 30-day heart failure readmissions in 89% of U.S. hospitals” during 2009-2016, “30-day heart failure mortality rates increased at 73%* of these ‘successful’ hospitals” during the same period,” Ahmad A. Abdul-Aziz, MD, said at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

*This article was updated October 5, 2017

BACKGROUND: Patient preferences regarding cardiopulmonary resuscitation (CPR) are important, especially during hospitalization when a patient’s health is changing, yet many patients are not adequately informed or involved in the decision-making process.

OBJECTIVES: We examined the effect of an informational video about CPR on hospitalized patients’ code status choices.

DESIGN: This was a prospective, randomized trial conducted at the Veteran’s Affairs Hospital in Minneapolis.

PARTICIPANTS: We enrolled 119 patients who were hospitalized on the general medicine service and at least 65 years old. The majority were men (97%) with a mean age of 75.

INTERVENTION: A video described code status choices: full code (CPR and intubation if required), do not resuscitate (DNR), and do not resuscitate/do not intubate (DNR/DNI). Participants were randomized to watch the video (n = 59) or usual care (n = 60).

MEASUREMENTS: The primary outcome was participants’ code status preferences. Secondary outcomes included a questionnaire designed to evaluate participants’ trust in their health care team and their knowledge and perceptions about CPR.

RESULTS: Participants who viewed the video were less likely to choose full code (37%), compared with participants in the usual-care group (71%), and were more likely to choose DNR/DNI (56% in the video group vs. 17% in the control group) (P < .00001). We did not see a difference in trust in their health care team or knowledge and perceptions about CPR as assessed by our questionnaire.

CONCLUSIONS: Hospitalized patients who watched a video about CPR and code status choices were less likely to choose full code and more likely to choose DNR/DNI.
 

Also in JHM this month

Influenza season hospitalization trends in Israel: A multi-year comparative analysis 2005/2006 through 2012/2013

AUTHORS: Aharona Glatman-Freedman, MD, MPH, Zalman Kaufman, MS, Yaniv Stein, BS, Hanna Sefty, MS, Hila Zadka, PhD, Barak Gordon, MD, MHA, Jill Meron, BSc, Ethel-Sherry Gordon, PhD, Rita Dichtiar, BSc, Ziona Haklai, MSc, Arnon Afek, MD, Tamy Shohat, MD, MPH



Appropriate reconciliation of cardiovascular medications after elective surgery and postdischarge acute hospital and ambulatory visits

AUTHORS: Jonathan S. Lee, MD, Ralph Gonzales, MD, MSPH, Eric Vittinghoff, PhD, Kitty K. Corbett, PhD, MPH, Kirsten E. Fleischmann, MD, Neil Sehgal, MD, MPH, Andrew D. Auerbach, MD, MPH



Patterns and appropriateness of thrombophilia testing in an academic medical center

AUTHORS: Nicholas Cox, PharmD, Stacy A. Johnson, MD, Sara Vazquez, PharmD, Ryan P. Fleming, PharmD, BCPS, Matthew T. Rondina, MD, David Kaplan, MD, Stephanie Chauv, PharmD, Gabriel V. Fontaine, PharmD, Scott M. Stevens, MD, Scott Woller, MD, Daniel M. Witt, PharmD, BCPS, FCCP



National trends (2007-2013) of Clostridium difficile infection in patients with septic shock: Impact on outcome

AUTHORS: Kshitij Chatterjee, MD, Abhinav Goyal, MD, Aditya Chada, MD, Krishna Siva Sai Kakkera, MD, Howard L Corwin, MD



Blood products provided to patients receiving inappropriate critical care

AUTHORS: Thanh H. Neville, MD, MSHS, Alyssa Ziman, MD, Neil S. Wenger, MD, MPH

BACKGROUND: Patient preferences regarding cardiopulmonary resuscitation (CPR) are important, especially during hospitalization when a patient’s health is changing, yet many patients are not adequately informed or involved in the decision-making process.

OBJECTIVES: We examined the effect of an informational video about CPR on hospitalized patients’ code status choices.

DESIGN: This was a prospective, randomized trial conducted at the Veteran’s Affairs Hospital in Minneapolis.

PARTICIPANTS: We enrolled 119 patients who were hospitalized on the general medicine service and at least 65 years old. The majority were men (97%) with a mean age of 75.

