Acessibilidade / Reportar erro

Clinical protocols for oral anticoagulant reversal during high risk of bleeding for emergency surgical and nonsurgical settings: a narrative review

Abstract

Background and objectives

Oral anticoagulants prevent thromboembolic events but expose patients to a significant risk of bleeding due to the treatment itself, after trauma, or during surgery. Any physician working in the emergency department or involved in the perioperative care of a patient should be aware of the best reversal approach according to the type of drug and the patient's clinical condition. This paper presents a concise review and proposes clinical protocols for the reversal of oral anticoagulants in emergency settings, such as bleeding or surgery.

Contents

The authors searched for relevant studies in PubMed, LILACS, and the Cochrane Library database and identified 82 articles published up to September 2020 to generate a review and algorithms as clinical protocols for practical use. Hemodynamic status and the implementation of general supportive measures should be the first approach under emergency conditions. The drug type, dose, time of last intake, and laboratory evaluations of anticoagulant activity and renal function provide an estimation of drug clearance and should be taken into consideration. The reversal agents for vitamin K antagonists are 4-factor prothrombin complex concentrate and vitamin K, followed by fresh frozen plasma as a second-line treatment. Direct oral anticoagulants have specific reversal agents, such as andexanet alfa and idarucizumab, but are not widely available. Another possibility in this situation, but with less evidence, is prothrombin complex concentrates.

Conclusion

The present algorithms propose a tool to help healthcare providers in the best decision making for patients under emergency conditions.

KEYWORDS
Reversal of oral anticoagulants; Warfarin; Non-vitamin K antagonists; Direct oral anticoagulants; Prothrombin complex concentrates; Idarucizumab; Andexanet alfa

Introduction

Oral anticoagulants are broadly used in the prevention of thromboembolic events and stroke in patients with atrial fibrillation and mechanical heart valves, those undergoing treatment for deep venous thrombosis, and patients with pulmonary embolism, as well as in the prevention of venous thromboembolism in medical and orthopedic surgery patients.11 Tadros R, Shakib S. Warfarin indications, risks and drug interactions. Aus Fam Phys. 2010;39:476-9.,22 Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e278S-325S. Oral anticoagulants have been used for more than 60 years, and its use is tending to increase worldwide as the population ages.

The vitamin K antagonist (VKA) warfarin was the pioneer oral anticoagulation drug and still has clinical importance. Its prescription has increased by 3.6 times in a 15-year period.33 Huhtakangas J, Tetri S, Juvels S, et al. Effect of increased warfarin use on warfarin-related cerebral hemorrhage: a longitudinal population-based study. Stroke. 2011;42:2431-5. Warfarin is a VKA that inhibits the synthesis of factors II, VII, IX, X and the anticoagulant proteins C and S.11 Tadros R, Shakib S. Warfarin indications, risks and drug interactions. Aus Fam Phys. 2010;39:476-9. Warfarin has a very high bioavailability and a long half-life, and its elimination is almost entirely via hepatic metabolism44 Kelly JG, OʼMalley K. Clinical Pharmacokinetics of Oral Anticoagulants. Clin Pharmacokinet. 1979;4:1-15.,55 O'Reilly RA. Vitamin K and other oral anticoagulant drugs. Annu Rev Med. 1976;27:245-61. (Table 1).

Table 1
Pharmacological properties of oral anticoagulants.

More recently, direct oral anticoagulants (DOACs) have become available as an alternative to warfarin. They provide direct, selective, and reversible inhibition of the coagulation factors showing similar efficacy and a safer bleeding profile with a faster onset of action, shorter duration after discontinuation, fewer food and drug interactions, easier administration with a fixed dose, and no need for routine laboratory monitoring of the anticoagulant effect.66 Cameron C, Coyle D, Richter T, et al. Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation. BMJ Open. 2014;4:e004301-12.

7 Jun M, Lix LM, Durand M, et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicenter, population based, observational study. BMJ. 2017;359:j4323.

8 Senoo K, Kondo Y, Miyazawa K, et al. Safety and efficacy of direct oral anticoagulants over warfarin in Japanese patients with acute venous thromboembolism: A meta-analysis. J Cardiol. 2017;69:763-8.
-99 Sardar P, Chatterjee S, Lavie CJ, et al. Risk of major bleeding in different indications for new oral anticoagulants: insights from a meta-analysis of approved dosages from 50 randomized trials. Int J Cardiol. 2015;179:279-87. The drugs available are factor Xa inhibitors (rivaroxaban, apixaban, betrixaban, and edoxaban) and direct thrombin inhibitors (dabigatran). Rivaroxaban, apixaban, and edoxaban have high bioavailability, short half-lives, and a high plasma protein binding ability (54-95%).1010 Mueck W, Lensing AW, Agnelli G, et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011;50:675-86.

11 Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37:74-81.
-1212 Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50:743-53. The direct thrombin inhibitor dabigatran is rapidly absorbed after oral administration, and it has low bioavailability, a longer half-life than Xa inhibitors, and low protein-binding ability1313 Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64:292-303. (Table 1).

Nonetheless, warfarin continues to be the most commonly used anticoagulant in the world because DOACs are not globally accessible, are expensive, and have not yet been extensively studied with regard to their use for all VKA indications.1414 Burn J, Pirmohamed M. Direct oral anticoagulants versus warfarin: is new always better than the old?. Open Heart. 2018;5:e000712.

Patients taking oral anticoagulants could face situations in which the acute reversal of therapy is necessary, such as life-threatening bleeding due to treatment or acute injury, prior to invasive procedures, or other emergency circumstances with a high risk of bleeding. Coagulation factor replacement with prothrombin complex concentrates (PCCs), which consist of 3-factor PCC (II, IX, and X), 4-factor PCC (II, VII, IX, and X), and activated PCC (aPCC) with four coagulation factors (in inactive and activated forms), as well as fresh frozen plasma (FFP), are well-known nonspecific reversal agents for oral anticoagulants.1515 Thigpen JL, Limdi NA. Reversal of oral anticoagulation. Pharmacotherapy. 2013;33:1199-213. Recently, specific reversal agents for DOACs were approved, including andexanet alfa for the reversal of apixaban and rivaroxaban, and idarucizumab for dabigatran.1616 Almegren M. Reversal of direct oral anticoagulants. Vasc Health Risk Manag. 2017;13:287-92.

Clinicians and surgeons working in emergency departments or involved in the perioperative care of a patient taking oral anticoagulants must know the best approach to the rapid reversal of anticoagulant activity and should choose the safest and most efficient protocol according to the type of drug, its pharmacokinetic profile, and the patient's medical history and clinical condition. This paper provides a concise narrative review regarding the reversal of anticoagulants and recommends clinical algorithms for patients taking oral anticoagulants who need urgent reversal of the therapy. These protocols include emergency surgical and nonsurgical scenarios and provide algorithms for both VKA and DOAC reversal.

Methods

In this review, the authors searched national and international literature to identify currently available data on the main points of the management of oral anticoagulant reversal for the development of this clinical protocol.

