US Pharm. 2018;32(2):13-14.

Anticoagulants include a variety of agents that inhibit one or more steps in the coagulation cascade. In recent years, the search for new anticoagulants has generated novel agents for preventing and managing thromboembolic disorders. Specifically, anticoagulants that directly target the enzymatic activity of thrombin and factor Xa have been developed. Application of these new agents requires knowledge of their individual properties, dosing, risks, and benefits. These direct thrombin inhibitors and direct factor Xa inhibitors block major procoagulant activities involved in the generation of a fibrin clot.1


Thrombin
is the final enzyme in the clotting cascade that produces fibrin; it is formed by the proteolytic cleavage of prothrombin by factor Xa. Factor Xa acts immediately upstream of thrombin in the clotting cascade, and direct factor Xa inhibitors bind to the active site of factor Xa and inhibit its activity without requiring cofactors. Both thrombin and factor Xa are active in circulating and clot-bound forms.2

The predictable pharmacologic profile of these new agents allows physicians to use these drugs without the need for routine coagulation monitoring, which is necessary with warfarin therapy. In addition, these agents have not been demonstrated to have any food interactions and exhibit limited drug-drug interactions owing to their minimal metabolism through the CYP450 system. Their unique pharmacokinetic profile may help clinicians more quickly manage thromboembolic disorders.3

In this brief review, the pharmacology of these novel oral anticoagulants (NOACs), their applications in total hip and knee replacement, the treatment of venous thromboembolic disorders, stroke prevention in atrial fibrillation (AF), and their advantages over vitamin K antagonists (VKAs) will be discussed.

MECHANISM OF ACTION

Direct Thrombin Inhibitors: These agents prevent thrombin from cleaving fibrinogen to form fibrin. They bind to thrombin directly, rather than enhancing the activity of antithrombins, as is done by heparin. The only oral drug in this group is dabigatran (Pradaxa).4

Direct Factor Xa Inhibitors: Factor Xa is a trypsin-like serine protease that plays a key role in the blood coagulation cascade. It holds a central position that links the intrinsic and extrinsic pathways to the final common coagulation pathway. Factor Xa converts the prothrombin to its active form, thrombin. These agents prevent factor Xa from cleaving prothrombin to form thrombin and bind directly to factor Xa, rather than enhancing the activity of antithrombin. There are no parenteral direct factor Xa inhibitors in clinical use. The drugs include rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Lixiana), and betrixaban (Bevyxxa). Of note, the generic names for these agents all end in “Xa-ban.”5

Recommendations for each agent are based largely on the efficacy and safety in specific patient populations and clinical indications. Dabigatran was the first of the direct oral anticoagulants to become clinically available (2010). The direct factor Xa inhibitors became available in subsequent years. Many clinicians, however, are still unfamiliar with appropriate dosing of these drugs. Pharmacokinetic differences may make one medication a better choice compared to another for a given patient.2,4

Premature discontinuation of rivaroxaban and other direct factor Xa inhibitors increase the risk of thrombotic events in the absence of adequate alternative anticoagulants. Also, epidural spinal hematomas have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. These patients, therefore, must be monitored for signs and symptoms of neurologic impairment.2,5

DIRECT THROMBIN INHIBITORS

Dabitagran etexilate is a prodrug that is converted in the liver to dabigatran, an active direct thrombin inhibitor that inhibits both free and bound thrombin. The half-life of this medication is 12 to 17 hours in patients with normal renal function.6

Dabitagran etexilate is unaffected by food and has to be stored in the original container or blister package due to the potential for breakdown from moisture and loss of potency. This medication should not be stored in pill boxes or pill organizers. Once the bottle is opened, the medication must be used within 4 months, and removal of the capsule shell results in dramatic increases in oral bioavailability.6

This medication is used in the prevention and management of venous thromboembolism (VTE) and in stroke prevention in patients with atrial fibrillation (AF). It should not be used in patients with prosthetic heart valves or during pregnancy.6

Dosing: Dabitagran etexilate is available as 75-mg, 110-mg, and 150-mg capsules. It is given as a fixed dose without monitoring, and the maximum effect is achieved within 3 hours of ingestion. Renal excretion of unchanged drug is the predominant elimination pathway, with 80% excreting in the urine.6

Dosing for VTE prophylaxis in surgical patients is 110 mg 1 to 4 hours after surgery, followed by 220 mg once daily for 28 to 35 days after hip replacements and 10 days after knee replacements.2,6

For stroke prevention in AF, 110 mg is given twice daily or 150 mg twice daily if creatinine clearance (CrCl) >30 mL/min. For secondary prevention and treatment of VTE, 150 mg is administered twice daily with CrCl >30 mL/min. For stroke prevention in AF, 110 mg is given twice daily or 150 mg twice daily with CrCl >30 mL/min.

