Direct Oral Anticoagulants for Venous Thromboembolism: A Pharmacological Review

Venous thromboembolism (VTE) is an overarching term applied to either deep vein thrombosis (DVT) or pulmonary embolism. VTE is considered to be the third most common cardiovascular disorder after coronary heart disease and stroke.1 An estimated 900 000 cases of VTE occur each year in the United States, and upwards of 60% of cases occur in hospitals or nursing homes.2 Quite often, VTE develops within the hospital in association with central venous catheters, surgery, or immobilization. Evidence suggests that hospitalized patients have a 100-fold greater incidence of acute VTE than do patients who are not in the hospital.2Considering the additional risks for VTE among patients within the acute care environment, members of the health care team should be familiar with identifying manifestations of VTE as well as its proper management. In recent years, novel anticoagulant drugs have expanded the options for treating venous and arterial thrombotic events. Direct oral anticoagulants (DOACs) offer practitioners alternatives to traditional vitamin K antagonists, commonly known as warfarin (Coumadin), while maintaining similar efficacy and lowering the risk of bleeding. Consequently, the 2016 CHEST guidelines and expert panel report on antithrombotic therapy for VTE disease have updated their recommendations to include the preference of DOACs over vitamin K antagonists for VTE management.3 Prompt implementation of anticoagulation during the first 10 days is critical to minimize the risk of VTE-related death, complications, and recurrence.4 The purpose of this article is to provide an overview of VTE management, with a focus on treatment with DOACs in an effort to increase understanding of these agents within critical care settings.The cause of VTE may be related to several different factors that trigger the body’s coagulation cascade. The 3 primary factors are summarized by Virchow’s triad, which includes (1) an alteration in blood flow, often due to a lack of flow or stasis, (2) vascular endothelial injury, which may be caused by surgery or trauma, and (3) an alteration in the constituents of the blood such that there is an inherited or acquired hypercoagulable state, as with cancer.5 The body’s coagulation cascade begins with the initiation of platelet aggregation, leading to a “plug” that forms over a vascular injury. Next is a sequential activation and release of enzymes, which promotes coagulation factors. These coagulation factors result in the conversion of fibrinogen to fibrin, which reinforces the platelet plug (Figure 1). Consequently, these reinforced plugs can be dislodged or develop in inappropriate areas of vasculature, leading to occlusion of vessels and resulting in VTE.A pertinent physical examination, laboratory findings, and imaging can be used to diagnose VTE. Physical examination may reveal a palpable cord that is representative of a thrombosed vein, often associated with local pain. Unilateral edema or swelling accompanied by warmth, tenderness, erythema, and superficial venous dilatation may also be present. The noninvasive imaging approach of choice is compression ultrasonography for a suspected first episode of DVT. This imaging may be performed bedside, following the physical examination. A d-dimer assay may also be used to rule out VTE (negative for VTE if the result is < 0.5 μg/mL; to convert to nmol/L, multiply by 5.476). A positive d-dimer test is not specific enough to diagnose VTE and thus should be paired with the patient’s current clinical picture, risk factors, and other laboratory markers. Pulmonary emboli develop when a blood clot migrates to the lungs.A pulmonary embolism may also have a wide array of presenting symptoms, varying from an asymptomatic presentation to having mild, nonspecific symptoms (eg, fever), to respiratory symptoms (eg, dyspnea, pleuritic pain, and cough), or to more severe symptoms often requiring admittance to the intensive care unit (eg, hemodynamic shock).6 Samples for a complete blood cell count, basic metabolic panel, arterial blood gas analysis, and measurements of erythrocyte sedimentation rate and serum levels of lactate dehydrogenase, brain natriuretic peptide, troponins I and T, and aspartate aminotransferase may be collected to further elucidate the severity of the problem and the patient’s prognosis. Additionally, chest radiography, electrocardiography, and computed tomography may be performed to rule out other