The authors included systematic and nonsystematic literature reviews, randomized clinical trials, prospective and retrospective cohort studies with or without a control group, case reports, case series, and guidelines addressing the reversal of oral anticoagulation in humans under emergency circumstances. The studies were written in Portuguese or English, and published in the last 12 years up to September 2020. They excluded in vitro investigations as well as studies using animals.

The PubMed, LILACS, and Cochrane Library databases were used with the following search terms (keywords and delimiters): oral anticoagulant and reversal, warfarin and reversal, nonvitamin K antagonists, direct oral anticoagulants and reversal, prothrombin complex concentrates, idarucizumab, and andexanet alfa.

Results

The authors chose 82 articles jointly according to their relevance, with full agreement among the reviewers. Table 2 summarizes the most relevant evidence identified on the reversal of anticoagulants: clinical trials, systematic reviews, cohorts, and case series studies. A flow chart documenting the process of selecting the studies is presented in Figure 1.

Figure 1
Study selection process.

Table 2
Summarized evidence regarding the reversal of warfarin and DOACs.

Emergency anticoagulation reversal: general considerations

In an emergency scenario, the strategy for oral anticoagulant reversal depends on the type of drug; the presence, location, and level of bleeding; and the need for and type of invasive procedure.

Patients taking oral anticoagulants have a higher risk of spontaneous bleeding due to treatment or trauma. Attention should be given to head injuries; most anticoagulated patients are elderly, with a high risk of intracerebral hemorrhage (ICH).1717 Schols AM, Schreuder FH, van Raak EP, et al. Incidence of oral anticoagulant-associated intracerebral hemorrhage in the Netherlands. Stroke. 2014;45:268-70.

The first approach in a bleeding situation in anticoagulated patients is the identification of the bleeding source and severity of bleeding (Fig. 2). Evaluation of the patient's hemodynamic status should be performed and must be closely monitored.

Figure 2
Assessment of bleeding in patients taking oral anticoagulants. * All the measures are added according to the intensity of the bleeding.

General measures providing supportive care with hemostatic procedures (mechanical compression, use of topical hemostats, sutures, vessel clipping, etc.), volume replacement and/or transfusions should be established, with an evaluation of the necessity for an invasive procedure as treatment (surgery/embolization) and the risk of bleeding due to the procedure on its own versus the thrombotic risk due to anticoagulant withdrawal.

Concomitant medications, such as antiplatelet therapy, could interfere with anticoagulant activity. Patients taking warfarin should be questioned about the use of antibiotics, nonsteroidal anti-inflammatory drugs, acetaminophen, metronidazole, amiodarone, antiepileptic drugs, and selective serotonin reuptake inhibitors and the ingestion of foods that prolong the international normalized ratio (INR).11 Tadros R, Shakib S. Warfarin indications, risks and drug interactions. Aus Fam Phys. 2010;39:476-9. Patients taking DOACs have fewer drug interactions, but a pharmacokinetic study showed that azole-antimycotics, HIV protease inhibitors, phenytoin, rifampin, and amiodarone could interfere with drug activity.1818 Kustos SA, Fasinu PS. Direct-Acting Oral Anticoagulants and Their Reversal Agents—An Update. Medicines (Basel). 2019;6:E103.

19 Mueck W, Kubitza D, Becka M. Coadministration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76:455-66.
-2020 Chang SH, Chou IJ, Yeh YH, et al. Association between use of nonvitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA. 2017;318:1250-9.

Laboratory evaluations help guiding the management of patients during emergencies by detecting and quantifying the remaining anticoagulant activity, and are essential for the assessment of hemostasis before surgery. These evaluations must include the coagulation status, blood cell count, blood group, and hepatic and renal function. Abnormal renal and liver functions affect the metabolism and elimination of the drug. Renal perfusion and urine output should be maintained to help eliminate anticoagulant drugs. Laboratory evaluation of anticoagulation activity will be further discussed in this paper.

The type, dosage, and time of the last intake of an oral anticoagulant provide the time for elimination according to its half-life and patient renal function. The drug must be suspended immediately after a bleeding episode. At the time of reintroduction of the drug, the need for dose adjustment must be evaluated in cases of spontaneous bleeding.

The anticoagulant should not be suspended in cases of a small invasive procedure with minimal bleeding risk, such as blood tests, dental extraction, dermatological biopsies, and gastrointestinal endoscopic procedures without the risk of bleeding.2121 Zullo A, Hassan C, Radaelli F. Gastrointestinal endoscopy in patients on anticoagulant therapy and antiplatelet agents. Ann Gastroenterol. 2017;30:7-14. However, in cases of moderate to major bleeding or surgical indication, the balance between the risk of bleeding and the risk of a thromboembolic event must be considered, and withdrawal of the drug is recommended in cases of a high-risk scenario such as ICH; neuraxial anesthesia; and abdominal, cardiothoracic, intracranial, orthopedic operations.2222 Frontera JA, Lewin JJ, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: Executive Summary. A Statement for Healthcare Professionals From the Neurocritical Care Society and the Society of Critical Care Medicine. Crit Care Med. 2016;44:2251-7.

23 Kaatz S, Mahan CE, Nakhle A, et al. Management of Elective Surgery and Emergent Bleeding with Direct Oral Anticoagulants. Curr Cardiol Rep. 2017;19:124-34.
-2424 McIlmoyle K, Tran H. Perioperative management of oral anticoagulation. BJA Education. 2018;18:259-64. The possibility of postponing surgery should be evaluated, with a delay long enough to promote drug clearance. Surgery with a high risk of bleeding must be postponed as long as possible. In patients taking VKAs, drug withdrawal is necessary for at least 5 days prior to surgery for drug clearance.2424 McIlmoyle K, Tran H. Perioperative management of oral anticoagulation. BJA Education. 2018;18:259-64. The withdrawal of DOACs will vary according to the risk of bleeding, and it is recommended 2 days before a high-risk procedure and 1 day before a low-risk procedure.2525 Douketis JD, Spyropoulos AC, Duncan J, et al. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med. 2019;179:1469-78. For patients under dabigatran with a clearance of creatinine less than 50 mL.min-1, the withdrawal is 4 days before surgery with a high-risk of bleeding and 2 days for low-risk procedures.2525 Douketis JD, Spyropoulos AC, Duncan J, et al. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med. 2019;179:1469-78.

A reversal agent should be used in cases of bleeding not responding to supportive measures, uncontrolled, major, life-threatening bleeding, bleeding located in critical organs (central nervous system, abdominal, thoracic), trauma, or urgent surgery.2626 Xu Y, Schulman S, Dowlatshahi D, et al. Bleeding Effected by Direct Oral Anticoagulants (BLED-AC) Study Group. Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study. Chest. 2017;152:81-91. Urgent surgery requires immediate reversal, clotting factor supplements (provided by PCCs), and intensive care support.2626 Xu Y, Schulman S, Dowlatshahi D, et al. Bleeding Effected by Direct Oral Anticoagulants (BLED-AC) Study Group. Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study. Chest. 2017;152:81-91.