Laboratory Testing and Monitoring: Prior to initiating dabigatran, healthcare practitioners should measure platelet count, prothrombin time, and activated partial thromboplastin time to assess and document coagulation status before coagulation therapy.

Dyspepsia is a common side effect of dabigatran, with an incidence of 12% to 33% in some studies. In addition, as with all anticoagulants, dabigatran increases bleeding risk. However, the dabigatran antidote idarucizumab was approved by the FDA in 2015.2,6

Dabigatran Reversal: Idarucizumab (Praxbind) is a humanized antidabigatran monoclonal antibody fragment that may be used for emergency reversal of the anticoagulant effect of dabigatran. This agent should be administered in patients for whom more conservative bleeding management measures have been ineffective. It should be administered only to patients with convincing evidence of significant dabigatran levels based on clinical history of ingestion or laboratory testing. Idarucizumab should not be administered to patients with a normal thrombin time. The dose is 5 g (two 2.5-g vials), which can be administered either as two consecutive infusions or as a bolus (i.e., injecting both vials consecutively via syringe).2

DIRECT FACTOR Xa INHIBITORS

These drugs inactivate the free and bound factor Xa. Several are clinically available as oral agents, but there are no parenteral drugs available in this group. Otamixaban was developed as an intravenous drug but discontinued owing to excessive bleeding. All of these drugs are metabolized in the kidney and liver.7,8

Rivaroxaban

This is the first direct factor Xa inhibitor with a half-life of 7 to 17 hours. It is used for prevention and treatment of VTE and in stroke prevention in patients with AF. Rivaroxaban is generally given at a fixed dose without monitoring. The 15- and 20-mg tablets are taken with food. Dosing is based on clinical condition and renal status. For VTE, 15 mg is given twice daily for 21 days, followed by 20 mg once daily. The AF dose is 20 mg once daily with the evening meal (CrCl >50 mL/min) or 15 mg once daily with CrCl <50 mL/min.2,9,10

This drug should not be used in patients with CrCl <15 mL/min or with CYP3A4 and P-glycoprotein dual inhibitors, such as ketoconazole, itraconazole, voriconazole, posaconazole, or ritonavir. Routine monitoring of coagulation time is not necessary because drug levels are relatively predictable for a given dose. As with all anticoagulants, this drug increases bleeding risk, and a new antidote is under study.2,9,10

Because of high plasma protein binding, this drug is not dialyzable. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, platelet inhibitors, fibrinolytic therapy, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. They must be used with caution in patients with CrCl <30 mL/min. This drug should be used during pregnancy only if the potential benefits justify the potential risk to mother and fetus. There is no antidote available for rivaroxaban overdose, and the use of activated charcoal to reduce absorption is recommended.2

Apixaban

Apixaban is a newer orally active factor Xa inhibitor with a half-life of 5 to 9 hours. It is also used for the prevention and treatment of VTE and stroke prevention in patients with AF. This drug is used for VTE prophylaxis and for initial and extended treatment. It should not be used during pregnancy. The dosing of apixaban differs according to clinical indication, age, weight, and renal function. Dosing for VTE prophylaxis is 2.5 mg twice daily for 35 days (hip replacement) or 12 days (knee replacement). For secondary prevention and treatment of VTE, 10 mg is administered twice daily for 7 days, followed by 5 mg twice daily. For stroke prevention in AF, 5 mg is given twice daily (CrCl >50 mL/min) or 2.5 mg twice daily.

