Review of Direct Oral Anticoagulants and Guide for Effective Drug Utilization

Tigran Khachatryan; Christopher Hauschild; Jason Hoff; Tahmeed Contractor; Arthur Khachatryan; Huyentran Tran; Bert Matsuo; Alan Jacobson; Anthony Hilliard

Disclosures

Am J Cardiovasc Drugs. 2019;19(6):525-539. 

In This Article

Direct Factor Xa Inhibitors

The direct Factor Xa inhibitors comprise four medications: apixaban (Eliquis®), edoxaban (Savaysa®), rivaroxaban (Xarelto®), and the newest member, betrixaban (Bevyxxa®). All members of this class directly inhibit Factor Xa, but their pharmacologic properties and approved indications differ. As with dabigatran, routine monitoring of anticoagulant effect is not required. General considerations for monitoring the effects of these agents are similar to those for dabigatran and were discussed in Sect. 2.1. Assays to measure the effect or the presence of the anti-Xa inhibitors have shortcomings similar to those for dabigatran. Although all these agents can affect aPTT and prothrombin time (PT), the effect varies between agents and can be influenced by the reagent used for the test. Furthermore, these global tests may indicate the presence of a drug but do not quantify serum concentration. Rivaroxaban has the strongest effect on PT and, when sensitive reagent is used, a normal PT will exclude the presence of the medication. This is also true for edoxaban when trough level is measured.[19] Apixaban will produce variable effects on PT, which may be normal despite its use. Calibrated anti-Xa chromogenic assays are available and can quantify the concentration of serum Factor Xa inhibitors. These assays have shown good correlation with mass spectroscopy, which is regarded as the gold standard and can be performed in minutes. However, these assays are also affected by heparin and therefore cannot discriminate between heparin and Factor Xa inhibitors.[18,19]

General considerations for periprocedural management of patients receiving direct Factor Xa inhibitors are similar to those for dabigatran and bridging and were discussed in Sect. 2.5. In patients receiving apixaban, rivaroxaban, or edoxaban who are at low procedural bleeding risk, these agents should be interrupted for ≥ 24 h for CrCl ≥ 30 mL/min and for ≥ 36 h for CrCl 15–29 mL/min, and measuring agent-specific anti-Xa levels or holding for ≥ 48 h should be considered where CrCl is ≤ 15 mL/min. In patients for whom the procedural bleeding risk is uncertain, intermediate, or high, these agents should be held for ≥ 48 h for CrCl ≥ 30 mL/min, and measuring agent-specific anti-Xa levels or holding for ≥ 72 h should be considered where CrCl is ≤ 30 mL/min.[37] No recommendations are given regarding betrixaban, which was approved after the publication of the ACC expert consensus document, but a longer interrupted period will be needed given its longer half-life.

The contraindication to mechanical heart valves is a class limitation. Until recently, no approved reversible agent was available, but andexanet alfa (Andexxa®) was approved on 3 May 2018 as a reversal agent for the Factor Xa inhibitors apixaban and rivaroxaban.[40,41] It is a recombinant human Factor Xa protein that binds and neutralizes Factor Xa inhibitors.[42,43] It has not been approved for edoxaban or betrixaban. For major bleeding in this situation, general measures should be employed, such as mechanical compression, surgical or endoscopic intervention, red blood cell transfusion, fluids, and administration of 4F-PCC or aPCC.[21]

Apixaban (Eliquis®)

Pharmacology. Apixaban is a selective, reversible, and competitive inhibitor of Factor Xa. The medication is readily absorbed and reaches Cmax about 1–3 h after oral administration. It has bioavailability of about 50% at doses up to 10 mg, protein binding of approximately 87%, and a half-life of 8–15 h. Apixaban is an active drug that is metabolized predominantly by the cytochrome P450 (CYP)-3A4 enzyme in the liver.[44,45] Strong dual inhibitors of CYP3A4 and P-gp, such as ketoconazole, itraconazole, ritonavir, or clarithromycin, can increase blood drug levels and the risk of bleeding, whereas strong dual inducers, such as rifampin, carbamazepine, phenytoin, and St. John's wort, can decrease blood drug levels and increase the risk of thromboembolic events (Table 4).[15,17,46] The medication and its metabolites are primarily excreted via the fecal route, and about 27% is excreted through the kidneys.[45,47–49]