conditions.Management of VTE includes 3 phases: (1) acute therapy, (2) long-term therapy, and (3) extended therapy. Acute therapy corresponds to the first 10 days of anticoagulant treatment. Long-term therapy spans from the acute phase up to 3 to 6 months of therapy, which may conclude anticoagulant treatment of VTE for some patients. Determining if the patient should receive extended therapy instead of long-term therapy is an individualized process. For example, a patient with a first episode of lower-extremity DVT following a long flight would be considered to have a provoked DVT and most likely would complete therapy after 3 months. Extended therapy is the indefinite continuation of anticoagulation and is typically employed for patients with repeat VTE or in cases where definitive causes were not identified with the initial presentation.Pharmacological treatment options have expanded in recent years, allowing for a new era in anticoagulant therapy with greater flexibility and individualized VTE management. During the acute phase, the primary goal of therapy is to attenuate thrombin and fibrin clot generation. This attenuation leads to rapid diminution of symptoms associated with acute VTE and mitigates further sequela.Traditionally, parenteral therapy with unfractionated heparin or low-molecular-weight heparin (eg, enoxaparin [Lovenox], or fondaparinux [Arixtra]) has been employed during the acute therapy phase while overlapping with warfarin until a therapeutic international normalized ratio of 2 to 3 is attained. Unfractionated heparin works by inhibiting thrombin (factor IIa) and factor Xa and is administered as a continuous infusion titrated to an activated partial thromboplastin time of 1.5 to 2.5 times the upper limit of normal. When anti-Xa monitoring is used, a therapeutic target of 0.3 to 0.7 U/mL is suggested. At least 5 days of parenteral anticoagulation is recommended to overlap with warfarin until the international normalized ratio is 2.0 or greater for at least 24 hours.3 Now, DOACs can be implemented early in VTE treatment regimens, and in some cases, can be used instead of parenteral agents and vitamin K antagonists.7 Specifically, rivaroxaban (Xarelto) and apixaban (Eliquis) can be initiated for treatment of VTE without prior parenteral anticoagulation. Edoxaban (Savaysa) and dabigatran (Pradaxa) require 5 days of parenteral anticoagulation before initiation. A summary of the agents and their respective therapy time lines is provided in Figure 2.The 2 main mechanisms of action of the DOACs are direct inhibition of thrombin and inhibition of factor Xa (Figure 1). Thrombin (factor IIa) is the final enzyme in the clotting cascade that cleaves fibrinogen to fibrin. Thrombin also activates platelets and other procoagulant factors. Inhibition of thrombin interrupts the final steps in the coagulation pathway. Factor Xa acts 1 step upstream of thrombin in the clotting cascade, where the intrinsic and extrinsic coagulation pathways converge. Factor Xa functions to cleave prothrombin to thrombin. As such, the inhibition of factor Xa prevents thrombin generation, which subsequently prevents clot formation. Four DOACs are currently approved by the Food and Drug Administration (FDA) in the United States: dabigatran, edoxaban, apixaban, and rivaroxaban. In general, DOACs offer advantages over warfarin such as the absence of food interactions, fewer drug-drug interactions, short half-lives, and the absence of the need for laboratory monitoring (see Table).Dabigatran was the first FDA-approved DOAC in the United States. The prodrug of dabigatran (dabigatran etexilate) is rapidly transformed after oral ingestion and hepatic processing. A prodrug is a compound that undergoes chemical conversion in the body by metabolic processes before becoming a pharmacologically active drug. Dabigatran 150 mg twice daily can be administered without regard to food and is rapidly absorbed. The primary route for dabigatran elimination is through the kidneys, and thus dabigatran should be avoided in patients with decreased renal function (creatinine clearance < 30 mL/min) and patients who are on dialysis.8 The drug can be continued in patients with Child-Pugh class A or B liver cirrhosis and has low potential for drug-drug interactions. Of concern, the risk of major gastrointestinal bleeding may be greater than the risk with warfarin, especially in patients more than 65 years old. Additionally, patients report dyspepsia as the most common side effect. Many anticoagulants may be administered