Expanded Treatment Options for Venous Thromboembolism


RELEASE DATE

February 1, 2020

EXPIRATION DATE

February 28, 2022

FACULTY

Jennifer LaPreze, PharmD, BCACP, CDE, CPP
Atrium Health
Fort Mill, South Carolina

FACULTY DISCLOSURE STATEMENTS

Dr. LaPreze has no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-20-006-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL

To provide the participant with an overview of direct oral anticoagulants (DOACs) and their role in therapy for the treatment of venous thromboembolism (VTE).

OBJECTIVES

After completing this activity, the participant should be able to:

  1. Describe approved indications and pharmacokinetic and pharmacodynamic characteristics for the DOACs.
  2. Develop appropriate treatment recommendations based on available clinical studies and guidelines for the management of VTE.
  3. Describe drug interactions with dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban.
  4. Describe the role pharmacists have in the realm of DOACs.

ABSTRACT: Venous thromboembolism (VTE) impacts a significant number of people each year and can be fatal. For years, the only treatment option available was warfarin, a vitamin K antagonist. In the past decade, direct oral anticoagulants (DOACs) have become available. Compared with warfarin, these newer anticoagulants have different pharmacokinetic and pharmacodynamic principles that allow less invasive monitoring and provide expanded treatment options for patients. This article will discuss the treatment recommendations available for VTE for the DOACs and the literature available for these indications. In addition, the drug interactions that effect the newer anticoagulants will be described.

As many as 900,000 cases of venous thromboembolism (VTE) occur in the United States each year, and up to 100,000 patients die of pulmonary embolism (PE) or deep vein thrombosis (DVT).1 One-third of individuals affected will have a recurrence within 10 years. The occurrence of risk for VTE doubles in each decade of life after age 50 years.2 In the U.S., VTE is a leading cause of pre ventable hospital death.3

Virchow's triad, a common theory describing the risk factors that lead to the formation of thrombosis, proposes that VTE occurs due to vascular endothelial injury, alterations in blood flow, and hypercoagulability. VTE occurs due to inherited and acquired risk factors for thrombosis. Many people who have hereditary hypercoagulable conditions experience an event only when in situations that present a high risk of thrombosis, including pregnancy, use of estrogen-containing oral contraceptives, surgery, or immobilization.4

Warfarin became available in 1954.5 The first direct oral anticoagulant (DOAC) to become available was dabigatran in 2010.6 Rivaroxaban was approved in the U.S. in 2011, followed by apixaban in 2012, edoxaban in 2015, and betrixaban in 2017.7-10 When looking at the coagulation cascade, warfarin inhibits vitamin K epoxide reductase, reducing the clotting factors II, VII, IX, and X and proteins S and C. Dabigatran inhibits thrombin IIA, while rivaroxaban, apixaban, edoxaban, and betrixaban inhibit factor Xa. While warfarin is dosed to a targeted international normalized ratio (INR), the doses of DOACs for VTE treatment, VTE prophylaxis, risk reduction of major cardiovascular events, and stroke/systemic embolism prophylaxis in nonvalvular atrial fibrillation (NVAF) are shown in TABLE 1.


tbl1

When selecting an anticoagulant for a patient, therapy should be individualized. TABLE 2 shows characteristics of the DOACs. The pharmacokinetic and pharmacodynamic profiles of each anticoagulant differ. All of the DOACs are renally excreted to a certain extent, and the doses need to be adjusted based on renal function since they can have increased risk of bleeding events. Certain agents now have FDA-approved antidotes.


tbl2

Role in Therapy

The 2016 CHEST guidelines recommend dabigatran, apixaban, edoxaban, or rivaroxaban over vitamin K antagonist therapy for patients without cancer who have DVT or PE. Treatment options include rapid-acting injectable anticoagulant (fondaparinux, low molecular weight heparin, or unfractioned heparin) transitioned to warfarin, including a minimum of 5-day combined therapy or rapid-acting injectable anticoagulant transitioned to dabigatran or edoxaban or sole treatment with apixaban or rivaroxaban.13 To date, there is limited information regarding DOACs in patients with cancer, and additional trials would need to be conducted in this population to determine the role of the newer anticoagulants.