INTERVENTION: A video described code status choices: full code (CPR and intubation if required), do not resuscitate (DNR), and do not resuscitate/do not intubate (DNR/DNI). Participants were randomized to watch the video (n = 59) or usual care (n = 60).

MEASUREMENTS: The primary outcome was participants’ code status preferences. Secondary outcomes included a questionnaire designed to evaluate participants’ trust in their health care team and their knowledge and perceptions about CPR.

RESULTS: Participants who viewed the video were less likely to choose full code (37%), compared with participants in the usual-care group (71%), and were more likely to choose DNR/DNI (56% in the video group vs. 17% in the control group) (P < .00001). We did not see a difference in trust in their health care team or knowledge and perceptions about CPR as assessed by our questionnaire.

CONCLUSIONS: Hospitalized patients who watched a video about CPR and code status choices were less likely to choose full code and more likely to choose DNR/DNI.
 

Also in JHM this month

Influenza season hospitalization trends in Israel: A multi-year comparative analysis 2005/2006 through 2012/2013

AUTHORS: Aharona Glatman-Freedman, MD, MPH, Zalman Kaufman, MS, Yaniv Stein, BS, Hanna Sefty, MS, Hila Zadka, PhD, Barak Gordon, MD, MHA, Jill Meron, BSc, Ethel-Sherry Gordon, PhD, Rita Dichtiar, BSc, Ziona Haklai, MSc, Arnon Afek, MD, Tamy Shohat, MD, MPH



Appropriate reconciliation of cardiovascular medications after elective surgery and postdischarge acute hospital and ambulatory visits

AUTHORS: Jonathan S. Lee, MD, Ralph Gonzales, MD, MSPH, Eric Vittinghoff, PhD, Kitty K. Corbett, PhD, MPH, Kirsten E. Fleischmann, MD, Neil Sehgal, MD, MPH, Andrew D. Auerbach, MD, MPH



Patterns and appropriateness of thrombophilia testing in an academic medical center

AUTHORS: Nicholas Cox, PharmD, Stacy A. Johnson, MD, Sara Vazquez, PharmD, Ryan P. Fleming, PharmD, BCPS, Matthew T. Rondina, MD, David Kaplan, MD, Stephanie Chauv, PharmD, Gabriel V. Fontaine, PharmD, Scott M. Stevens, MD, Scott Woller, MD, Daniel M. Witt, PharmD, BCPS, FCCP



National trends (2007-2013) of Clostridium difficile infection in patients with septic shock: Impact on outcome

AUTHORS: Kshitij Chatterjee, MD, Abhinav Goyal, MD, Aditya Chada, MD, Krishna Siva Sai Kakkera, MD, Howard L Corwin, MD



Blood products provided to patients receiving inappropriate critical care

AUTHORS: Thanh H. Neville, MD, MSHS, Alyssa Ziman, MD, Neil S. Wenger, MD, MPH

BACKGROUND: Patient preferences regarding cardiopulmonary resuscitation (CPR) are important, especially during hospitalization when a patient’s health is changing, yet many patients are not adequately informed or involved in the decision-making process.

OBJECTIVES: We examined the effect of an informational video about CPR on hospitalized patients’ code status choices.

DESIGN: This was a prospective, randomized trial conducted at the Veteran’s Affairs Hospital in Minneapolis.

PARTICIPANTS: We enrolled 119 patients who were hospitalized on the general medicine service and at least 65 years old. The majority were men (97%) with a mean age of 75.

INTERVENTION: A video described code status choices: full code (CPR and intubation if required), do not resuscitate (DNR), and do not resuscitate/do not intubate (DNR/DNI). Participants were randomized to watch the video (n = 59) or usual care (n = 60).

MEASUREMENTS: The primary outcome was participants’ code status preferences. Secondary outcomes included a questionnaire designed to evaluate participants’ trust in their health care team and their knowledge and perceptions about CPR.

RESULTS: Participants who viewed the video were less likely to choose full code (37%), compared with participants in the usual-care group (71%), and were more likely to choose DNR/DNI (56% in the video group vs. 17% in the control group) (P < .00001). We did not see a difference in trust in their health care team or knowledge and perceptions about CPR as assessed by our questionnaire.

CONCLUSIONS: Hospitalized patients who watched a video about CPR and code status choices were less likely to choose full code and more likely to choose DNR/DNI.
 

