American College of Cardiology Foundation

10/08/2019 | Press release | Distributed by Public on 10/08/2019 12:35

Managing Anticoagulant-related Bleeding in Patients with Venous Thromboembolism

Introduction

Bleeding is a common side effect of anticoagulant use. However, the majority of bleeding events are not life threatening and can be managed conservatively.1 To assess the severity of an anticoagulant-related bleeding event, clinicians should identify the source (if possible) and location of bleeding, evaluate laboratory studies (including blood counts and coagulation studies), and closely monitor vital signs. The first step in managing any significant bleeding event is to temporarily stop using the anticoagulant. Local measures, such as manual compression, can be useful in the case of skin-bleeds and epistaxis. Transfusion of blood products may be needed for more significant bleeding events. Ultimately, the decision to reverse an anticoagulant should be made based on the location of bleeding, time since last use of the anticoagulant, and patient's hemodynamic stability. The decision to reverse an anticoagulant is largely the same for patients with atrial fibrillation and venous thromboembolism. But the strategies for reversal differ based on the specific anticoagulant, as detailed in the next two paragraphs. The decision to restart the anticoagulant after bleeding has been controlled may differ based on indication, and is summarized in the final paragraph of this review.

Management of Vitamin K Antagonist-related Bleeding

In the setting of a life-threatening bleed related to vitamin K antagonist (VKA) use, rapid reversal of the VKA drug effects and replenishing clotting factors is a priority. To achieve that goal, administer vitamin K 10 mg intravenously along with prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) to achieve a sustained reduction of the international normalized ratio (INR).1-5 Generally, a goal INR of ≤1.3-1.5, depending on the site of the bleed, is targeted. Several studies have demonstrated that PCC infusion results in more rapid and complete reversal of the INR as compared to use of FFP for VKA-related bleeding. However, there is inconsistency on whether this rapid resolution of the INR results in improved hemostatic efficacy or clinical outcomes.6-10 In one of the few prospective, randomized controlled trials in acutely bleeding patients, 4F-PCC achieved a more rapid INR correction and significantly lower INR in the 12 hours after infusion compared to FFP, however hemostatic efficacy was similar in the two groups.10 In contrast, a second prospective randomized trial in patients with VKA-related intracranial hemorrhage (ICH) found a significant difference in INR correction and hematoma expansion at 3 hours favoring 4F-PCC.9 Other limitations of FFP use to reverse VKA-associated bleeding include: need for blood typing and thawing that results in administration delays;9 large volume requirement that leads to prolonged infusion times and potential for transfusion-associated circulatory overload (TACO);9,10 and risk of transfusion-related acute lung injury (TRALI).

Historically, PCC has been dosed based on body weight and adjustment for initial INR in VKA-related bleeding events. There has been interest in fixed dose PCC (1000-1500 IU) for ease of ordering, reduced cost and potential reduction in thromboembolic complications. While some retrospective reports demonstrate acceptable reversal and no difference in clinical response,11-15 others have shown less complete INR reversal and need for additional PCC administration with fixed dose strategies.16,17 This may be particularly prominent in those with large body weight, INR >4.0, or intracranial bleeding (where target INR may be lower). However, it is important to note that clinical response to the two dosing strategies has not been different and larger trials would be helpful in determining the optimal dosing strategy.

Management of Direct Oral Anticoagulant-related Bleeding

Direct oral anticoagulants (DOACs) are now widely used in treatment of venous thromboembolism (VTE) and are recommended first-line over VKAs in non-cancer associated VTE.18 While routine assessment of anticoagulant effect is unnecessary, it can be helpful in determining the appropriate management strategy for an acutely bleeding patient. Unlike VKAs, standard coagulation tests such as activated partial thromboplastin time (aPTT) and prothrombin time (PT)/INR are unreliable markers of anticoagulant effect in DOAC-treated patients. Time since last dose and end-organ function affecting DOAC clearance should be used to guide the decision on need for reversal of the DOAC. Availability of drug specific assays or use of a low-molecular weight heparin calibrated anti-Xa level can be useful to determine activity but should not delay treatment in those known to have DOAC on board.

Until recently, supportive measures and infusion of clotting factors were the only available options for reversal of DOACs. Initial animal models evaluating activated PCC (aPCC) [FEIBA], 4-factor PCC, and recombinant factor VII demonstrated mixed and inconsistent effects on coagulation parameters, bleeding time, and hemostatic efficacy.19-23 Additionally, high dose 4F-PCC (50 units/kg) in healthy subjects reversed abnormal coagulation tests from rivaroxaban but not dabigatran.24 The use of aPCC in dabigatran-associated acute bleeding suggests good hemostatic efficacy as compared to historical controls25 and specific antidote trials26 (Table 2). In apixaban and rivaroxaban patients, two observational cohort reports describe 4F-PCC use with hemostasis rates of 70-80% and low rates of thromboembolism27,28 (Table 2).