Indications. The FDA-approved indications for apixaban are to reduce the risk of stroke or TIA in NVAF, treat DVT and PE, reduce the risk for DVT and PE in previously treated patients, and to provide prophylaxis for DVT and PE in patients undergoing hip or knee replacement surgery.[47] The safety and efficacy of apixaban for these indications were established by the ARISTOTLE, AMPLIFY, AMPLIFY-EXT, and ADVANCE trials, respectively.[2,50–53] In the ARISTOTOLE trial, apixaban demonstrated superiority in preventing stroke or systemic embolism and lowering overall bleeding events and mortality in patients with NVAF.[2] Furthermore, the AVERROES trial demonstrated the superiority of apixaban in preventing stroke or systemic embolism compared with aspirin in patients with NVAF who were not suitable candidates for warfarin therapy.[54] It is also an option for patients with AF and bioprosthetic heart valves or valve repairs given the similar risk of stroke, systemic embolism, and bleeding compared with warfarin in the subanalysis of the ARISTOTLE trial.[55]

Dosing. Apixaban has a twice-daily dosing regimen. This stems in part from single- and multiple-dose trials demonstrating that apixaban peak-to-trough ratios were lower with twice-daily than with once-daily dosing, indicative of less fluctuation to drug exposure. Single-dose and twice-daily dosing were also evaluated in the early safety and efficacy trial of apixaban in patients with total knee replacement surgery, which demonstrated twice-daily dosing to be more efficacious, with bleeding rates similar to those with daily dosing.[56,57] The dosing of apixaban differs for each indication (Table 1). For NVAF, it is prescribed at 5 mg twice daily. Dose adjustment to 2.5 mg twice daily is recommended for patients with NVAF who meet two of the following three patient characteristics: serum creatinine > 1.5 mg/dL, age ≥ 80 years, or weight ≤ 60 kg. No renal dose adjustments are recommended for other indications or patients on hemodialysis.[34,47] This is a unique aspect of apixaban based on pharmacokinetic and pharmacodynamic data as patients with serum creatinine > 2.5 mg/dL were excluded from the main clinical trials.[47,58]

The recommendation for DVT or PE is to start with 10 mg twice daily for 7 days, then 5 mg twice daily thereafter. Unlike dabigatran, apixaban therapy for DVT or PE in a stable patient can be initiated without parenteral anticoagulation for the first few days but requires a higher initial dose for reasons discussed in Sect. 2.2. A lower dose of 2.5 mg twice daily is recommended to reduce the risk for DVT and PE in previously treated patients after 6 months of therapy and for DVT prophylaxis after hip or knee replacement surgery, for 35 days and 12 days, respectively. For prophylaxis after hip or knee surgery, medication should be initiated 12–24 h after achieving hemostasis.[37,47] A dose reduction of 50% is recommended for patients receiving 5–10 mg twice daily and strong dual inhibitors of CYP3A4 and P-gp. Apixaban should be avoided in patients receiving 2.5 mg twice daily and strong dual CYP3A4 and P-gp inhibitors. Apixaban should also be avoided in patients receiving strong dual inducers of CYP3A4 and P-gp (Table 4).[47]

Making the Switch. Conversion from other anticoagulants to apixaban is similar to that with dabigatran. For patients receiving warfarin, apixaban can be started once warfarin has been stopped and INR is < 2. To convert from other oral or parenteral anticoagulants, apixaban can be given at the next scheduled dose. For patients receiving unfractionated heparin, apixaban should be started immediately after discontinuing the infusion.[47]

Rivaroxaban (Xarelto®)

Pharmacology. Rivaroxaban is a selective, reversible, and competitive inhibitor of Factor Xa. It is an active drug and is readily absorbed, reaching Cmax 2–4 h after administration. Rivaroxaban is 92–95% protein bound and has a half-life of around 5–9 h but up to 11–13 h in the elderly.[48,59,60] Furthermore, the Cmax and AUC of rivaroxaban are proportional up to the 10-mg dose, beyond which the increase is less than proportional.[60] The absolute bioavailability of rivaroxaban 10 mg is 80–100% but only 66% for 20 mg in a fasting state and 76% when administered after a meal, leading to the recommendation that doses > 10 mg be taken with food.[59] It is metabolized by the liver through the CYP450 system. Therefore, similar to apixaban, blood drug levels can be affected by strong dual inhibitors and inducers of the CYP3A4 and P-gp systems (Table 4).[15] Renal excretion of the drug and its metabolites is about 66%, with the rest excreted via the fecal route.[48,59]