TABLE 3 shows clinical trials for various DOAC indications. The study designs of the trials differed regarding initiation, dosing frequency, and dose intensity. When discussing the oral anticoagulants, information will focus on indications regarding VTE.


tbl3

Apixaban

Apixaban is approved for the treatment of DVT and PE. In the AMPLIFY trial, patients with symptomatic DVT and/or PE were randomized to apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily or enoxaparin 1 mg/kg twice daily for at least 5 days and INR >2 followed by warfarin. The primary outcome looked at VTE or VTE-related death, which was 2.3% in the apixaban group and 2.7% in the enoxaparin/warfarin group (relative risk [RR], 0.84; CI 0.60-1.18; P <.0001). Overall bleeding rates were significantly lower following the use of apixaban (0.6% vs. 1.8%, P <.001).14

The AMPLIFY-EXT study looked at patients who had been treated for DVT and/or PE for 6 to 12 months with anticoagulant therapy without a recurrent event and who received treatment with apixaban 2.5 mg twice daily, apixaban 5 mg twice daily, or placebo for a year. The primary outcome looked at recurrent VTE or death from VTE, which occurred in 1.7% of the apixaban 2.5-mg group (95% CI, 5.0-9.3; P <.001), 1.7% of the apixaban 5-mg group (95% CI, 4.9-9.1; P <.001), and 8.8% of the placebo group. Overall, the rates of major bleeding were 0.2% in the 2.5-mg apixaban group, 0.1% of the 5-mg apixaban group, and 0.5% of the placebo group. The findings showed that using either 2.5 mg or 5 mg of apixaban reduced the risk of recurrent VTE without increasing major bleeding.15

Apixaban is approved for the prophylaxis of DVT following hipor knee-replacement surgery. ADVANCE-1 and ADVANCE-2 compared enoxaparin to apixaban post total knee replacement. In ADVANCE-1, patients received either apixaban 2.5 mg twice daily or enoxaparin 30 mg twice daily for 10 to 14 days afterwards.

In ADVANCE-2, patients received either apixaban 2.5 mg twice daily or enoxaparin 40 mg once daily and received therapy for 10 to 14 days. The primary outcome for both was the number of asymptomatic and symptomatic DVTs, nonfatal PEs, and all-cause death during treatment. In ADVANCE-1 the primary outcome occurred 9% with apixaban compared with 8.8% with enoxaparin (RR, 1.02; 95% CI, 0.78-1.32), and the incident of major bleeding and clinically relevant nonmajor bleeding was 2.9% with apixaban and 4.3% with enoxaparin (P = .03). Therefore, apixaban did not meet criteria for noninferiority, but it did have lower rates of bleeding.

In ADVANCE-2 the primary outcome occurred in 15% of apixaban patients and 24% of enoxaparin patients (RR, 0.62 [95% CI, 0.51-0.74]; P <.0001). In this study major or clinically relevant nonmajor bleeding occurred in 4% of apixaban patients and 5% of enoxaparin patients (P = .09). These results suggest that apixaban is effective for VTE prevention without increased risk of bleeding.

There are several options for bleeding reversal caused by apixaban. In 2018, Andexxa became available as an agent to reverse
the anticoagulation effects of apixaban and rivaroxaban.ADVANCE-3 compared patients undergoing total hip replacement receiving either apixaban 2.5 mg twice daily or enoxaparin 40 mg daily. The primary outcome was the same as ADVANCE 1 and ADVANCE 2; there was a 1.4% occurrence in the apixaban group and 3.9% in the enoxaparin group (RR, 0.36; 95% CI, 0.22-0.54; P <.001 for noninferiority and for superiority). Major or clinically relevant nonmajor bleeding occurred in 4.8% of the apixaban patients and 5% of the enoxaparin patients (P = .72). Overall, the studies showed that apixaban was superior to enoxaparin 40 mg once daily but not to enoxaparin 30 mg twice daily for prevention of VTE post orthopedic procedures.16-18

In patients with renal impairment, there is no recommendation for dose adjustment for apixaban for treatment of VTE or prophylaxis of DVT following orthopedic surgery. It should be noted that apixaban did not enroll patients with end-stage renal disease on dialysis or patients with a creatinine clearance (CrCl) <15 mL/min.8

There are several options for bleeding reversal caused by apixaban. In 2018, Andexxa (coagulation factor Xa [recombinant], inactivated-zhzo) became available as an agent to reverse anticoagulation effects of apixaban and rivaroxaban.12 Andexxa may not be used commonly due to the high expense. In patients with an overdose or accidental ingestion, activated charcoal may be an option.8 In healthy subjects, activated charcoal was administered 2 and 6 hours after subjects received a 20-mg dose of apixaban and reduced area under the curve by 60% and 27%.