The use of tranexamic acid (TXA) as a hemostatic agent significantly reduces mortality in bleeding trauma patients,2727 Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23-32. and it is inexpensive with few side effects.2828 Pabinger I, Fries D, Schöchl H, et al. Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis. Wien Klin Wochenschr. 2017;129:303-16. TXA can be used in cases of major bleeding in patients taking oral anticoagulants and/or trauma patients within 3 hours. Its mechanism of action is based on competitive inhibition of the activation of plasminogen to plasmin, preventing clot lysis.

The reversal of warfarin

The reversal of warfarin is based on the clinical scenario and the evaluation of INR, with a therapeutic range of 2 to 3. For these patients, the prothrombin time (PT) and INR provide the status of VKA activity.2929 Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:160S-98S. Warfarin reversal is accomplished with the administration of PCCs, preferably 4-factor PCC, and vitamin K.3030 Goldstein JN, Refaai MA, Milling TJ, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, noninferiority, randomised trial. Lancet. 2015;385(9982):2077-87. If those are not available, fresh frozen plasma (FFP), 3-PCC, or aPCC could also be used (Fig. 3).

Figure 3
Reversal due to bleeding after trauma, due to spontaneous bleeding and/or before surgery in patients taking warfarin. VKA, Vitamin K antagonist; BP, Blood pressure; HR, Heart rate; FFP, Fresh frozen plasma.** Tranexamic acid.*** Low molecular weight heparin.

Patients at very high risk of a thromboembolic event should use low molecular weight heparin (LMWH) after warfarin discontinuation as a bridging anticoagulation strategy.2424 McIlmoyle K, Tran H. Perioperative management of oral anticoagulation. BJA Education. 2018;18:259-64.

Vitamin K is not a direct hemostatic agent but rather a cofactor for the activation of factors II, VII, IX, X, and the anticoagulant proteins C and S.3131 Dzik WS. Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion. 2012;52:45S-55S. The usual dose of vitamin K varies from 5 to 10 mg or an even lower dose (1 to 3 mg) via the intravenous route, and it should be combined with coagulation factor administration in an emergency setting because, alone, it could take from 4 to 24 hours to normalize coagulation.3232 Bhatia M, Talawadekar G, Parihar S, et al. An audit of the role of vitamin K in the reversal of International Normalised Ratio (INR) in patients undergoing surgery for hip fracture. Ann R Coll Surg Engl. 2010;92:473-6.

33 Burbury KL, Milner A, Snooks B, et al. Short-term warfarin reversal for elective surgery using low-dose intravenous vitamin K: safe, reliable and convenient. Br J Haematol. 2011;154:626-34.
-3434 Pautas E, Peyron I, Bouhadiba S, et al. Reversal of over anticoagulation in very elderly hospitalized patients with an INR above 5.0: 24-hour INR response after vitamin K administration. Am J Med. 2011;124:527-33.

PCCs are considered the treatment of choice for VKA reversal in emergency settings, such as in patients with significant bleeding.3535 Chai-Adisaksopha C, Hillis C, Siegal DM, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost. 2016;116:879-90. Four-factor PCC is a plasma-derived product that restocks the vitamin K-dependent proteins, factors II, VII, IX, X, and proteins C and S. It is used for warfarin reversal, and it shows efficacy in factor Xa inhibitor reversal but limited evidence for thrombin inhibitor reversal.3636 Allison TA, Lin PJ, Gass JA, et al. Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients. J Intensive Care Med. 2020;35:903-8.

The administration of 4-factor PCC is performed intravenously with rapid infusion and low volume, promoting reversal of warfarin in 10 minutes.3737 Kerebel D, Joly LM, Honnart D, et al. A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal. Crit Care. 2013;17:R4. The risk involved in the use of PCCs is mainly allergic reactions, heparin-induced thrombocytopenia (HIT, for preparations containing heparin), and thromboembolic complications;3838 Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011;106:429-38.,3939 Milling TJ, Refaai MA, Goldstein JN, et al. Thromboembolic Events After Vitamin K Antagonist Reversal With 4-Factor Prothrombin Complex Concentrate: Exploratory Analyses of Two Randomized, Plasma-Controlled Studies. Ann Emerg Med. 2016;67:96-105.e5. however, proteins C and S in 4-factor PCC may improve its safety profile as they are coagulation inhibitors, decreasing the risk of thromboembolic events after reversal.

Prospective, randomized clinical trials show the clinical efficacy of 4-factor PCC in the reversal of warfarin as being superior to that of FFP in patients presenting VKA-related ICH4040 Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15:566-73. and achieving faster homeostasis in patients needing reversal for surgical interventions.3030 Goldstein JN, Refaai MA, Milling TJ, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, noninferiority, randomised trial. Lancet. 2015;385(9982):2077-87. A retrospective observational study demonstrated the efficacy and safety of warfarin reversal using 4-factor PCC and vitamin K in acute ischemic stroke patients before undergoing intravenous thrombolysis;4141 Chausson N, Soumah D, Aghasaryan M, et al. Reversal of Vitamin K Antagonist Therapy Before Thrombolysis for Acute Ischemic Stroke. Stroke. 2018;49:2526-8. in patients with continuous flow left ventricular assistive devices presenting bleeding or the need for urgent surgery, with no thromboembolic event observed;4242 Rimsans J, Levesque A, Lyons E, et al. Four-factor prothrombin complex concentrate for warfarin reversal in patients with left ventricular assist devices. J Thromb Thrombolysis. 2018;46:180-5. in patients with intracranial bleeding requiring urgent neurosurgical intervention;4343 Mačiukaitienė J, Bilskienė D, Tamašauskas A, et al. Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Bleeding in Neurosurgical Patients: A Single-Center Experience. Medicina. 2018;54:22-31. and in patients undergoing early orthopedic surgery (within 24 hours) due to hip fractures.4444 Mattisson L, Lapidus LJ, Enocson A. Is fast reversal and early surgery (within 24 h) in patients on warfarin medication with trochanteric hip fractures safe? A case-control study. BMC Musculoskelet Disord. 2018;19:203-10. In an observational study of 143 patients on warfarin, the use of 4-factor PCC was safe as a reversal agent mainly for bleeding and prior to surgery, with 5 cases of thromboembolic complications.4545 Hedges A, Coons JC, Saul M, et al. Clinical effectiveness and safety outcomes associated with prothrombin complex concentrates. J Thromb Thrombolysis. 2015;42:1-5. Evidence regarding fixed doses of 1000 units and 1500 units of 4-factor PCC showed a similar efficacy compared to weight-based dosing.4646 Scott R, Kersten B, Basior J, et al. Evaluation of Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal in Patients with Intracranial Hemorrhage. J Emerg Med. 2018;54:861-6.,4747 Astrup G, Sarangarm P, Burnett A. Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis. J Thromb Thrombolysis. 2018;45:300-5.

