Guidance for Transitioning Among Anticoagulants.

Abstract

Anticoagulants are commonly used in intensive care units (ICUs). Patients may need to transition from one anticoagulant medication to another because of changes in clinical status such as planned or emergency procedures, lack of enteral access, concern for heparin-induced thrombocytopenia (HIT), change in renal or hepatic function, or drug-drug interactions. As the number of anticoagulants available to clinicians has grown, understanding how to transition between agents has become more important. There are no randomized controlled trials comparing strategies for transitioning between agents, so guidance for transitioning between anticoagulants is mostly extrapolated from pharmacokinetic parameters. Proper transitioning from one agent to another can minimize the risk of bleeding or clotting events.Because oral anticoagulants have longer half-lives than parenteral options, they are commonly administered to patients once they are clinically stable rather than before, as they may need to undergo surgical procedures. Oral anticoagulants can be divided into 2 major groups based on mechanism of action: vitamin K antagonists (VKAs) and direct-acting oral anticoagulants (DOACs). Warfarin has been the primary oral anticoagulant for nearly 50 years. However, DOACs have been introduced as anticoagulant alternatives and represent a milestone in anticoagulant care. Direct oral anticoagulants provide an attractive alternative to VKAs and offer new options for patients requiring oral anticoagulant therapy. Table 1 includes a comparison of the oral anticoagulants available for clinical use in the United States.Vitamin K is essential for the synthesis of coagulation factors II, VII, IX, and X; protein C; and protein S. Vitamin K antagonists such as warfarin antagonize the effects of vitamin K, ultimately reducing the production of vitamin K–dependent clotting factors in the liver. However, warfarin inhibits proteins C and S, paradoxically increasing the risk of clotting upon initiation of warfarin therapy. Warfarin was the first oral anticoagulant approved in the United States and is indicated for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE), prevention of systemic emboli and stroke related to non-valvular atrial fibrillation (NVAF), and after myocardial infarction to reduce the risk of recurrent myocardial infarction, stroke, and death.4 It is the only oral anticoagulant approved for the prophylaxis of systemic emboli related to mechanical heart valves.1 Warfarin requires routine monitoring of the international normalized ratio (INR) for both efficacy and toxicity and has many drug-food interactions based on the vitamin K content of the food. Additionally, warfarin has multiple drug interactions that can cause unpredictable fluctuations in the INR, necessitating frequent monitoring and dosage adjustments in some patients. Combined, these factors can make warfarin dosing quite complex.Because of the issues associated with the use of warfarin, a growing number of newer-generation anticoagulants known as DOACs have replaced warfarin as the anticoagulants of choice in some patients. Direct oral anticoagulants can be further classified as direct factor Xa inhibitors and direct thrombin inhibitors.Direct factor Xa inhibitors work by inhibiting activated factor X in the clotting cascade and inhibiting complement activation.5 Rivaroxaban was approved by the US Food and Drug Administration (FDA) in July 2011 for prevention of stroke related to NVAF, treatment and prevention of DVT/PE, and prevention of venous thromboembolism (VTE) after total hip or knee replacement.6 Apixaban was FDA approved in December 2012 to prevent stroke and systemic embolism in patients with NVAF, to treat DVT/PE, and to prevent VTE in patients who have undergone total hip or knee replacement. Apixaban is primarily metabolized hepatically and should be avoided in patients with moderate to severe liver impairment (Child-Pugh category B or C).1 For patients transitioning from apixaban to warfarin and parenteral anticoagulant agents, the manufacturer recommends starting the new anticoagulant at the time of the next scheduled dose of the DOAC.7 Edoxaban was FDA approved in October 2014 for prevention of stroke and systemic embolic events in patients with NVAF and for the treatment of VTE.1 Betrixaban was approved in June 2018; it is FDA approved for prophylaxis of VTE in hospitalized adult patients who are at risk for VTE.2 Limited data regarding transitioning patients to or from betrixaban are currently available, and no data exist regarding its use in the critically ill patient population.Dabigatran is the only oral direct thrombin/factor IIa inhibitor available in the United States. Dabigatran is FDA approved for prevention of stroke related to NVAF, prevention of recurrent DVT and PE, and treatment of DVT/PE in adult patients.8Direct oral anticoagulants have a number of advantages and disadvantages. Transitioning a patient from a VKA to a DOAC requires an assessment of the potential risks and benefits before conversion. Potential benefits of transitioning from a VKA to a DOAC include increased patient convenience and satisfaction, reduced need for routine