Betrixaban

Betrixaban is indicated for the prophylaxis of VTE in adult patients hospitalized for acute medical illness who are at risk of thromboembolic complications due to restricted mobility and other risk factors. The recommended duration of therapy is 35 to 42 days. An initial single dose of 160 mg is administered, followed by 80 mg once daily taken at the same time each day with food.

Betrixaban was evaluated compared with conventional enoxaparin therapy in the APEX study. The primary efficacy outcome was a composite of asymptomatic proximal DVT and symptomatic VTE. In cohort 1, the primary outcome occurred in 6.9% of the betrixaban group and 8.5% of the enoxaparin group (RR in the betrixaban group, 0.81; 95% CI, 0.65-1.00; P = .054). Since the first cohort did not meet statistical significance, all subsequent efficacy outcomes were considered to be exploratory; however, betrixaban showed benefit in the other cohort and in the overall study population.19

When looking at safety outcomes, major bleeding occurred similarly between the therapies: 0.7% in the betrixaban group and 0.6% in the enoxaparin group (RR, 1.19; 95% CI, 0.67-2.12; P = .55). When looking at some of the other oral anticoagulants, the safety outcomes differed. Apixaban in the ADOPT trial and rivaroxaban in the MAGELLAN trial showed that the use of apixaban and rivaroxaban was associated with significantly more major bleeding than standardduration enoxaparin in medically ill patients.20, 21

However, in the APEX study the secondary safety outcome of major or clinically relevant nonmajor bleeding occurred more frequently in the betrixaban group: 3.1% compared with 1.6% in the enoxaparin group (RR, 1.97; 95% CI, 1.44-2.68; P <.001). It should be noted that in patients with renal impairment (CrCl >15 mL/min and <30 mL/min), betrixaban should be decreased to an initial dose of 80 mg followed by 40 mg daily. At this time, there is no FDA-approved reversal agent available for patients with an active bleed from betrixaban.19

Edoxaban

Edoxaban is FDA approved for the treatment of DVT and PE following initial parenteral anticoagulant therapy for 5 to 10 days.9 Edoxaban was compared with warfarin in the Hokusai-VTE study. All patients received either unfractionated heparin or enoxaparin for at least 5 days followed by either edoxaban or warfarin for at least 3 months and no more than 12 months. The primary efficacy outcome was recurrent symptomatic VTE (fatal/nonfatal PE and DVT). Results showed that the primary outcome occurred in the edoxaban group 3.2% versus 3.5% in the warfarin group demonstrating that edoxaban was noninferior to warfarin (hazard radio [HR] 0.89; 95% CI, 0.70-1.13; P <.001 for noninferiority). The safety outcome was major or clinically relevant nonmajor bleeding. Regarding clinically relevant major or nonmajor bleeding, edoxaban demonstrated superiority compared with warfarin (8.5% vs. 10.3%; HR, 0.81; 95% CI, 0.71-0.94; P = .004 for superiority).22

Edoxaban is not currently approved in the U.S. for prevention of VTE following total knee arthroplasty; however, it is approved for this indication in Japan based on clinical trials.Edoxaban is not currently approved in the U.S. for prevention of VTE following total knee arthroplasty (TKA); however, it is approved for this indication in Japan based on clinical trials. One of these studies was the STARS E-3 trial. STARS E-3 was a phase III study that compared patients receiving edoxaban 30 mg once daily or enoxaparin 2,000 IU (equivalent to 20 mg) twice daily in prevention of thrombosis following TKA in patients in Japan and Taiwan. The primary efficacy outcome was the composite of symptomatic PE and symptomatic and asymptomatic DVT. Edoxaban showed to be more effective than enoxaparin: edoxaban group 7.4% versus enoxaparin group 13.9%, with a relative risk reduction of 46.8%, indicating noninferiority (P <.001) and superiority (P = .010). The occurrence of major bleeding was similar between the groups: edoxaban 1.1% versus 0.3% in the enoxaparin group (P = .373).23