Four-factor PCC is preferred over 3-factor PCC because 4-factor PCC leads to a more significant reduction in the INR,4848 Holt T, Taylor S, Abraham P, et al. Three- versus four-factor prothrombin complex concentrate for the reversal of warfarin-induced bleeding. Int J Crit Illn Inj Sci. 2018;8:36-40. and the survival rate is higher.4949 Voils SA, Holder MC, Premraj S, et al. Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for emergent warfarin reversal. Thromb Res. 2015;136:595-8. aPCC proved to be more effective and faster than FFP for warfarin reversal in patients with traumatic ICH,5050 Carothers C, Giancarelli A, Ibrahim J, et al. Activated prothrombin complex concentrate for warfarin reversal in traumatic intracranial hemorrhage. J Surg Res. 2018;223:183-7.,5151 Rowe AS, Mahbubani PS, Bucklin MH, et al. Activated Prothrombin Complex Concentrate versus Plasma for Reversal of Warfarin-Associated Hemorrhage. Pharmacotherapy. 2016;36:1132-7. but it is not indicated for all patients because it may present a higher thrombotic risk compared to 4-PCC due to a high content of both prothrombin and thrombin; however, no comparative safety study has been identified.

Although FFP is much less expensive than 4-PCC, current guidelines recommend the use of 4-factor PCC over FFP.5252 Tran HA, Chunilal SD, Harper PL, et al. Australasian Society of Thrombosis and Haemostasis (ASTH). An update of consensus guidelines for warfarin reversal. Med J Aust. 2013;198:198-9.

53 Spahn DR, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019;23:98.
-5454 Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032-60.,7070 Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76:594-622. Four-factor PCC has a safer profile and faster action than FFP in patients undergoing cardiopulmonary bypass surgery.5555 Demeyere R, Gillardin S, Arnout J, et al. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99:251-60. A systematic review and meta-analysis of 13 studies showed that PCC significantly reduces all-cause mortality, reduces the INR faster and is effective in smaller volumes compared to FFP, without an increased risk of thromboembolic events.3535 Chai-Adisaksopha C, Hillis C, Siegal DM, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost. 2016;116:879-90. FFP is a human product that contains all coagulation factors, including fibrinogen, and it should be administered with Vitamin K.3131 Dzik WS. Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion. 2012;52:45S-55S. To use FFP, it is essential to verify ABO compatibility. A larger infused volume is required (15 mL.kg-1), increasing the risk of transfusion-associated circulatory overload and worsening renal function in patients with renal impairment.3535 Chai-Adisaksopha C, Hillis C, Siegal DM, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost. 2016;116:879-90. All the characteristics of FFP, including long defrosting time and long infusion time, show that it is not an ideal therapy for urgent or emergency settings. Additionally, the use of FFP requires consideration of the risk of venous thromboembolism, allergic reactions, anaphylactic reactions, transfusion-related acute lung injury (TRALI), hemolysis, and infections.5656 Choi S, Casias M, Tompkins D, et al. Blood, blood components, plasma, and plasma products. Side Effects of Drugs Annual. 2019;41:373-86.

Recombinant activated factor VII (rFVIIa) is a hemostatic agent that increases thrombin generation by activating factor X at the site of vascular injury. It should not be used as a single agent to reversal because it is usually not capable of restoring hemostasis. The actual recommendation is not to use rFVIIa for warfarin reversal unless no other option is available, or in case of failure with previous treatments. A review of 63 patients with warfarin-ICH showed that both rFVIIa and PCC, in addition to vitamin K, are more effective with faster reversal than FFP but are associated with more INR rebound with rFVIIa.5757 Woo CH, Patel N, Conel C, et al. Rapid warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII and prothrombin complex concentrate. World Neurosurg. 2014;81:110-5. rFVIIa seems superior to 3-factor PCC for warfarin reversal,5858 Chapman SA, Irwin ED, Abou-Karam NM, et al. Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal. World J Emerg Surg. 2014;9:27-34. and their joint administration could be an option because 3-factor PCC has a lack of adequate levels of factor VII; however, their efficacy remains inferior to 4-factor PCC alone.5959 Sarode R, Matevosyan K, Bhagat R, et al. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg. 2012;116:491-7.,6060 Barton CA, Hom M, Johnson NB, et al. Protocolized warfarin reversal with 4-factor prothrombin complex concentrate versus 3-factor prothrombin complex concentrate with recombinant factor VIIa. Am J Surg. 2018;215:775-9. rFVIIa is more expensive than PCCs and has a rapid but short duration of action. Data from a literature review show that the use of rFVIIa as a prothrombotic agent could result in an increased risk of thromboembolic events, especially in elderly patients and when used for off-label indications such as the reversal of anticoagulant agents.6161 Mehringer SL, Klick Z, Bain J, et al. Activated Factor 7 Versus 4-Factor Prothrombin Complex Concentrate for Critical Bleeding Post-Cardiac Surgery. Ann Pharmacother. 2018;52:533-7.

62 Yank V, Tuohy CV, Logan AC, et al. Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications. Ann Intern Med. 2011;154:529-40.

63 Matino D, Makris M, Dwan K, et al. Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors. Cochrane Database Syst Rev. 2015;:CD004449.
-6464 OConnell KA, Wood JJ, Wise RP, et al. Thromboembolic Adverse Events After Use of Recombinant Human Coagulation Factor VIIa. JAMA. 2006;295:293-8.

The reversal of DOACs

Active charcoal could be useful by helping reduce the absorption of DOACs (if the last dose was less than 2 hours before an emergency).6565 Exner T, Ahuja M, Ellwood L. Effect of an activated charcoal product (DOAC Stop™) intended for extracting DOACs on various other APTT-prolonging anticoagulants. Clin Chem Lab Med. 2019;57:690-6. Hemostatic strategies using specific DOACs reversal agents should always be considered for patients with major bleeding, if available.7070 Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76:594-622.

The factor Xa inhibitors

Rivaroxaban, apixaban, and edoxaban anticoagulant action can be monitored by anti-FXa activity.1818 Kustos SA, Fasinu PS. Direct-Acting Oral Anticoagulants and Their Reversal Agents—An Update. Medicines (Basel). 2019;6:E103. The factor Xa inhibitors at on-therapy or above on-therapy levels may not affect PT values or may induce a significant prolongation of the PT.6666 Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the nonvitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64:1128-39.,6767 Conway SE, Hwang AY, Ponte CD, et al. Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know. Pharmacotherapy. 2017;37:236-48.

Andexanet alfa is the specific Xa inhibitor that is currently on the market. Literature reports the use of 4-factor PCC or aPCC as non-specific, off-label, Xa inhibitor reversal agents, if andexanet alfa is not available (Fig. 4).

Figure 4
Reversal due to bleeding after trauma, due to spontaneous bleeding and/or before surgery in patients taking DOACs. BP, Blood pressure; HR, Heart rate; Hb, Hemoglobin.* Direct oral anticoagulant.** Tranexamic acid.