laboratory monitoring, rapid onset of newer agents, fixed dosing, and fewer drug-food and drug-drug interactions compared with warfarin.6 Potential risks associated with transitioning to DOACs are an unpredictable anticoagulant effect, need for strict regimen adherence because of short half-life, less flexibility in dosing, increased cost, need for dosage adjustment in patients with renal impairment, and until recently, lack of an available reversal agent.1 The use of DOACs has increased worldwide, perhaps because of the potential benefits compared with warfarin and increased endorsement in some clinical scenarios.6Some patients should not be considered for transition from a VKA to a DOAC, including those who have active bleeding or severe renal impairment (creatinine clearance < 15 mL/min). Additionally, DOACs should not be considered in patients with liver disease associated with coagulopathy (Child-Pugh category B or C).9Despite the benefits of DOACs, some patients derive more benefit from a VKA. Potential reasons for transitioning from a DOAC to VKA include the presence of valvular disease, worsening renal function, or clinically significant drug-drug interactions with a DOAC.10 Direct Xa inhibitors and thrombin inhibitors interfere with INR assays and falsely impact INR, so INR monitoring is not reliable for determining when to transition to warfarin.1,5 Renal function is a key factor when transitioning from dabigatran to warfarin because the recommended overlapping period for coadministration of these agents changes. As renal function worsens, the duration of overlap shortens due to the extended duration of action for dabigatran (Table 2).11 In patients receiving edoxaban, the edoxaban dose should be reduced to half of the starting dose, and warfarin should be started concurrently. Edoxaban therapy should be discontinued once the INR is 2 or higher.3 Refer to Table 2 for further guidance on transitioning between oral anticoagulants.Parenteral anticoagulants can be divided into 2 subgroups: indirect anticoagulants and direct anticoagulants. Indirect anticoagulants require plasma cofactors to produce an anticoagulant effect on thrombin.12 Direct anticoagulants do not exert their effect through plasma cofactors; rather, they affect thrombin directly. The main action of thrombin is to convert fibrinogen to fibrin. Thrombin also stimulates platelet activity.12 The relatively shorter half-lives of parenteral agents compared with oral agents is beneficial for patients who may have procedures planned. The therapeutic efficacy of parenteral agents can be monitored, making them attractive options for anticoagulation in the ICU. Table 3 presents a summary of parenteral anticoagulants.The prototypical indirect anticoagulant is unfractionated heparin (UFH), commonly referred to simply as heparin. Heparin exerts its main anticoagulant effect through the action of antithrombin III. Antithrombin III binds thrombin and other enzymes to inhibit their procoagulant activity.12 Heparin clearance is believed to occur through 2 mechanisms: rapid clearance mediated by endothelial cell receptors and macrophages and first-order clearance through renal excretion.18The anticoagulant effects of UFH vary among patients, so consistent monitoring is required to maintain a therapeutic level. Heparin activity is traditionally monitored with activated partial thromboplastin time (aPTT), but activated clotting time may be used in select patients undergoing percutaneous coronary intervention or cardiopulmonary bypass surgery. The aPTT values are calibrated to laboratory-specific reagents. A general therapeutic target range is 1.5 to 2.5 times the control value.12 A drawback of using aPTT to monitor heparin infusions is its lack of specificity for heparin and need for frequent monitoring.13,18 Therefore, some institutions have implemented anti–factor Xa (anti-Xa) monitoring for heparin infusions.12,18 Because the anti-Xa assay is more specific than aPTT for heparin activity, monitoring can be less frequent. A therapeutic range of 0.3 to 0.7 U/mL has been proposed. Ultimately, the optimal monitoring parameter for heparin has yet to be determined.Low-molecular-weight heparins (LMWHs) are also indirect anticoagulants. Examples of LMWHs are enoxaparin and dalteparin. The many favorable characteristics of LMWHs include a more predictable dose-response relationship, longer plasma half-life, and reduced binding to platelets.12 Similar to UFH, LMWHs exert most of their anticoagulant effect via antithrombin III but are also capable of promoting factor Xa inactivation. Low-molecular-weight heparins are primarily eliminated renally, so prolonged exposure is observed in patients with renal impairment (creatinine clearance < 30 mL/min).13 Unlike UFH, LMWHs can be monitored using anti-Xa activity, although this remains controversial and is not commonly performed. Anti-Xa monitoring may be beneficial in patients with altered pharmacokinetics, such as pregnant or obese patients.19 Anti-Xa monitoring is performed by obtaining a peak anti-Xa level 4 hours after subcutaneous administration.20Fondaparinux is a modified synthetic analogue of the antithrombin-binding molecule in UFH and LMWH. Fondaparinux binds to antithrombin III