The edoxaban dose should be reduced to 30 mg daily in patients with reduced renal function (CrCl 15-50 mL/min), body weight <60 kg, or using certain P-gp inhibitors, which will be discussed in the druginteraction section. It should be noted that in patients with NVAF with CrCl >95 mL/min, edoxaban should not be used due to an increased rate of ischemic stroke compared with patients using warfarin as shown in the ENGAGE AF-TIMI 48 study.9,24 These patients will need an alternative anticoagulant.

Rivaroxaban

Rivaroxaban is approved for the treatment of DVT and PE with a dose of 15 mg twice daily with food for 21 days, followed by 20 mg once daily with the evening meal. Patients who have received at least 6 months of treatment can be reduced to 10 mg once daily with or without food.7

Einstein-DVT compared oral rivaroxaban with enoxaparin and a vitamin K antagonist (warfarin or acenocoumarol) in patients with a symptomatic DVT in a noninferiority study, followed by a superiority study that compared rivaroxaban 20 mg once daily alone with placebo for an additional 6 or 12 months in patients who had already completed 6 to 12 months of treatment. Rivaroxaban was noninferior to enoxaparin followed by vitamin K antagonist (95% CI, 0.44-1.04, P <.001) for recurrent VTE. Rivaroxaban showed superiority compared with placebo (95% CI, 0.09-0.39; P <.001) in the continuation study. Major bleeding was similar between the groups.25

The primary efficacy outcome was any DVT, nonfatal PE, or death from any cause up to Day 17 after surgery and occurred 6.9% in the rivaroxaban group and 10.1% in the enoxaparin group (95% CI, 0.71-5.67; P = .0118).Einstein-PE compared oral rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily) with enoxaparin followed by a vitamin K antagonist. Like Einstein-DVT, the primary efficacy outcome was symptomatic recurrent VTE. Rivaroxaban was non inferior to enoxaparin followed by vitamin K antagonist therapy. Major bleeding occurred more in the enoxaparin group, followed by vitamin K antagonist group (P = .003).26

The treatment of VTE is given for 3 months or longer depending on the risk of recurrent VTE and the risk of bleeding. In Einstein Choice, patients who already completed 6 to 12 months of anticoagulation therapy and were in equipoise received rivaroxaban 20 mg or 10 mg daily or 100 mg of aspirin once daily.

The primary outcome was symptomatic recurrent VTE (fatal or nonfatal). Patients taking rivaroxaban 20 mg or 10 mg had a lower recurrent VTE rate than those taking aspirin (P <.001). The occurrence of bleeding was similar between the groups (0.5% in rivaroxaban 20 mg, 0.4% in rivaroxaban 10 mg, and 0.3% in the aspirin group).27 Rivaroxaban is approved for prophylaxis following orthopedic surgery (total knee or hip replacement) with a dose of 10 mg once daily with or without food.7 RECORD 1 and RECORD 2 data studied rivaroxaban in patients with total hip replacement. Patients received either enoxaparin 40 mg once daily or rivaroxaban 10 mg daily for an average of 35 days. The modified intention-to-treat population showed superiority of rivaroxaban compared with enoxaparin with the primary efficacy outcome of composite of DVT, nonfatal PE, or death from any cause occurring in 1.1% of patients taking rivaroxaban and 3.7% of patients taking enoxaparin (95% CI, 1.5-3.7; P <.001). Major bleeding occurred in 0.3% of patients taking rivaroxaban compared with 0.1% with enoxaparin (P = .18). In RECORD 2, patients received rivaroxaban 10 mg daily for 31 to 39 days or enoxaparin 40 mg once daily for 10 to 14 days. The primary outcome was the same as RECORD 1 and occurred in 2% of the rivaroxaban group and 9.3% of the enoxaparin group in the modified intention-to-treat population (95% CI, 5.2-9.4; P <.0001), showing that rivaroxaban is more effective than enoxaparin for prevention of VTE in this population. Bleeding events were similar between both groups (P = .25).28,29