Within the last 4 years, approval of specific antidotes has led to hopes for improved outcomes in DOAC-related acute bleeding, however limitations remain including cost, availability (andexanet alfa), and 'real-world' data. Relevant information regarding agent specific characteristics and study data can be found in Tables 1 and 2, respectively. A majority of patients in both trials demonstrated normalization of thrombin activity and reduction in unbound drug concentration. In REVERSE-AD, unbound dabigatran levels were suppressed for 12 hours at which point 23% of patients had re-elevation of levels.29 In ANNEXA-4, unbound apixaban and rivaroxaban levels returned to that of the placebo group two hours after the end of the 2-hour infusion, however endogenous thrombin potential remained normalized.30 Hemostasis was reported in a majority of patients in both trials. Use of agent specific antidotes is recommended over non-specific reversal agents for DOAC-associated life-threatening bleeding or bleeding at a critical site. If agent specific antidotes are not available, based on observational data, aPCC (25-50 units/kg) is recommended for reversal of dabigatran and 4F-PCC (25-50 units/kg) is recommended for reversal of oral anti-Xa inhibitors.1,18,31,32

Resuming Anticoagulation

The acute management of anticoagulant-related bleeding in patients with VTE should also include an assessment for restarting anticoagulation once bleeding has been resolved. This is of particular importance for patients with VTE, who remain at elevated risk for recurrence. In fact, the majority of thromboembolic events and deaths occurring in the ANNEXA-4 study occurred after bleeding had been controlled but before anticoagulation had been resumed.30 Among patients with atrial fibrillation who experienced an anticoagulant-related bleeding, data suggests lower rates of ischenmic stroke and death when the anticoagulant is restarted.33 The same is likely to be true for patients with VTE. Recent guidelines recommend resuming anticoagulation within 90 days if the patient is at moderate-high risk for VTE recurrence and the risk of recurrent bleeding is adequately low.34

Conclusion

Bleeding is a common complication of chronic anticoagulant therapy. Most bleeding events can be managed conservatively, usually by omitting a few doses of the anticoagulant. In severe and life-threatening bleeding events, use of non-specific (e.g. PCC) or specific (e.g. idarucizumab, andexanet alpha) reversal agents are recommended. However, further data is needed to compare outcomes between these two management strategies and identify the cost-effectiveness of these various strategies. Once bleeding has been controlled, clinicians and patients should discuss the appropriateness of resuming anticoagulant therapy to prevent potentially life-threatening future thrombotic events.

Table 1: Specific Reversal Agents for Direct Oral Anticoagulants

Idarucizumab Andexanet Alpha Ciraparantag
Drug Reversed Dabigatran Rivaroxaban
Apixaban
Edoxaban (non-FDA)
LMWH (non-FDA)
Dabigatran
Xa Inhibitors
LMWH
UFH
Mechanism Monoclonal Ab; binds dabigatran with high affinity Recombinant human factor Xa protein; acts as a decoy Noncovalent bonding and charge-charge interactions
Published Clinical Studies Healthy volunteers; bleeding patients; emergent reversal Healthy volunteers; bleeding patients Healthy volunteers
FDA Approval Approved Approved Not approved

Table 2: Studies of DOAC-reversal with Specific and Non-specific Agents

Schulman et al.
(n=14)
Dager et al.
(n= 64)
Smith et al.
(n=31)
Majeed et al.
(n=84)
RE-VERSE AD
(n=301)
ANNEXA-4
(n=352)
DOAC, n (%)
Apixaban
Rivaroxaban
Dabigatran

--
--
14

20
28
16

17 (55)
14 (45)
--

39 (46)
45 (54)
--

--
--
301

194 (55)
128 (36)
--
Bleeding Site, n (%)
ICH
Non-ICH

5 (35.7)
9 (64.3)

28 (29)
36 (37)

18 (58)
13 (42)

59 (70)
25 (30)

98 (33)
203 (67)

227 (64)
125 (36)
Reversal Agent aPCC ~50 units/kg aPCC ~10-25 units/kg 4F-PCC 25-50 units/kg 4F-PCC ~25 units/kg
(1500-2000 units)
Idarucizumab Andexanet alfa
Efficacy, n (%) Good
Moderate
Poor
9 (64.3)
5 (35.7)
0
62/64 without active bleeding or hematoma expansion Effective
Ineffective
25 (81)
6 (19)
Effective
Ineffective
58 (69)
26 (31)
Hemostasis
Not determined
(n=203)
134 (67.7)
67 (33)
Excellent
Good
Poor/None
(n=249)
171 (69)
33 (13)
45 (18)
Thrombotic Events
(30 day), n (%)
0 9 (14.1) 0* 3 (4) 14 (4.8) 34 (10)
Mortality (30 day), n (%) 1 (8) 5 (7.8) 5 (16)* 27 (32); 20 had ICH 41 (13.5) 49 (14)