This drug has the least dependence on renal clearance of the direct factor Xa inhibitors. Laboratory testing prior to intiating apixaban and monitoring is the same as for rivaroxaban. In cases of emergency surgery in a patient receiving apixaban, monitoring can be accomplished through the measurement of antifactor Xa activity.11,12

Edoxaban

Edoxaban is an oral direct, specific inhibitor of factor Xa with an approximate 10,000-fold selectivity for factor Xa over thrombin. Edoxaban was approved by the FDA in January 2015 for the prevention of stroke and noncentral nervous system systemic embolisms. This drug is also an orally active factor Xa inhibitor with a half-life of 10 to 14 hours, and it has the same indications as rivaroxaban and apixaban. It is given at a fixed rate with no monitoring. The typical dosage is 30 or 60 mg once daily. Possible improvements in efficacy and/or safety with monitoring have been suggested. Edoxaban is renally excreted and is a substrate for P-glycoprotein. The dose must be adjusted in patients with CrCl of 15 to 50 mL/min.

As with other anticoagulants, edoxaban increases bleeding risk and is administered in the setting of increased thrombotic risk. Edoxaban is rapidly absorbed, and it was estimated that its absolute bioavailability is 58.3%. This drug has dual mechanisms of elimination: Approximately one-third is eliminated via the kidney and the remainder via feces.2,13

Betrixaban

This is a long-acting inhibitor with a half-life of 19 to 27 hours. It is used in the prevention of VTE in hospitalized adult patients. It is also given in a fixed rate with no monitoring. The typical dosage is 160 mg on the first day followed by 80 mg once daily. Doses are given at the same time with food. For individuals with CrCl <30 mL/min, 80 mg is given on the first day, followed by 40 mg daily. For VTE prophylaxis, the duration of therapy is 35 to 42 days.2,14

Reversal of Rivaroxaban, Apixaban, Edoxaban, Betrixaban: There is no specific antidote for the direct factor Xa inhibitors. The following may be helpful, although evidence from randomized trials is lacking regarding these strategies.2

Imminent Risk of Death: For patients who are at imminent risk of death from bleeding associated with direct factor Xa inhibitor anticoagulation, administering an unactivated 4-factor prothrombin complex concentrate (PCC) at a dosage of 25 to 50 units/kg is suggested. If a 4-factor PCC is unavailable, a 3-factor PCC may be used; supplementation of 3-factor PCC with fresh frozen plasma has been used to supply factor VII, which is present at minimal levels in 3-factor PCCs.2

Major Bleeding: For patients with major bleeding (including life-threatening bleeding), administering an antifibrinolytic agent (e.g., tranexamic acid) is suggested. The use of this agent may also be appropriate in individuals with less serious bleeding if the patient has ongoing bleeding or other comorbidities that increase bleeding risk.2

ADVANTAGES OF NOACs OVER VKAs

NOACs have various advantages in the prevention and treatment of patients with a predisposition toward AF, deep venous thrombosis, pulmonary embolism, stroke, and other conditions that are related to inherited or acquired thrombophilia.2

The following are the main advantages of NOACs compared with VKAs in preventing various factors that are responsible for thromboembolic disorders and in the treatment of thromboembolic diseases: absence of food interactions; few strong drug interactions; predictable pharmacokinetic and pharmacodynamic profiles; rapid onset and offset of action; short half-life; and absence of the need for laboratory monitoring. Routine monitoring is not required, regardless of body weight, age, sex, race, and demographic variations.2,15

Additional advantages of NOACs over VKAs include wide therapeutic windows, greater efficacy in AF, and lower risk of intracranial hemorrhage, except for dabigatran, which has an intracranial hemorrhage rate equal to that of warfarin at doses of 150 mg.2

CONCLUSION

Long-term use of oral anticoagulant therapy with VKAs presented several problems related to major drug and food interactions, individual variability in the effect, and the need for continuous monitoring. This caused a search for new ways to discover additional anticoagulant medications.

The advantages of NOACs over VKAs are their high efficacy in preventing stroke in AF and nonvalvular AF, lower incidence of major bleeding, convenience of use, minor drug and food interactions, rapid onset and offset of action, short half-life, and lack of the need for laboratory monitoring.

Disadvantages of NOACs, such as their higher cost, absence of specific antidotes, and limited experience and dosing, however, should be taken into consideration. In addition, NOACs should not be used in patients with severe renal and hepatic disease, patients with mechanical heart valves, patients younger than age 18 years, and  the elderly.

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