RECORD 3 and RECORD 4 studied rivaroxaban in patients with total knee replacement. RECORD 3 compared rivaroxaban 10 mg once daily to enoxaparin 40 mg once daily. The primary outcome looked at any DVT, nonfatal PE, or death from any cause occurring 13 to 17 days following the procedure. The primary outcome occurred in 9.6% of patients taking rivaroxaban and 18.9% of patients taking enoxaparin (95 CI, 5.9-12.4; P <.001). Rivaroxaban was superior to enoxaparin in reducing VTE. Major bleeding was similar between these groups, with rivaroxaban at 0.6% and enoxaparin at 0.5%. RECORD 4 compared rivaroxaban 10 mg once daily with enoxaparin 30 mg twice daily. The primary efficacy outcome was any DVT, nonfatal PE, or death from any cause up to Day 17 after surgery and occurred 6.9% in the rivaroxaban group and 10.1% in the enoxaparin group (95% CI, 0.71-5.67; P = .0118). Ultimately, rivaroxaban showed superiority over enoxaparin. Major bleeding was similar between these groups.30,31

Acutely ill patients who are at risk of thromboembolism but not at high risk of bleeding are approved for rivaroxaban 10 mg with or without food in the hospital for 31 to 39 days. Rivaroxaban is approved in patients with chronic coronary artery disease or peripheral artery disease to reduce the risk of cardio vascular (CV) events (CV death, myocardial infarction [MI], and stroke) at a dose of 2.5 mg twice daily in combination with aspirin 75 mg to 100 mg once daily. In the COMPASS trial, patients with stable atherosclerotic vascular disease received rivaroxaban

2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg once daily. The primary outcome was total CV death, stroke, or MI. After 23 months, the trial was stopped due to superiority in the rivaroxaban-plus-aspirin group (HR, 0.76; 95% CI, 0.66-0.86; P <.001). Major bleeding events occurred more in patients receiving both rivaroxaban and aspirin than aspirin alone (HR, 1.7; 95% CI, 1.40-2.05; P <.001). However, there was no significant difference between the groups in fatal bleeding, and the rate of death was similar between rivaroxaban plus aspirin versus aspirin alone. Rivaroxaban alone resulted in more major bleeding and did not improve CV outcomes more than aspirin alone. Other studies have shown that using aspirin as secondary prevention reduced major CV events by 19%.32

Dabigatran

Dabigatran is approved for the treatment of DVT/PE and reducing the risk of recurrent DVT/PE after receiving 5 to 10 days of parenteral anticoagulation. If renal function is CrCl >30 mL/min, the recommended dose is 150 mg twice daily; however, if renal function is impaired (CrCl <30 mL/min) or the patient is on dialysis, dosing recommendations are not provided.6 In RECOVER 1 and RECOVER 2, dabigatran 150 mg twice daily was compared with warfarin in patients treated with low-molecular-weight or unfractionated heparin for 6 months. In the prevention of recurrent or fatal VTE, pooled results showed dabigatran was noninferior to warfarin (HR, 1.09; 95% CI, 0.76-1.57).33

To further evaluate dabigatran's role in therapy for long-term prophylaxis after VTE, it was studied in the trials RE-MEDY and RE-SONATE. Study participants had to be treated in either RE-COVER or RE-COVER II. RE-MEDY compared dabigatran 150 mg twice daily to warfarin while RE-SONATE compared dabigatran 150 mg twice daily to placebo. The results of RE-MEDY showed dabigatran was noninferior to warfarin for the prevention of recurrent VTE. Major or clinically relevant bleeding occurred in 5.6% of patients using dabigatran compared with 10.2% of patients using warfarin (HR, 0.54; 95% CI, 0.41-0.71; P <.001).34 In RE-SONATE, VTE occurrence happened less frequently in the dabigatran group compared with placebo (95% CI, 0.02-0.25; P <.001), while major or clinically relevant bleeding occurred more frequently in the dabigatran group than placebo.34