and enhances its reactivity with factor Xa to form a complex. These structure modifications increase its anti-Xa activity and increases its half-life compared with LMWH.12 Fondaparinux activity should not be monitored with an anti-Xa assay unless an assay specifically designed for fondaparinux is used. Elimination relies heavily on renal function, therefore fondaparinux is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).14Advantages of direct thrombin inhibitors include their more predictable anticoagulant effect, reduced effect on plasma proteins, anti-platelet effect, and lack of immune-mediated thrombocytopenia that can be seen in some patients receiving UFH or LMWHs.21 Argatroban is a direct thrombin inhibitor that binds to the active site of thrombin in a reversible manner.15,19 Argatroban is FDA approved, with indications for prophylaxis or treatment of patients with HIT and for patients undergoing percutaneous coronary intervention who have HIT or are at risk for HIT.15 The dose should be adjusted and caution should be exercised in patients with hepatic dysfunction. Activity should be monitored using aPTT, with 1.5 to 2.5 times the reference range defined as the target range for efficacy.12Bivalirudin exerts its effects by creating a complex with thrombin, but the effects are reversible because thrombin itself cleaves bonds to restore activity.12,16 Because of its rapid onset and offset and other pharmacokinetic properties, bivalirudin is primarily used in patients undergoing percutaneous coronary intervention. Bivalirudin is cleared through proteo-lytic cleavage and liver metabolism, although approximately 20% of the drug is excreted via the kidneys.21 The dose should be adjusted for patients with moderate to severe renal dysfunction. If bivalirudin is continued for an extended time, such as for off-label indications including treatment of HIT, it can be monitored by using aPTT, with a goal range of 1.5 to 2.5 times the baseline.12One of the most common reasons for transitioning a patient from one parenteral anticoagulant to another is a change in renal function.17 Because of the high degree of renal elimination with LMWH and fondaparinux, patients who develop renal impairment while in the ICU may be transitioned to UFH or another parenteral anticoagulant. When transitioning patients between parenteral anticoagulants, clinicians should have a clear understanding of the reason for use because drug dosing may vary depending on the indication. There are no clear guidelines for changing between prophylactic doses of these agents. However, initiating the new parenteral anticoagulant when the next dose is due is a possible option (Table 4).A change from UFH to LMWH or fondaparinux is warranted when there is a concern for fluid overload because of the large difference in volumes of administration of these agents. This transition can also be particularly useful for patients who have not achieved a therapeutic INR while receiving warfarin. Another potential reason to transition a patient from one parenteral anticoagulant to another is concern for HIT, a situation in which heparin products should not be administered.23To facilitate patient discharge and long-term anticoagulation, transitioning from parenteral anticoagulants to warfarin requires an overlap between the 2 agents. This “bridging” period is needed to provide anticoagulation while the vitamin K–dependent clotting factors are depleted. After a therapeutic INR is achieved for at least 2 consecutive readings with concomitant administration of both agents for 5 days, the parenteral anticoagulant can be discontinued.24 When transitioning from parenteral anticoagulants to direct Xa inhibitors, overlapping the 2 agents is not required (Table 5).Transitioning from argatroban or bivalirudin to an oral anticoagulant requires a different approach because of the ability of argatroban and bivalirudin to falsely elevate the INR, which can make transitioning to warfarin challenging. Argatroban or bivalirudin must be continued for 5 days after warfarin initiation because of the paradoxical increased risk of clotting with warfarin use upon initiation of therapy.24 Specifics regarding the transition of argatroban or bivalirudin to warfarin are included in Table 5. Limited data for transitioning from argatroban or bivalirudin to DOACs are available. Despite the lack of clinical data, recommendations can be made on the basis of the rapid onset of action and short half-life of DOACs, which are typically initiated within 2 to 4 hours after discontinuation of argatroban or bivalirudin. Table 6 presents a summary of transitioning from oral to parenteral anticoagulants.A drug-specific factor that clinicians should consider when transitioning patients between anticoagulants is the pharmacokinetic profile of the oral and parenteral anticoagulants, including the onset and offset of action. Patient-specific factors to be considered include availability of enteral access, degree of anti-coagulation required, and renal and hepatic function. Although recommendations can be made on the basis of drug-and patient-specific considerations, further research would be helpful to guide clinicians in transitioning patients among various anticoagulants.