Andexanet alfa binds Xa inhibitors competitively with high affinity. It is indicated only for patients with severe, life-threatening bleeding, 18 hours within the last dose of anticoagulant.6868 Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373:2413-24. The administration is performed intravenously, as a bolus and via infusion, and the effect is observed 5 minutes after intravenous administration, up to 2 hours after administration of the bolus and 1 to 2 hours after a 2-hour infusion.6868 Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373:2413-24. The efficacy of andexanet alfa regarding the reversal of rivaroxaban and apixaban was first evaluated in 101 healthy volunteers, showing at least 80% reversal of anti-factor Xa activity.6868 Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373:2413-24. This effect started 2 to 5 minutes after the bolus and lasted 2 hours after the bolus. In patients receiving Xa inhibitors (n = 352) presenting with major acute bleeding (mostly gastrointestinal or intracranial), treatment with andexanet alfa in a bolus followed by a 2-hour infusion showed that effective hemostasis was achieved in 82% of patients after 12 hours of reversal administration, and 10% of patients presented thromboembolic events within 30 days.6969 Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019;380:1326-35.

High cost, limited availability, and the lack of clinical experience limit the use of andexanet alfa and other specific reversal agents. Anti-factor Xa is almost all protein bound; therefore, it is not possible to remove it by dialysis. Four-factor PCC is the non-specific agent most commonly used for reversal and guidelines support its use despite low evidence level.2222 Frontera JA, Lewin JJ, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: Executive Summary. A Statement for Healthcare Professionals From the Neurocritical Care Society and the Society of Critical Care Medicine. Crit Care Med. 2016;44:2251-7.,7070 Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76:594-622.,7171 Cuker A, Burnett A, Triller D, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol. 2019;94:697-709. Data on the use of PCC for anti-factor Xa are still limited. A single bolus of 50 IU.kg-1 of 4-factor PCC completely reversed the effect of rivaroxaban in 12 healthy subjects, with normal PT in 12.8 ± 1.0 seconds and maintained this effect for 24 hours.7272 Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-9. In a meta-analysis, PCCs efficiently reversed the factor Xa inhibitors, represented by a significantly decreased PT and increased endogenous thrombin potential.7373 da Luz LT, Marchand M, Nascimento B, et al. Efficacy and safety of the drugs used to reverse direct oral anticoagulants: a systematic review and meta-analysis. Transfusion. 2017;57:1834-46. Four-factor PCC promoted hemostasis without any thromboembolic event in trauma patients (n = 33) presenting major bleeding using direct factor Xa inhibitors, mostly rivaroxaban,3636 Allison TA, Lin PJ, Gass JA, et al. Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients. J Intensive Care Med. 2020;35:903-8. and in 21 patients undergoing emergency surgery/procedures.7474 Piran S, Gabriel C, Schulman S. Prothrombin complex concentrate for reversal of direct factor Xa inhibitors prior to emergency surgery or invasive procedure: a retrospective study. J Thromb Thrombolysis. 2018;45:486-95. The use of a fixed dose of 2000 IU (approximately 25 IU.kg-1) of 4-factor PCC in 84 patients with major bleeding, mostly ICH and gastrointestinal bleeding, was effective in 69.1% of patients for the reversal of rivaroxaban and apixaban, with a low incidence of thromboembolic events and death (3 ischemic strokes leading to death).7575 Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrate: a cohort study. Blood. 2017;130:1706-12. In a prospective cohort of 66 patients on rivaroxaban or apixaban with major bleeding, 65% achieved good hemostasis with 2000 IU 4-factor PCC, but 8% presented thromboembolic events.7676 Schulman S, Gross PL, Ritchie B, et al. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemost. 2018;118:842-51. A dose-weight-based 50 IU.kg-1 to a maximum of 5000 IU of 4-factor PCC was evaluated in the reversal of apixaban and rivaroxaban action in 29 bleeding patients (most of them exhibiting ICH and gastrointestinal bleeding)7777 Sheikh-Taha M. Treatment of apixaban- and rivaroxaban-associated major bleeding using 4-factor prothrombin complex concentrate. Intern Emerg Med. 2019;14:265-9. and 14 ICH patients,7878 Harrison SK, Garrett JS, Kohman KN, et al. Comparison of outcomes in patients with intracranial hemorrhage on factor Xa inhibitors versus vitamin K antagonists treated with 4-factor prothrombin complex concentrate. BUMC Proc. 2018;31:153-6. with no thromboembolic events observed. Forty-three patients received 25 to 50 IU.kg-1 4-factor PCC for the reversal of rivaroxaban or apixaban due to major bleeding or invasive emergency procedures, with only one thromboembolic event.7979 Tao J, Bukanova EN, Akhtar S. Safety of 4-factor prothrombin complex concentrate (4F-PCC) for emergent reversal of factor Xa inhibitors. J Intensive Care. 2018;6:34-40. The efficacy and safety of 4-factor PCC for the reversal of Xa inhibitors were demonstrated in 18 patients presenting with traumatic ICH, hemorrhage stroke, subarachnoid hemorrhage, and tumoral hemorrhage, with one thromboembolic event.8080 Grandhi R, Newman WC, Zhang X, et al. Administration of 4-factor prothrombin complex concentrate as an antidote for intracranial bleeding in patients taking direct factor Xa inhibitors. World Neurosurg. 2015;84:1956-61. In a retrospective cohort, reversal of direct factor Xa inhibitors with 4-factor PCC did not increase mortality or thromboembolic events in patients with traumatic ICH.8181 Dybdahl D, Walliser G, Chance Spalding M, et al. Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage. Am J Emerg Med. 2019;37:1907-11. A meta-analysis with ten case series including 340 patients receiving 4-factor PCC showed that it was safe and effective for the reversal of factor Xa inhibitor in patients with major bleeding. However, the authors classified this meta-analysis as low-quality evidence because they did not identify comparative studies.8282 Piran S, Khatib R, Schulman S, et al. Management of direct factor Xa inhibitor-related major bleeding with prothrombin complex concentrate: a meta-analysis. Blood Adv. 2019;3:158-67. The use of PCCs for the reversal of factor Xa inhibitors before immediate neurosurgery was reported in six cases, but 50% of the cases presented severe bleeding during the operation, with three deaths due to bleeding.8383 Senger S, Keiner D, Hendrix P, et al. New target-specific oral anticoagulants and intracranial bleeding: management and outcome in a single-center case series. World Neurosurg. 2016;88:132-9. In the observation of the reversal of DOACs using PCC to manage bleeding, the dose of 25 IU.kg-1 seemed to result in a better outcome than did a higher dose.8484 Green L, Tan J, Antoniou S, et al. Haematological management of major bleeding associated with direct oral anticoagulants- UK experience. Br J Haematol. 2019;185:514-22. Preference should be given to nonactivated PCC because it presents more data available in the literature and probably has lower prothrombotic activity. Reports of case series studies and retrospective analyses show that aPCC was effective for the reversal of rivaroxaban in a patient with subdural hematoma8585 Maurice-Szamburski A, Graillon T, Bruder N. Favorable outcome after a subdural hematoma treated with FEIBA in a 77-year-old patient treated by rivaroxaban. J Neurosurg Anesthesiol. 2014;26:183. and in the setting of hemorrhage or the need for urgent surgical procedures.8686 Engelbart JM, Zepeski A, Galet C, et al. Safety and effectiveness of Factor Eight Inhibitor Bypassing Activity for direct oral anticoagulant-related hemorrhage reversal. Am J Emerg Med. 2019;37:214-9.