Indications. The FDA-approved indications for rivaroxaban are the same as for apixaban, along with the recently approved indications for stable coronary artery disease (CAD) and peripheral artery disease (PAD).[59] The safety and efficacy of rivaroxaban for these indications were established by the ROCKET-AF, EINSTEIN-DVT, EINSTEIN-PE, EINSTEIN-CHOICE, and RECORD trials.[5,61–66] The ROCKET-AF trial investigated rivaroxaban compared with warfarin for NVAF and found rivaroxaban to be noninferior to warfarin in preventing stroke or systemic embolism and to have similar rates of major bleeding and improved rates of intracranial and fatal bleeding. Increased rates of gastrointestinal bleeding were seen in the rivaroxaban group.[5] More recently, based on results from the COMPASS trial, rivaroxaban was approved for the treatment of stable CAD and PAD. In this study, rivaroxaban 2.5 mg twice daily in addition to aspirin showed improved cardiovascular outcomes at the cost of higher rates of bleeding than aspirin alone.[67]

Rivaroxaban should not be used for NVAF in patients with CrCl < 15 or < 30 mL/min for all other indications, as these patients were excluded from the major trials.[59]

Dosing. Despite the short half-life of rivaroxaban, it is administered once daily for most indications, except when used to treat DVT and PE in the acute phase. This was primarily because of the observation that the pharmacodynamic effects of rivaroxaban remained even after 24 h in single-dose trials for doses > 5 mg.[60] The feasibility of once-daily dosing was tested in a phase I clinical trial of healthy subjects, where Factor Xa activity and peak and total thrombin generation were diminished 24 h after a rivaroxaban dose.[68] These observations led to major trials testing the once-daily regimen to differentiate rivaroxaban from other Factor Xa inhibitors.

Rivaroxaban dosages for the treatment of NVAF in patients with CrCl > 50 mL/min is 20 mg daily with the evening meal. In those with CrCl 15–50 mL/min, the recommended dose is 15 mg daily.

For the treatment of DVT or PE, the starting dose is 15 mg twice daily for 21 days and 20 mg daily thereafter. As with apixaban, a higher initial dose is required for the treatment of VTE without the need for run-in with parenteral anticoagulants as discussed in Sect. 2.2. A lower dose of 10 mg daily is recommended to reduce the risk for DVT and PE in previously treated patients. A daily dose of 10 mg has shown superior efficacy over aspirin without significant increase in bleeding risk, whereas 20 mg daily results in a more significant increase in bleeding risk without a significant increase in efficacy. For DVT prophylaxis after hip or knee replacement surgery, 10 mg daily is recommended for 35 days and 12 days, respectively. In this setting, prophylaxis should be initiated 6–10 h after achieving hemostasis. Furthermore, in patients with stable cardiovascular disease, rivaroxaban 2.5 mg twice daily in addition to daily aspirin can help reduce cardiovascular outcomes at the expense of higher bleeding risk (Table 1).[59,63] Rivaroxaban should be avoided for patients receiving dual CYP3A4 and P-gp inhibitors or inducers (Table 4).[59]

Making the Switch. Conversion from other anticoagulants to rivaroxaban is different from that with other DOACs. For patients receiving warfarin, rivaroxaban can be started once warfarin has been stopped and the INR is < 3. To convert from other oral or parenteral anticoagulants, rivaroxaban can be given 0–2 h before the next scheduled dose. For patients receiving unfractionated heparin, rivaroxaban should be started immediately after discontinuing the infusion.[59]

Edoxaban (Savaysa®)

Pharmacology. Edoxaban is a selective and competitive inhibitor of Factor Xa.[69,70] It is an active drug that is readily absorbed and reaches Cmax within 1–2 h after oral administration. It has an absolute bioavailability of 62%. The unchanged drug is the predominant form in the plasma, with protein binding of approximately 55%. A small portion of the medication is metabolized by hydrolysis, conjugation, and oxidation via CYP3A4.[39,69,70] Therefore, it has the fewest drug–drug interactions in its class. However, concomitant use with rifampin should still be avoided (Table 4). It has a half-life of 10–14 h, with 50% excreted via kidneys and the rest via the intestinal/fecal route.[69,70]

Indications. The FDA-approved indications for edoxaban include the prevention of stroke and systemic embolism in patients with NVAF and the treatment of DVT and PE in patients already treated with parenteral anticoagulation for 5–10 days. The rational for the parenteral anticoagulant run-in is similar to that for dabigatran as discussed in Sect. 2.2. The safety and efficacy of edoxaban for these indications were established by the ENGAGE AF-TIMI 48 and Hokusai-VTE trials, respectively.[4,71] ENGAGE AF-TIMI 48 demonstrated that edoxaban was noninferior to warfarin in preventing stroke or systemic embolism and resulted in less bleeding and lower mortality from cardiovascular causes.[4] Furthermore, edoxaban is an option for patients with AF and bioprosthetic heart valves given that the risk of stroke, systemic embolism, and bleeding was similar to that with warfarin in the subanalysis of ENGAGE AF-TIMI 48.[72]