References

  1. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017;70:3042-67.
  2. Frontera JA, Lewin JJ III, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016;24:6-46.
  3. Gibler WB, Racadio JM, Hirsch AL, Roat TW. Management of severe bleeding in patients treated with oral anticoagulants: proceedings monograph from the Emergency Medicine Cardiac Research and Education Group-International Multidisciplinary Severe Bleeding Consensus panel October 20, 2018. Crit Pathw Cardiol 2019;18:143-66.
  4. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018;2:3257-91.
  5. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e152S-e184S.
  6. Frontera JA, Gordon E, Zach V, et al. Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage. Neurocrit Care 2014;21:397-406.
  7. Hickey M, Gatien M, Taljaard M, Aujnarain A, Giulivi A, Perry JJ. Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation 2013;128:360-64.
  8. Majeed A, Meijer K, Larrazabal R, et al. Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate. Thromb Haemost 2014;111:233-39.
  9. 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 randomized trial. Lancet Neurol 2016;15:566-73.
  10. Sarode R, Millin TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin k antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013;128:1234-43.
  11. Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med 2015;33:1213-18.
  12. Yasaka M, Sakata T, Naritomi H, Minematsu K. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res 2005;115:455-59.
  13. Khorsand N, Veeger NJ, Muller M, et al. Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin k antagonist therapy. Transfus Med 2011;21:116-23.
  14. Khorsand N, Veeger NJ, van Hest RM, Ypma PF, Heidt J, Meijer K. An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies. Haematologica 2012;97:1501-6.
  15. Astrup G, Sarangram 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.
  16. Abdoellakhan RA, Miah IP, Khorsand N, Meijer K, Jellema K. Fixed versus variable dosing of prothrombin complex concentrate in vitamin K antagonist-related intracranial hemorrhage: a retrospective analysis. Neurocrit Care 2017;26:64-69.
  17. Zemrak W, Manuel F, Smith KE, et al. Low-dose compared to manufacturer-recommended dose four-factor prothrombin complex concentrate for acute warfarin reversal. J Thombo Thrombolysis 2019;47:263-71.
  18. Kearon C, Akl EA, Omelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315-52.
  19. Godier A, Niclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012;116:94-102.
  20. Zhou W, Zorn M, Nawroth P, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke 2013;44:771-8.
  21. Zhou W, Schwarting S, Illanes S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011;42:3594-99.
  22. Lambourne MD, Eltringham-Smith LJ, Gataiance S, Arnold DM, Crowther MA, Sheffield WP. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost 2012;10:1830-40.
  23. Martin AC, Le Bonniec B, Fischer AM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol 2013;168:4228-33.
  24. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-79.
  25. 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;152:44-48.
  26. 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;173:71-76.
  27. Majeed A, Agren A, Holmstrom M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017;130:1706-12.
  28. Smith MN, Deloney L, Carter C, Weant KA, Eriksson EA. Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study. J Thrombo Thrombolysis 2019;48:250-55.
  29. Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Eng J Med 2017;377:431-41.
  30. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Eng J Med 2019;380:1326-35.
  31. 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.
  32. Levy JH, Ageno W, Chan NC, et al. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016;14:623-27.
  33. Staerk L, Fosbol EL, Lamberts M, et al. Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in patients with atrial fibrillation: a nationwide cohort study. Eur Heart J 2018;39:1698-1705a.
  34. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018;2:3257-91.

Clinical Topics:Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Pulmonary Hypertension and Venous Thromboembolism, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents

Keywords:International Normalized Ratio, Anticoagulants, Vitamin K, Antidotes, Factor VII, Thrombin, Prothrombin Time, Partial Thromboplastin Time, Heparin, Low-Molecular-Weight, Bleeding Time, Venous Thromboembolism, Atrial Fibrillation, Retrospective Studies, Epistaxis, Cost-Benefit Analysis, Blood Grouping and Crossmatching, Healthy Volunteers, Prospective Studies, Blood Coagulation Factors, Factor Xa, Recombinant Proteins, Pyridones, Pyrazoles, Antibodies, Monoclonal, Humanized, Intracranial Hemorrhages, Hemostatics, Hemostasis, Stroke, Hematoma, Hemodynamics, Cohort Studies, Vascular Diseases, Aneurysm


< Back to Listings