87 Dager WE, Roberts AJ, Nishijima DK. Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thromb Res. 2019;173:71-6.

88 Schultz NH, Lundblad R, Holme PA. Activated prothrombin complex concentrate to reverse the factor Xa inhibitor (apixaban) effect before emergency surgery: a case series. J Med Case Rep. 2018;12:138.
-8989 Dibu JR, Weimer JM, Ahrens C, et al. The Role of FEIBA in Reversing Novel Oral Anticoagulants in Intracerebral Hemorrhage. Neurocrit Care. 2016;24:413-20.

The thrombin inhibitor

The diluted thrombin time (DTT) and the ecarin clotting time (ECT) are the assays suitable for quantification of dabigatran.6666 Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the nonvitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64:1128-39.,6767 Conway SE, Hwang AY, Ponte CD, et al. Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know. Pharmacotherapy. 2017;37:236-48.,9090 Van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-27. The ECT test provides a consistent direct measurement of thrombin inhibitor activity, but it is not widely available. Patients under dabigatran may present normal or increased aPTT and TT. A normal range of these parameters does not rule out the anticoagulation effect, and an increased range may not indicate a more imminent bleeding risk.9090 Van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-27.

Removal through dialysis is possible, taking at least 4 hours to eliminate approximately 60 to 70% of the drug.9191 Stangier J, Rathgen K, Stähle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-center study. Clin Pharmacokinet. 2010;49:259-68.,9292 Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-center study in patients with end-stage renal disease. Thromb Haemost. 2013;109:596-605. Therefore, patients who are hemodynamically unstable due to bleeding are not candidates for dialysis.

Reversal of dabigatran is achieved with idarucizumab. If this drug is not available, limited evidence supports the use of aPCC or PCC at 50 U.kg-1 (maximum dose 4000 units) (Fig. 4). Idarucizumab is a humanized monoclonal antibody fragment that binds dabigatran and acts as a specific reversal agent in cases of emergency surgery or urgent procedures, or major bleeding, life-threatening bleeding, or uncontrolled bleeding.9393 Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. N Engl J Med. 2017;377:431-41. It takes 2.5 hours for bleeding cessation after the intravenous administration of 5 g and 24 hours for complete reversal.9393 Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. N Engl J Med. 2017;377:431-41. However, some patients, especially those with comorbid renal failure, may rebound and need a repeated dose.9393 Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. N Engl J Med. 2017;377:431-41. Idarucizumab was evaluated for the reversal of dabigatran in a clinical study with 461 patients exhibiting uncontrolled bleeding or presenting before an urgent procedure.9393 Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. N Engl J Med. 2017;377:431-41. The results showed 100% of the median maximum percentage reversal, assessed by either DTT or ECT. Of 203 patients assessed for bleeding, 67.7% had confirmed bleeding cessation within 24 hours, and periprocedural hemostasis was normal in 93.4%.

The literature shows controversial results for the use of PCCs as a reversal agent for dabigatran. Limited evidence of efficacy was observed in reported case series in which aPCC reversed dabigatran, controlled bleeding, with no thromboembolic events.9494 Schulman S, Ritchie B, Goy JK, et al. Activated prothrombin complex concentrate for dabigatran associated bleeding. Br J Haematol. 2014;164:308-10.,9595 Schulman S, Ritchie B, Nahirniak S, et al. Reversal of dabigatran associated major bleeding with activated prothrombin concentrate: a prospective cohort study. Thromb Res. 2017;152:44-8. One patient was reported to have a rapid response after the administration of aPCC during cardiac ablation,9696 Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013;41:e42-6. and one patient responded to PCCs and FFP.9797 Dumkow LE, Voss JR, Peters M, et al. Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health Syst Pharm. 2012;69:1646-50. Other reported cases showed the inefficacy of PCCs and aFVII.7272 Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-9.,9898 Lillo-Le Louët A, Wolf M, Soufir L, et al. Life-threatening bleeding in four patients with an unusual excessive response to dabigatran: implications for emergency surgery and resuscitation. Thromb Haemost. 2012;108:583-5.

Conclusion

Emergency situations, such as trauma, bleeding, and urgent surgery, involve the reversal of anticoagulants. Reversal is achieved by the administration of hemoderivatives such as PCCs and FFP, and specific agents for DOACs. PCCs and vitamin K have the highest benefit-risk ratio for warfarin reversal in emergency settings; the preferred choice is 4-factor PCC. Patients taking DOACs should receive specific reversal agents (andexanet alfa, idarucizumab). In cases of non-availability of specific reversal agents, PCC or aPCC could be considered based on limited evidence.

Acknowledgments

The authors acknowledge the writing and editing assistance from Mariana Matos M.D., medical writer, on behalf of Springer Healthcare. Funding to support the preparation of this manuscript was provided by CSL Behring and did not influence the content of this publication.

