43 – Does the availability of reversal agents influence the choice of a selected chemical VTE prophylaxis agent?

Ricardo Sousa,Humaid Al Farii, Muadh Alzeedi, Sultan Al Maskari.

Response/Recommendation: Yes. Commonly used venous thromboembolism (VTE) prophylaxis agents have favorable safety profiles as well as established guidelines for reversal. Some agents may be safely continued during surgery (e.g., aspirin [ASA], clopidogrel), while others can be promptly reversed by discontinuation (e.g., low-molecular-weight heparin [LMWH]). Other agents such as vitamin K antagonists (e.g., warfarin) and direct-oral anticoagulants (DOAC) require a longer discontinuation interval before surgery, or expensive reversal agents with limited availability such as Prothrombin Complex Concentrates as well as specific antidotes such as Idarucizumab and Andexanet if urgent reversal is indicated. As such, local availability and cost are perhaps the most important factors that influence the choice of agent.

Strength of Recommendation: Limited.

Rationale: In general, orthopaedic surgeons are likely to face one of two scenarios that may require reversal of anticoagulation: (1) a patient who is on long-term anticoagulation (e.g., cardiac conditions) presenting with a fracture that requires urgent surgical intervention (e.g., proximal femur fracture); (2) a patient who is on short-term chemical thromboprophylaxis following an elective orthopaedic procedure (e.g., total joint arthroplasty) and develops a complication (e.g., wound breakdown or infection) or sustains a fracture that requires urgent surgical intervention. An increasing number of elderly patients on long-term anticoagulants and newer guidelines on rapid recovery surgical protocols have led to extensive research on this topic1-10. Deciding whether anticoagulation reversal is absolutely necessary or defining its specific indications are beyond the scope of this review.

Although there are a number platelet inhibitors alternatives, ASA, dipyridamole and clopidogrel are most commonly used for VTE prophylaxis after orthopaedic procedures. In contrast, newer, more potent platelet inhibitors are usually prescribed for severe cardiovascular disease. No specific reversal agent exists for platelet inhibitors, hence discontinuing antiplatelet therapy is the only method of reversal. Notwithstanding, ASA and dipyridamole are considered safe for surgery and no discontinuation is required before neuraxial anesthesia11. It has been shown that patients receiving ASA, dipyridamole, or both, who undergo proximal femur fracture surgery have no increased intraoperative blood loss12. Clopidogrel is a more potent antiplatelet and has a washout period of 5 – 7 days. Similarly, recent evidence has questioned the discontinuation of clopidogrel in the context of urgent surgery, as no clear negative outcomes have been reported despite a possible increase in the rate of blood transfusion especially when surgery is performed under dual ASA-clopidogrel treatment13-17. If unexpected or serious bleeding occurs, supportive treatment with platelet transfusions may be necessary18 (Table 1).

When platelet transfusions are indicated, the half-lives of platelet inhibitors and their metabolites should be considered. If the patient is on dual ASA-clopidogrel treatment, surgery should be delayed for at least 12 to 24 hours after the last intake of both drugs to allow clearance of free active metabolites from circulation before platelet transfusions are administered18-20.

Desmopressin: Is another alternative to minimize perioperative blood loss in patients receiving antiplatelet therapy, although the evidence for its use in orthopaedic surgery is scarce21.

Low-molecular-weight heparins (LMWH): Were developed for surgical VTE prophylaxis and are widely used in this context. There are several different drug types, and although all of them are derived from unfractionated heparin (UFH), each has its own specific pharmacokinetics.

Protamine: Is a classic antidote to use for UFH reversal. Both molecules combine to form a salt, making Protamine a highly effective reversal agent if dosed appropriately22. However, it incompletely reverses factor Xa inhibition of LMWH despite complete neutralization of the antithrombin effect. This results in only 60% reversal of LMWH effects. Consequently, drug discontinuation is the mainstay of reversal. Surgery is usually delayed for 12 hours after the last injection if prophylactic doses are administered and delayed for 24 hours in patients receiving higher (therapeutic) doses11.

Vitamin K antagonists: Such as warfarin or acenocoumarol are also frequently used as chemical VTE prophylaxis. The most commonly used reversal strategy is drug discontinuation and intravenous (IV) or oral administration of phytonadione (i.e., vitamin K) to overcome the antagonistic effect while allowing the liver to increase production of clotting factors. Although the IV route offers faster reversal of the international normalized ratio (INR) and hence less preoperative delay, this process may be lengthy and patients with very high prothrombin (PT)-INR or the need for urgent surgery may require accelerated reversal23-26.