Edoxaban should be avoided in patients with CrCl < 15 mL/min or on hemodialysis as these patients were excluded from the major trials. Furthermore, it is not recommended for patients with CrCl > 95 mL/min[69] as the subanalysis of ENGAGE AF-TIMI 48 noted that these patients had higher rates of stroke or systemic embolism.[73]

Dosing. Edoxaban is dosed once daily for all indications. This stems from early evidence in healthy subjects demonstrating inhibition of thrombin generation beyond 24 h. Furthermore, a phase II clinical trial comparing once- versus twice-daily dosing regimens showed higher bleeding rates with the twice-daily regimen even though the total daily dose was the same, which paved the way for daily dosing of edoxaban.[70,74]

Edoxaban is prescribed at 60 mg daily for NVAF with CrCl 50–95 mL/min and 30 mg daily for CrCl 15–50 mL/min. No dose adjustment is required for patients receiving concomitant P-gp inhibitors.[39,69] The recommendation for the treatment of DVT or PE is 60 mg daily for CrCl > 50 mL/min and patient weight > 60 kg or 30 mg daily for CrCl 15–50 mL/min or patient weight ≤ 60 kg or for those receiving P-gp inhibitors (specific P-gp inhibitors in the Hokusai-VTE trial included verapamil and quinidine or the short-term concomitant administration of azithromycin, clarithromycin, erythromycin, oral itraconazole, or oral ketoconazole; Table 1).[69,71]

Making the Switch. For patients with NVAF and receiving warfarin, edoxaban can be started once the INR is ≤ 2.5. For other oral or parenteral anticoagulants, edoxaban can be given at the next scheduled dose. For patients receiving unfractionated heparin, edoxaban can be started 4 h after the infusion is stopped. For patients with DVT or PE who have been treated for 5–10 days with parenteral anticoagulation, edoxaban should be started 4 h after discontinuation of unfractionated heparin or at the time of the next scheduled dose of low-molecular-weight heparin.[69]

Betrixaban (Bevyxxa®)

Pharmacology. Betrixaban is the newest member of the oral direct Factor Xa inhibitor class approved in June 2017. It is a selective and competitive inhibitor of Factor Xa. The medication should be taken with food, and the drug is readily absorbed, reaching Cmax within 3–4 h after oral administration. It has an absolute oral bioavailability of 34% for an 80-mg dose and protein binding of 60%. Betrixaban is an active drug, and its unchanged form predominates in the plasma. A small portion of the medication is metabolized via CYP-independent hydrolysis and accounts for 15–18% of the parent compound. Less than 1% of the metabolites are formed via the CYP system. Betrixaban is a substrate of P-gp, and the use of P-gp inhibitors can increase blood drug levels and the risk of bleeding (Table 4). Betrixaban has a half-life of 19–27 h, with 85% being excreted in the feces and 11% in the urine.[75,76]

Indications. The only FDA-approved indication for betrixaban is for VTE prevention in adult patients hospitalized for an acute medical illness who are at risk of thromboembolic complications because of moderately or severely restricted mobility. The medication is not recommended for patients with end-stage renal disease, patients on dialysis, or patients with hepatic impairment since it has not been studied in these patient populations.[75,76] The indication for betrixaban was approved based on the results of the APEX trial, in which it was compared with enoxaparin for the prevention of VTE and demonstrated to have improved efficacy relative to enoxaparin, without an increased risk for major bleeding.[3,76]

Dosing. The long half-life of betrixaban makes it suitable for once-daily dosing. However, in the EXPERT trial, a twice-daily regimen was selected to flatten the diurnal pharmacologic profiles and mimic the controlled-release formulation for the future. The APEX trial later tested the extended-duration betrixaban as a once-daily regimen and showed the efficacy of the 80-mg dose without an increased risk of bleeding compared with 40 mg daily.[3,77]

Betrixaban is administered as an initial dose of 160 mg followed by 80 mg daily with food, starting the next day. The recommended duration of therapy is 35–42 days. For patients with CrCl 15–30 mL/min or receiving a P-gp inhibitor, the dose is halved, with an initial loading dose of 80 mg followed by 40 mg daily.[75]

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