through feeding tubes, but dabigatran cannot be crushed or opened. Without the capsule, absorption increases by 75%, which may lead to increased exposure to dabigatran.9 When a dose is missed, maintain a separation of doses by at least 6 hours. If the next dose is due in less than 6 hours, do not administer the missed dose; wait for the next scheduled dose and do not double the dose. Finally, the medication should be stored in its original container or blister package to protect against moisture and avoid product breakdown and loss of potency.Rivaroxaban was the first anti-Xa inhibitor to receive FDA approval. Treatment of VTE may be initiated with rivaroxaban 15 mg orally twice daily for 21 days, then transitioned to 20 mg orally daily for the remainder of treatment. Rivaroxaban is given orally in its active form and has an onset of action of 1 to 4 hours.10,11 Metabolism occurs in the liver in healthy patients.12 Mild hepatic disease (Child-Pugh class A) does not result in clinically significant differences in pharmacokinetic and pharmacodynamic parameters. Continuation of rivaroxaban in hepatic insufficiency (Child-Pugh class B or C) and renal insufficiency (creatinine clearance < 30 mL/min) should be avoided. For patients who cannot swallow whole tablets, rivaroxaban may be crushed and mixed with applesauce or water immediately before administration via a feeding tube. Rivaroxaban bioavailability is reduced with the 15-mg and 20-mg tablets in the fasted state. It is recommended to administer the 15-mg and 20-mg tablets with food to improve absorption, whereas absorption of the 10-mg tablet is not affected by food and that tablet can be administered without regard to food. Additionally, rivaroxaban’s absorption is dependent on the site in the gastrointestinal tract where the drug is released. Administration via feeding tube placed distal to the stomach should be avoided to prevent decreased absorption.13 Patients prescribed 15 mg twice daily should receive 30 mg per day even if a dose is missed (two 15-mg tablets may be taken together). Normal twice-daily dosing should be resumed the following day. Patients who miss a dose who are prescribed once-daily dosing should take that dose on the same day as soon as possible. Normal dosing time should be resumed the following day. Drugs that are dual inhibitors of cytochrome P-450 3A4 and P-glycoprotein systems (eg, ketoconazole, ritonavir, and clarithromycin) interact with rivaroxaban; therefore, concurrent use should be avoided.Apixaban is a factor Xa inhibitor and the third DOAC approved by the FDA for use in the United States. Following the first 7 days of apixaban 10 mg twice daily therapy, apixaban 5 mg twice daily should be maintained. Apixaban is rapidly absorbed following oral administration and can be administered independently of food. Metabolism occurs in the liver.14 Despite liver metabolism, apixaban can be continued in liver cirrhosis (Child-Pugh class A or B). Interestingly, apixaban has the lowest renal clearance of the DOACs and has been documented to produce similar pharmacokinetics in dialysis patients.15 Apixaban may be crushed and given via gastric tube similarly to rivaroxaban. If a dose is missed, administer as soon as possible on the same day. Do not double up doses. Resume the dosing regimen the next day.Edoxaban is the most recently approved oral direct inhibitor of factor Xa. The recommended dose is 60 mg daily, or 30 mg daily if the patient weighs less than 60 kg. Edoxaban is rapidly absorbed after oral administration.16 It is recommended to lower the dose to 30 mg daily for patients with a creatinine clearance less than 50 mL/min.16,17 Edoxaban is also a substrate of P-glycoprotein and demonstrates drug-drug interactions similar to those of the other DOACs. Edoxaban pharmacokinetics for crushed tablets or administration via nasogastric tube have not been established. It is recommended to use an alternative oral agent that can be crushed, or switch to parenteral agents until oral administration of edoxaban can be resumed. Missed doses should be administered as soon as possible on the same day. Do not double up doses. The dosing regimen should be resumed the next day.Routine monitoring of coagulation laboratory values is not required for patients taking rivaroxaban, apixaban, edoxaban, or dabigatran, which is in stark contrast to the monitoring requirements of warfarin therapy. Although activated partial thromboplastin time and anti-Xa activity of the DOACs can be measured, these assays