References

  • 1
    Tadros R, Shakib S. Warfarin indications, risks and drug interactions. Aus Fam Phys. 2010;39:476-9.
  • 2
    Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e278S-325S.
  • 3
    Huhtakangas J, Tetri S, Juvels S, et al. Effect of increased warfarin use on warfarin-related cerebral hemorrhage: a longitudinal population-based study. Stroke. 2011;42:2431-5.
  • 4
    Kelly JG, OʼMalley K. Clinical Pharmacokinetics of Oral Anticoagulants. Clin Pharmacokinet. 1979;4:1-15.
  • 5
    O'Reilly RA. Vitamin K and other oral anticoagulant drugs. Annu Rev Med. 1976;27:245-61.
  • 6
    Cameron C, Coyle D, Richter T, et al. Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation. BMJ Open. 2014;4:e004301-12.
  • 7
    Jun M, Lix LM, Durand M, et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicenter, population based, observational study. BMJ. 2017;359:j4323.
  • 8
    Senoo K, Kondo Y, Miyazawa K, et al. Safety and efficacy of direct oral anticoagulants over warfarin in Japanese patients with acute venous thromboembolism: A meta-analysis. J Cardiol. 2017;69:763-8.
  • 9
    Sardar P, Chatterjee S, Lavie CJ, et al. Risk of major bleeding in different indications for new oral anticoagulants: insights from a meta-analysis of approved dosages from 50 randomized trials. Int J Cardiol. 2015;179:279-87.
  • 10
    Mueck W, Lensing AW, Agnelli G, et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011;50:675-86.
  • 11
    Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37:74-81.
  • 12
    Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50:743-53.
  • 13
    Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64:292-303.
  • 14
    Burn J, Pirmohamed M. Direct oral anticoagulants versus warfarin: is new always better than the old?. Open Heart. 2018;5:e000712.
  • 15
    Thigpen JL, Limdi NA. Reversal of oral anticoagulation. Pharmacotherapy. 2013;33:1199-213.
  • 16
    Almegren M. Reversal of direct oral anticoagulants. Vasc Health Risk Manag. 2017;13:287-92.
  • 17
    Schols AM, Schreuder FH, van Raak EP, et al. Incidence of oral anticoagulant-associated intracerebral hemorrhage in the Netherlands. Stroke. 2014;45:268-70.
  • 18
    Kustos SA, Fasinu PS. Direct-Acting Oral Anticoagulants and Their Reversal Agents—An Update. Medicines (Basel). 2019;6:E103.
  • 19
    Mueck W, Kubitza D, Becka M. Coadministration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76:455-66.
  • 20
    Chang SH, Chou IJ, Yeh YH, et al. Association between use of nonvitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA. 2017;318:1250-9.
  • 21
    Zullo A, Hassan C, Radaelli F. Gastrointestinal endoscopy in patients on anticoagulant therapy and antiplatelet agents. Ann Gastroenterol. 2017;30:7-14.
  • 22
    Frontera JA, Lewin JJ, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: Executive Summary. A Statement for Healthcare Professionals From the Neurocritical Care Society and the Society of Critical Care Medicine. Crit Care Med. 2016;44:2251-7.
  • 23
    Kaatz S, Mahan CE, Nakhle A, et al. Management of Elective Surgery and Emergent Bleeding with Direct Oral Anticoagulants. Curr Cardiol Rep. 2017;19:124-34.
  • 24
    McIlmoyle K, Tran H. Perioperative management of oral anticoagulation. BJA Education. 2018;18:259-64.
  • 25
    Douketis JD, Spyropoulos AC, Duncan J, et al. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med. 2019;179:1469-78.
  • 26
    Xu Y, Schulman S, Dowlatshahi D, et al. Bleeding Effected by Direct Oral Anticoagulants (BLED-AC) Study Group. Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study. Chest. 2017;152:81-91.
  • 27
    Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23-32.
  • 28
    Pabinger I, Fries D, Schöchl H, et al. Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis. Wien Klin Wochenschr. 2017;129:303-16.
  • 29
    Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:160S-98S.
  • 30
    Goldstein JN, Refaai MA, Milling TJ, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, noninferiority, randomised trial. Lancet. 2015;385(9982):2077-87.
  • 31
    Dzik WS. Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion. 2012;52:45S-55S.
  • 32
    Bhatia M, Talawadekar G, Parihar S, et al. An audit of the role of vitamin K in the reversal of International Normalised Ratio (INR) in patients undergoing surgery for hip fracture. Ann R Coll Surg Engl. 2010;92:473-6.
  • 33
    Burbury KL, Milner A, Snooks B, et al. Short-term warfarin reversal for elective surgery using low-dose intravenous vitamin K: safe, reliable and convenient. Br J Haematol. 2011;154:626-34.
  • 34
    Pautas E, Peyron I, Bouhadiba S, et al. Reversal of over anticoagulation in very elderly hospitalized patients with an INR above 5.0: 24-hour INR response after vitamin K administration. Am J Med. 2011;124:527-33.
  • 35
    Chai-Adisaksopha C, Hillis C, Siegal DM, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost. 2016;116:879-90.
  • 36
    Allison TA, Lin PJ, Gass JA, et al. Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients. J Intensive Care Med. 2020;35:903-8.
  • 37
    Kerebel D, Joly LM, Honnart D, et al. A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal. Crit Care. 2013;17:R4.
  • 38
    Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011;106:429-38.
  • 39
    Milling TJ, Refaai MA, Goldstein JN, et al. Thromboembolic Events After Vitamin K Antagonist Reversal With 4-Factor Prothrombin Complex Concentrate: Exploratory Analyses of Two Randomized, Plasma-Controlled Studies. Ann Emerg Med. 2016;67:96-105.e5.
  • 40
    Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15:566-73.
  • 41
    Chausson N, Soumah D, Aghasaryan M, et al. Reversal of Vitamin K Antagonist Therapy Before Thrombolysis for Acute Ischemic Stroke. Stroke. 2018;49:2526-8.
  • 42
    Rimsans J, Levesque A, Lyons E, et al. Four-factor prothrombin complex concentrate for warfarin reversal in patients with left ventricular assist devices. J Thromb Thrombolysis. 2018;46:180-5.
  • 43
    Mačiukaitienė J, Bilskienė D, Tamašauskas A, et al. Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Bleeding in Neurosurgical Patients: A Single-Center Experience. Medicina. 2018;54:22-31.
  • 44
    Mattisson L, Lapidus LJ, Enocson A. Is fast reversal and early surgery (within 24 h) in patients on warfarin medication with trochanteric hip fractures safe? A case-control study. BMC Musculoskelet Disord. 2018;19:203-10.
  • 45
    Hedges A, Coons JC, Saul M, et al. Clinical effectiveness and safety outcomes associated with prothrombin complex concentrates. J Thromb Thrombolysis. 2015;42:1-5.
  • 46
    Scott R, Kersten B, Basior J, et al. Evaluation of Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal in Patients with Intracranial Hemorrhage. J Emerg Med. 2018;54:861-6.
  • 47
    Astrup G, Sarangarm P, Burnett A. Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis. J Thromb Thrombolysis. 2018;45:300-5.
  • 48
    Holt T, Taylor S, Abraham P, et al. Three- versus four-factor prothrombin complex concentrate for the reversal of warfarin-induced bleeding. Int J Crit Illn Inj Sci. 2018;8:36-40.
  • 49
    Voils SA, Holder MC, Premraj S, et al. Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for emergent warfarin reversal. Thromb Res. 2015;136:595-8.
  • 50
    Carothers C, Giancarelli A, Ibrahim J, et al. Activated prothrombin complex concentrate for warfarin reversal in traumatic intracranial hemorrhage. J Surg Res. 2018;223:183-7.
  • 51
    Rowe AS, Mahbubani PS, Bucklin MH, et al. Activated Prothrombin Complex Concentrate versus Plasma for Reversal of Warfarin-Associated Hemorrhage. Pharmacotherapy. 2016;36:1132-7.