Also in JHM this month

Influenza season hospitalization trends in Israel: A multi-year comparative analysis 2005/2006 through 2012/2013

AUTHORS: Aharona Glatman-Freedman, MD, MPH, Zalman Kaufman, MS, Yaniv Stein, BS, Hanna Sefty, MS, Hila Zadka, PhD, Barak Gordon, MD, MHA, Jill Meron, BSc, Ethel-Sherry Gordon, PhD, Rita Dichtiar, BSc, Ziona Haklai, MSc, Arnon Afek, MD, Tamy Shohat, MD, MPH



Appropriate reconciliation of cardiovascular medications after elective surgery and postdischarge acute hospital and ambulatory visits

AUTHORS: Jonathan S. Lee, MD, Ralph Gonzales, MD, MSPH, Eric Vittinghoff, PhD, Kitty K. Corbett, PhD, MPH, Kirsten E. Fleischmann, MD, Neil Sehgal, MD, MPH, Andrew D. Auerbach, MD, MPH



Patterns and appropriateness of thrombophilia testing in an academic medical center

AUTHORS: Nicholas Cox, PharmD, Stacy A. Johnson, MD, Sara Vazquez, PharmD, Ryan P. Fleming, PharmD, BCPS, Matthew T. Rondina, MD, David Kaplan, MD, Stephanie Chauv, PharmD, Gabriel V. Fontaine, PharmD, Scott M. Stevens, MD, Scott Woller, MD, Daniel M. Witt, PharmD, BCPS, FCCP



National trends (2007-2013) of Clostridium difficile infection in patients with septic shock: Impact on outcome

AUTHORS: Kshitij Chatterjee, MD, Abhinav Goyal, MD, Aditya Chada, MD, Krishna Siva Sai Kakkera, MD, Howard L Corwin, MD



Blood products provided to patients receiving inappropriate critical care

AUTHORS: Thanh H. Neville, MD, MSHS, Alyssa Ziman, MD, Neil S. Wenger, MD, MPH

BARCELONA – A program promoting broader anticoagulation of patients with atrial fibrillation that used education and feedback from practice audits produced a substantial increase in sustained anticoagulant use and cut strokes in a multinational study with almost 2,300 patients in 48 practices.

Among atrial fibrillation (AF) patients who were not on an anticoagulant at baseline (34% of the enrolled group) 48% of patients in the intervention group began anticoagulant treatment and remained on it for a year with intervention compared with 18% of patients in the control arm without the intervention, Christopher B. Granger, MD, said at the annual congress of the European Society of Cardiology.

The intervention, which highlighted to health care providers the opportunity to start their AF patients on anticoagulant treatment, “transforms how care is provided to this population” of AF patients, Dr. Granger said in a video interview. “Doing something like this can have enormous public health implications.”

IMPACT AF (The Clinical Trial to Improve Treatment With Blood Thinners in Patients With Atrial Fibrillation) randomized 2,281 AF patients in 48 practices in five middle-income countries: Argentina, Brazil, China, India, and Romania. Randomization was by practice, and patients were assigned to either usual care or to an intervention that ran educational sessions for patients and providers on the benefits of and best practices for using anticoagulants. The intervention also monitored anticoagulant use by the patients in each practice and gave providers case-by-case feedback on the care patients received. The educational component customized the feedback to focus on overcoming treatment barriers specific for each patient. This audit and feedback process was a key part of the intervention, Dr. Granger said.

In an adjusted analysis, among patients not on an anticoagulant at baseline, the ones managed in practices that received the intervention had a greater than fourfold likelihood of receiving anticoagulant treatment, compared with patients in practices with no intervention. The intervention was especially successful in transitioning patients off of aspirin treatment, considered ineffective for AF stroke prevention, and onto an anticoagulant, most commonly warfarin.

Overall, anticoagulant use rose by 12 percentage points from baseline among patients in the intervention practices and by 3 percentage points over baseline among the control patients, a statistically significant difference for the study’s primary endpoint.

During 1-year follow-up, 11 strokes occurred among patients managed in practices that received the intervention and 21 in those in control practices, a 52% relative hazard reduction linked with the intervention that was statistically significant, Dr. Granger reported. Concurrently with his talk, the results also appeared online (Lancet. 2017. doi: 10.1016/S0140-6736[17]32165-7).

“How will we take what we have learned [in IMPACT AF] and have it available to people who want to replicate this?” asked Dr. Granger. “We have partnered with several national cardiology societies, and we are working with them to optimize the tools and provide the tools we’ve used,” he said. “We will develop a website for people who want to take this information and use it in their practices.” Dr. Granger and his associates also are working with the Food and Drug Administration and other groups to come up with interventions specially designed for U.S. practice.