Fresh-frozen plasma (FFP): Is a commonly used alternative, although its efficacy in this context has never been definitively proven, and it has several well-known drawbacks related to blood-typing and transfusion-related complications owing to the large volume of infusion necessary.

Prothrombin Complex Concentrates (PCC): Have been shown to be superior to plasma, offering significant reduction in all-cause mortality, more rapid INR reduction, and less volume overload without a significantly increased risk of thromboembolic events27-28. Three different PCC products (a 3-factor PCC, a 4-factor PCC, and an activated PCC) and one recombinant-activated factor VII are commercially available. The 4-factor PCC is the most commonly used and has been proven to be superior to plasma both in INR reduction and clinical efficacy in patients requiring urgent surgery including major orthopaedic procedures29-30, and proximal femur fractures in particular31.

Regarding non-vitamin K anticoagulants or DOAC, evidence for reversal in patients in need for urgent surgery is scarce. Before the advent of specific antidotes, several trials have examined the use of off-label PCC in major bleeding with somewhat conflicting results32-35. A study focusing on patients undergoing urgent surgery (only 8 orthopaedic procedures) showed favorable results. More recently, specific reversal agents have been approved both for direct thrombin inhibitors (i.e., dabigatran) and factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban).

Idarucizumab: A monoclonal antibody fragment antigen binding, has 350 times more affinity for dabigatran than thrombin, and hence effectively neutralizes its activity36. In a subgroup analysis of patients undergoing surgery, it was shown to offer normal periprocedural hemostasis in over 90% of 45 orthopaedic procedures37, and no intraprocedural bleeds were reported among 31 orthopaedic procedures in a real-world setting38.

Andexanet: Is a modified recombinant Factor Xa protein that rapidly binds to Factor Xa inhibitors so that native Factor Xa can function normally39. Although its use has been approved both in North-America (Food and Drug administration [FDA]) and Europe (EMA) for patients with major bleeding, no specific data on patients requiring urgent surgery exists to date40. The safety profile of idarucizumab and andexanet alfa use has been addressed in a recent systematic review and meta-analysis, which showed that the incidence of thrombotic events was 3.3% for idarucizumab, and 10.6% for andexanet alfa41. This result should be interpreted with caution, as the incidence of thrombotic events was only 0.7% when examining patients who required urgent or emergent surgery (although no andexanet data available in this context)41.

Ciraparantag: Is the newest agent in this category. It is a synthetic molecule that binds to UFH and LMWH, as well as fondaparinux, dabigatran, and Factor Xa inhibitors42. At present, there is no data from phase III trials and this drug has not been approved for clinical use.

Table 1. Costs and availability of reversal agents.

 Reversal TargetAvailabilityCost*
Platelet transfusionsPlatelet InhibitorsWidespread$5,258 – $13,117 (1)
DesmopressinPlatelet InhibitorsWidespread$26 – $50 (2) (10mL IV)
ProtamineUFH (LMWH less effective)Widespread$34 – $40 (2) (25mL IV)
Phytonadione (vitamin K)Vitamin K antagonistsWidespreadAround $200 (2) (1mg IV) or $30 (2) (5mg PO)
Prothrombin Complex ConcentratesVitamin K antagonists (DOAC less effective)Widespread$4,050 –  $8,100 (3)
IdarucizumabDabigatranLimited$4,500 (2) (2.5g/50mL)
Andexanet alfaFactor Xa inhibitorsLimited$24,750 –$49,500 (3) (200mg)
CiraparantagLMWH, Dabigatran, Factor Xa inhibitorsNot commercially available 
* approximate cost per unit (recommended dosages/associated costs may vary according to different protocols) 1) Barnett  CL, Mladsi D, Vredenburg M, Aggarwal K. Cost estimate of platelet transfusion in the United States for patients with chronic liver disease and associated thrombocytopenia undergoing elective procedures J Med Econ. 2018 Aug;21(8):827-834. 2) https://www.drugs.com/price-guide/ 3) Frontera JA, Bhatt P, Lalchan R, Yaghi S, Ahuja T, Papadopoulos J, et al. Cost comparison of andexanet versus prothrombin complex concentrates for direct factor Xa inhibitor reversal after hemorrhage. J Thromb Thrombolysis 2020;49:121–31.

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