User login
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 dabigatran4-8 (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 Inhibitors4-8, 23
tmax t1/2, CrCl 50-80 t1/2 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
tmax = time to peak serum concentration after ingestion, t1/2= 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 dabigatran4-8 (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 Inhibitors4-8, 23
tmax t1/2, CrCl 50-80 t1/2 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
tmax = time to peak serum concentration after ingestion, t1/2= 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 dabigatran4-8 (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 Inhibitors4-8, 23
tmax t1/2, CrCl 50-80 t1/2 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
tmax = time to peak serum concentration after ingestion, t1/2= 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).