IMPACT AF received partial funding from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. Dr. Granger has received honoraria and research funding from all of these companies, and also from Janssen and Medtronic.

[email protected]

On Twitter @mitchelzoler

BARCELONA – A program promoting broader anticoagulation of patients with atrial fibrillation that used education and feedback from practice audits produced a substantial increase in sustained anticoagulant use and cut strokes in a multinational study with almost 2,300 patients in 48 practices.

Among atrial fibrillation (AF) patients who were not on an anticoagulant at baseline (34% of the enrolled group) 48% of patients in the intervention group began anticoagulant treatment and remained on it for a year with intervention compared with 18% of patients in the control arm without the intervention, Christopher B. Granger, MD, said at the annual congress of the European Society of Cardiology.

The intervention, which highlighted to health care providers the opportunity to start their AF patients on anticoagulant treatment, “transforms how care is provided to this population” of AF patients, Dr. Granger said in a video interview. “Doing something like this can have enormous public health implications.”

IMPACT AF (The Clinical Trial to Improve Treatment With Blood Thinners in Patients With Atrial Fibrillation) randomized 2,281 AF patients in 48 practices in five middle-income countries: Argentina, Brazil, China, India, and Romania. Randomization was by practice, and patients were assigned to either usual care or to an intervention that ran educational sessions for patients and providers on the benefits of and best practices for using anticoagulants. The intervention also monitored anticoagulant use by the patients in each practice and gave providers case-by-case feedback on the care patients received. The educational component customized the feedback to focus on overcoming treatment barriers specific for each patient. This audit and feedback process was a key part of the intervention, Dr. Granger said.

In an adjusted analysis, among patients not on an anticoagulant at baseline, the ones managed in practices that received the intervention had a greater than fourfold likelihood of receiving anticoagulant treatment, compared with patients in practices with no intervention. The intervention was especially successful in transitioning patients off of aspirin treatment, considered ineffective for AF stroke prevention, and onto an anticoagulant, most commonly warfarin.

Overall, anticoagulant use rose by 12 percentage points from baseline among patients in the intervention practices and by 3 percentage points over baseline among the control patients, a statistically significant difference for the study’s primary endpoint.

During 1-year follow-up, 11 strokes occurred among patients managed in practices that received the intervention and 21 in those in control practices, a 52% relative hazard reduction linked with the intervention that was statistically significant, Dr. Granger reported. Concurrently with his talk, the results also appeared online (Lancet. 2017. doi: 10.1016/S0140-6736[17]32165-7).

“How will we take what we have learned [in IMPACT AF] and have it available to people who want to replicate this?” asked Dr. Granger. “We have partnered with several national cardiology societies, and we are working with them to optimize the tools and provide the tools we’ve used,” he said. “We will develop a website for people who want to take this information and use it in their practices.” Dr. Granger and his associates also are working with the Food and Drug Administration and other groups to come up with interventions specially designed for U.S. practice.

IMPACT AF received partial funding from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. Dr. Granger has received honoraria and research funding from all of these companies, and also from Janssen and Medtronic.

[email protected]

On Twitter @mitchelzoler

BARCELONA – A program promoting broader anticoagulation of patients with atrial fibrillation that used education and feedback from practice audits produced a substantial increase in sustained anticoagulant use and cut strokes in a multinational study with almost 2,300 patients in 48 practices.

Among atrial fibrillation (AF) patients who were not on an anticoagulant at baseline (34% of the enrolled group) 48% of patients in the intervention group began anticoagulant treatment and remained on it for a year with intervention compared with 18% of patients in the control arm without the intervention, Christopher B. Granger, MD, said at the annual congress of the European Society of Cardiology.

The intervention, which highlighted to health care providers the opportunity to start their AF patients on anticoagulant treatment, “transforms how care is provided to this population” of AF patients, Dr. Granger said in a video interview. “Doing something like this can have enormous public health implications.”

IMPACT AF (The Clinical Trial to Improve Treatment With Blood Thinners in Patients With Atrial Fibrillation) randomized 2,281 AF patients in 48 practices in five middle-income countries: Argentina, Brazil, China, India, and Romania. Randomization was by practice, and patients were assigned to either usual care or to an intervention that ran educational sessions for patients and providers on the benefits of and best practices for using anticoagulants. The intervention also monitored anticoagulant use by the patients in each practice and gave providers case-by-case feedback on the care patients received. The educational component customized the feedback to focus on overcoming treatment barriers specific for each patient. This audit and feedback process was a key part of the intervention, Dr. Granger said.