are not readily available in most institutions for the determination of the efficacy of DOAC drugs.7 Baseline assessment and the routine use of a complete blood cell count is recommended to monitor hemoglobin and hematocrit levels, and a basic metabolic panel is recommended to monitor serum level of creatinine. Additionally, patients should have regular physical monitoring for signs of bleeding, such as “coffee ground” emesis, excessive bruising, or tarry stools as well as monitoring for clinical improvement of the VTE.Understanding the parameters associated with when to withhold and when to restart therapies is important within the intensive care unit, particularly in the perioperative setting. Procedures can be stratified on the basis of risk of bleeding: low, moderate, or high risk. It is generally suggested that DOACs be withheld for 24 hours before low-risk procedures and restarted 24 hours after such procedures. It is recommended to withhold DOACs for 48 hours before moderate- and high-risk procedures. In patients with renal dysfunction and in elderly patients, DOACs are eliminated slowly and should be discontinued several days before procedures. DOACs should be reinitiated after consideration of the patient’s risk factors and the drug characteristics.18 In the event of gastrointestinal bleeding, it is suggested to wait to reinitiate therapeutic anticoagulation until no evidence of active bleeding is apparent and endoscopic treatment of the bleeding has been performed. The placement of an inferior vena cava filter may be considered as a last resort in patients who have a contraindication to anticoagulation (eg, the presence of active bleeding), complications of anticoagulation (eg, recent major bleeding event, major surgery, or major trauma), or failure of anticoagulation.3One advantage of warfarin is that an established antidote is available for patients needing immediate reversal. Several reversal modalities may be considered when a patient has bleeding while being treated with a DOAC. Oral activated charcoal binds any drug remaining in the gastrointestinal tract, which may be useful when ingestion of drug product occurred within 1 to 2 hours. Dialysis is effective in clearing dabigatran, but not factor Xa inhibitors, given their high protein-binding affinity. Prothrombin complex concentrates (eg, Kcentra, CSL Behring GmbH) can be helpful in patients with active bleeding. In the case of active major bleeding, antifibrinolytic agents such as tranexamic acid (Cyklokapron) have been suggested for reversal.19 No good clinical data are available to support the use of any of these agents for reversal of the effect of the factor Xa inhibitors; thus, these reversal agents are not considered the standard of care.7Idarucizumab (Praxbind) is the first dabigatran-specific antidote to receive FDA approval. It is a humanized monoclonal antibody that binds dabigatran and can be used to emergently reverse the effects of dabigatran for urgent procedures or in life-threatening or uncontrolled bleeding. It is recommended to administer idarucizumab 5 g intravenously in 2 divided doses with no more than 15 minutes between doses.19 The anticoagulant effects of dabigatran are neutralized within minutes following idarucizumab administration. Adverse effects may include hypersensitivity reactions, which may occur with any monoclonal antibody. It is important to monitor for development of a rash or bronchospasms following administration. Additionally, patients on anticoagulation therapy have underlying disease states that predispose them to VTE thus, reversing the effects of dabigatran may escalate the risk of recurrence in such patients. Although no agents for Xa inhibitor reversal are currently available, some specific reversal agents (eg, andexanet alfa, a recombinant decoy of factor Xa) are currently in phase 3 clinical trials.19DOACs have similar efficacy to warfarin in the treatment of VTE and are recognized as preferred agents by the 2016 CHEST VTE guidelines. Treatment with a DOAC is associated with a significant reduction in the risk of major bleeding, intracranial bleeding, fatal bleeding, and clinically relevant nonmajor bleeding.3 Increased prescribing of DOACs is expected because of their convenience, fewer dietary requirements, and safety and efficacy profiles. The recognition, monitoring, and management of patients receiving DOAC therapy will be an ever-increasing component of health systems and is important to successful patient care within the intensive care unit.