  • 52
    Tran HA, Chunilal SD, Harper PL, et al. Australasian Society of Thrombosis and Haemostasis (ASTH). An update of consensus guidelines for warfarin reversal. Med J Aust. 2013;198:198-9.
  • 53
    Spahn DR, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019;23:98.
  • 54
    Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032-60.
  • 55
    Demeyere R, Gillardin S, Arnout J, et al. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99:251-60.
  • 56
    Choi S, Casias M, Tompkins D, et al. Blood, blood components, plasma, and plasma products. Side Effects of Drugs Annual. 2019;41:373-86.
  • 57
    Woo CH, Patel N, Conel C, et al. Rapid warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII and prothrombin complex concentrate. World Neurosurg. 2014;81:110-5.
  • 58
    Chapman SA, Irwin ED, Abou-Karam NM, et al. Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal. World J Emerg Surg. 2014;9:27-34.
  • 59
    Sarode R, Matevosyan K, Bhagat R, et al. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg. 2012;116:491-7.
  • 60
    Barton CA, Hom M, Johnson NB, et al. Protocolized warfarin reversal with 4-factor prothrombin complex concentrate versus 3-factor prothrombin complex concentrate with recombinant factor VIIa. Am J Surg. 2018;215:775-9.
  • 61
    Mehringer SL, Klick Z, Bain J, et al. Activated Factor 7 Versus 4-Factor Prothrombin Complex Concentrate for Critical Bleeding Post-Cardiac Surgery. Ann Pharmacother. 2018;52:533-7.
  • 62
    Yank V, Tuohy CV, Logan AC, et al. Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications. Ann Intern Med. 2011;154:529-40.
  • 63
    Matino D, Makris M, Dwan K, et al. Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors. Cochrane Database Syst Rev. 2015;:CD004449.
  • 64
    OConnell KA, Wood JJ, Wise RP, et al. Thromboembolic Adverse Events After Use of Recombinant Human Coagulation Factor VIIa. JAMA. 2006;295:293-8.
  • 65
    Exner T, Ahuja M, Ellwood L. Effect of an activated charcoal product (DOAC Stop™) intended for extracting DOACs on various other APTT-prolonging anticoagulants. Clin Chem Lab Med. 2019;57:690-6.
  • 66
    Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the nonvitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64:1128-39.
  • 67
    Conway SE, Hwang AY, Ponte CD, et al. Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know. Pharmacotherapy. 2017;37:236-48.
  • 68
    Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373:2413-24.
  • 69
    Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019;380:1326-35.
  • 70
    Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76:594-622.
  • 71
    Cuker A, Burnett A, Triller D, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol. 2019;94:697-709.
  • 72
    Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-9.
  • 73
    da Luz LT, Marchand M, Nascimento B, et al. Efficacy and safety of the drugs used to reverse direct oral anticoagulants: a systematic review and meta-analysis. Transfusion. 2017;57:1834-46.
  • 74
    Piran S, Gabriel C, Schulman S. Prothrombin complex concentrate for reversal of direct factor Xa inhibitors prior to emergency surgery or invasive procedure: a retrospective study. J Thromb Thrombolysis. 2018;45:486-95.
  • 75
    Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrate: a cohort study. Blood. 2017;130:1706-12.
  • 76
    Schulman S, Gross PL, Ritchie B, et al. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemost. 2018;118:842-51.
  • 77
    Sheikh-Taha M. Treatment of apixaban- and rivaroxaban-associated major bleeding using 4-factor prothrombin complex concentrate. Intern Emerg Med. 2019;14:265-9.
  • 78
    Harrison SK, Garrett JS, Kohman KN, et al. Comparison of outcomes in patients with intracranial hemorrhage on factor Xa inhibitors versus vitamin K antagonists treated with 4-factor prothrombin complex concentrate. BUMC Proc. 2018;31:153-6.
  • 79
    Tao J, Bukanova EN, Akhtar S. Safety of 4-factor prothrombin complex concentrate (4F-PCC) for emergent reversal of factor Xa inhibitors. J Intensive Care. 2018;6:34-40.
  • 80
    Grandhi R, Newman WC, Zhang X, et al. Administration of 4-factor prothrombin complex concentrate as an antidote for intracranial bleeding in patients taking direct factor Xa inhibitors. World Neurosurg. 2015;84:1956-61.
  • 81
    Dybdahl D, Walliser G, Chance Spalding M, et al. Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage. Am J Emerg Med. 2019;37:1907-11.
  • 82
    Piran S, Khatib R, Schulman S, et al. Management of direct factor Xa inhibitor-related major bleeding with prothrombin complex concentrate: a meta-analysis. Blood Adv. 2019;3:158-67.
  • 83
    Senger S, Keiner D, Hendrix P, et al. New target-specific oral anticoagulants and intracranial bleeding: management and outcome in a single-center case series. World Neurosurg. 2016;88:132-9.
  • 84
    Green L, Tan J, Antoniou S, et al. Haematological management of major bleeding associated with direct oral anticoagulants- UK experience. Br J Haematol. 2019;185:514-22.
  • 85
    Maurice-Szamburski A, Graillon T, Bruder N. Favorable outcome after a subdural hematoma treated with FEIBA in a 77-year-old patient treated by rivaroxaban. J Neurosurg Anesthesiol. 2014;26:183.
  • 86
    Engelbart JM, Zepeski A, Galet C, et al. Safety and effectiveness of Factor Eight Inhibitor Bypassing Activity for direct oral anticoagulant-related hemorrhage reversal. Am J Emerg Med. 2019;37:214-9.
  • 87
    Dager WE, Roberts AJ, Nishijima DK. Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thromb Res. 2019;173:71-6.
  • 88
    Schultz NH, Lundblad R, Holme PA. Activated prothrombin complex concentrate to reverse the factor Xa inhibitor (apixaban) effect before emergency surgery: a case series. J Med Case Rep. 2018;12:138.
  • 89
    Dibu JR, Weimer JM, Ahrens C, et al. The Role of FEIBA in Reversing Novel Oral Anticoagulants in Intracerebral Hemorrhage. Neurocrit Care. 2016;24:413-20.
  • 90
    Van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-27.
  • 91
    Stangier J, Rathgen K, Stähle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-center study. Clin Pharmacokinet. 2010;49:259-68.
  • 92
    Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-center study in patients with end-stage renal disease. Thromb Haemost. 2013;109:596-605.
  • 93
    Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. N Engl J Med. 2017;377:431-41.
  • 94
    Schulman S, Ritchie B, Goy JK, et al. Activated prothrombin complex concentrate for dabigatran associated bleeding. Br J Haematol. 2014;164:308-10.
  • 95
    Schulman S, Ritchie B, Nahirniak S, et al. Reversal of dabigatran associated major bleeding with activated prothrombin concentrate: a prospective cohort study. Thromb Res. 2017;152:44-8.
  • 96
    Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013;41:e42-6.
  • 97
    Dumkow LE, Voss JR, Peters M, et al. Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health Syst Pharm. 2012;69:1646-50.
  • 98
    Lillo-Le Louët A, Wolf M, Soufir L, et al. Life-threatening bleeding in four patients with an unusual excessive response to dabigatran: implications for emergency surgery and resuscitation. Thromb Haemost. 2012;108:583-5.

Publication Dates

  • Publication in this collection
    30 July 2021
  • Date of issue
    Jul-Aug 2021

History

  • Received
    11 Jan 2020
  • Accepted
    13 Mar 2021
Sociedade Brasileira de Anestesiologia (SBA) Rua Professor Alfredo Gomes, 36, Botafogo , cep: 22251-080 - Rio de Janeiro - RJ / Brasil , tel: +55 (21) 97977-0024 - Rio de Janeiro - RJ - Brazil
E-mail: editor.bjan@sbahq.org