In an adjusted analysis, among patients not on an anticoagulant at baseline, the ones managed in practices that received the intervention had a greater than fourfold likelihood of receiving anticoagulant treatment, compared with patients in practices with no intervention. The intervention was especially successful in transitioning patients off of aspirin treatment, considered ineffective for AF stroke prevention, and onto an anticoagulant, most commonly warfarin.

Overall, anticoagulant use rose by 12 percentage points from baseline among patients in the intervention practices and by 3 percentage points over baseline among the control patients, a statistically significant difference for the study’s primary endpoint.

During 1-year follow-up, 11 strokes occurred among patients managed in practices that received the intervention and 21 in those in control practices, a 52% relative hazard reduction linked with the intervention that was statistically significant, Dr. Granger reported. Concurrently with his talk, the results also appeared online (Lancet. 2017. doi: 10.1016/S0140-6736[17]32165-7).

“How will we take what we have learned [in IMPACT AF] and have it available to people who want to replicate this?” asked Dr. Granger. “We have partnered with several national cardiology societies, and we are working with them to optimize the tools and provide the tools we’ve used,” he said. “We will develop a website for people who want to take this information and use it in their practices.” Dr. Granger and his associates also are working with the Food and Drug Administration and other groups to come up with interventions specially designed for U.S. practice.

IMPACT AF received partial funding from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. Dr. Granger has received honoraria and research funding from all of these companies, and also from Janssen and Medtronic.

[email protected]

On Twitter @mitchelzoler

Receiving a statin prescription within a year after diagnosis of chronic obstructive pulmonary disease was associated with a 21% decrease in the subsequent risk of all-cause mortality and a 45% drop in risk of pulmonary mortality, according to the results of a large retrospective administrative database study.

The findings belie those of the recent Simvastatin in the Prevention of COPD Exacerbation (STATCOPE) trial, in which daily simvastatin (40 mg) did not affect exacerbation rates or time to first exacerbation in high-risk COPD patients, wrote Adam Raymakers, MSc, a doctoral candidate at the University of British Columbia, Vancouver, and his associates. Their study was observational, but the association between statin use and decreased mortality “persisted across several measures of statin exposure,” they wrote. “Our findings, in conjunction with previously reported evidence, suggests that there may be a specific subtype of COPD patients that may benefit from statin use.” The study appears in the September issue of Chest (2017;152;486-93).

copyright designer491/Thinkstock

Receiving a statin prescription within a year after diagnosis of chronic obstructive pulmonary disease was associated with a 21% decrease in the subsequent risk of all-cause mortality and a 45% drop in risk of pulmonary mortality, according to the results of a large retrospective administrative database study.

The findings belie those of the recent Simvastatin in the Prevention of COPD Exacerbation (STATCOPE) trial, in which daily simvastatin (40 mg) did not affect exacerbation rates or time to first exacerbation in high-risk COPD patients, wrote Adam Raymakers, MSc, a doctoral candidate at the University of British Columbia, Vancouver, and his associates. Their study was observational, but the association between statin use and decreased mortality “persisted across several measures of statin exposure,” they wrote. “Our findings, in conjunction with previously reported evidence, suggests that there may be a specific subtype of COPD patients that may benefit from statin use.” The study appears in the September issue of Chest (2017;152;486-93).

copyright designer491/Thinkstock

Receiving a statin prescription within a year after diagnosis of chronic obstructive pulmonary disease was associated with a 21% decrease in the subsequent risk of all-cause mortality and a 45% drop in risk of pulmonary mortality, according to the results of a large retrospective administrative database study.

The findings belie those of the recent Simvastatin in the Prevention of COPD Exacerbation (STATCOPE) trial, in which daily simvastatin (40 mg) did not affect exacerbation rates or time to first exacerbation in high-risk COPD patients, wrote Adam Raymakers, MSc, a doctoral candidate at the University of British Columbia, Vancouver, and his associates. Their study was observational, but the association between statin use and decreased mortality “persisted across several measures of statin exposure,” they wrote. “Our findings, in conjunction with previously reported evidence, suggests that there may be a specific subtype of COPD patients that may benefit from statin use.” The study appears in the September issue of Chest (2017;152;486-93).

copyright designer491/Thinkstock