Patients initially received half doses of dabigatran postoperatively followed by 150 mg or 220 mg once daily. The primary efficacy outcome was total VTE events and death.Dabigatran is also approved to prevent DVT/PE following total knee and hip replacement surgery. In RE-MODEL, patients received either dabigatran etexilate 150 mg or 220 mg once daily or enoxaparin 40 mg subcutaneously once daily for 6 to 10 days following total knee replacement. Patients initially received half doses of dabigatran postoperatively followed by 150 mg or 220 mg once daily. The primary efficacy outcome was total VTE events and death. This occurred 40.5% in the 150-mg group (95% CI, –3.1-8.7), 36.4% in the 220-mg group (95% CI, –7.3-4.6), and 37.7% in the enoxaparin group, concluding that the dabigatran etexilate doses were noninferior to enoxaparin. There were no significant major bleeding events among enoxaparin (1.3%; 95% CI, 0.6-2.4) and the dabigatran etexilate 150-mg group (1.3%; 95% CI, 0.6-2.4) or in the 220-mg group (1.5%; 95% CI, 0.7-2). In patients with CrCl >30 mL/min, dosing is 110 mg for first day, then 220 mg once daily. Again, dosing cannot be recommended for impaired renal function CrCl <30 mL/min.35

In RE-MOBILIZE, patients received either dabigatran 220 mg or 150 mg once daily compared with enoxaparin 30 mg twice daily after total knee replacement surgery. Both doses of dabigatran showed inferior results in the prevention of VTE compared to enoxaparin.36

RE-NOVATE I and RE-NOVATE II compared dabigatran to enoxaparin in patients undergoing total hip replacement. RE-NOVATE I compared dabigatran 150 mg or 220 mg while RE-NOVATE II compared dabigatran 220 mg to enoxaparin 40 mg once daily. In both studies, dabigatran 220 mg showed noninferiority to enoxaparin and is as effective as enoxaparin for total hip replacement to prevent VTE. Total VTE and all-cause mortality occurred in 129 patients (7.7%) treated with enoxaparin and 114 patients (6.8%) treated with dabigatran 220 mg (P = .35). The rate of major VTE and VTE-related death was significantly lower with dabigatran (P = .03) compared with enoxaparin.37

If the antithrombotic effects of dabigatran need to be reversed, idarucizumab is a humanized monoclonal antibody fragment that can be used as a reversal agent. It is supplied as two 2.5-gram vials that can be given in consecutive bolus injections or two consecutive infusions.11

Drug Interactions

TABLE 4 shows common drug interactions with the newer anticoagulant agents. Apixaban is a substrate for both CYP3A4 and P-glycoprotein (P-gp). Inhibitors of P-gp and CYP3A4 increase the risk of bleeding, while inducers of P-gp and CYP3A4 decrease exposure to apixaban and increase the risk of thromboembolic events. If patients are receiving CYP3A4 inhibitors combined with P-gp inhibitors and are taking apixaban 5 mg or 10 mg twice daily, the dose of apixaban should be reduced by 50%. However, if patients are on a 2.5-mg dose of apixaban, it is recommended to avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp. Combining strong dual inducers of P-gp and CYP3A4 should be avoided due to decreasing exposure of apixaban and increasing risk of thromboembolic events.8


tbl4

Betrixaban is a substrate of P-gp, and concomitant use of P-gp inhibitors results in an increased risk of bleeding with betrixaban. Therefore, the dose of betrixaban should be reduced with P-gp inhibitors and should be avoided with P-gp inducers due to the risk of increased thromboembolic events.10

Dabigatran is a substrate of P-gp. Coadministration of dabigatran and P-gp inhibitors in patients with renal impairment (CrCl <50 mL/min) being treated for the reduction in risk of recurrent DVT/PE should be avoided. Patients who are being managed with dabigatran to prevent VTE following hip surgery with a CrCl >50 mL/min should separate P-gp inhibitors (i.e., dronedarone or systemic fluconazole) by several hours from dabigatran. However, if renal function is impaired (CrCl <50 mL/min), coadministration should be avoided.6

Edoxaban is a substrate of P-gp transporter. P-gp inhibitors can increase concentrations of edoxaban, and recommendations are to reduce the dose of edoxaban to 30 mg daily for patients with VTE. P-gp inducers significantly reduce edoxaban concentrations and should be avoided. Edoxaban has not been studied with antiretroviral therapies (i.e., ritonavir, nelfinavir, indinavir, saquinavir, or cyclosporine).9

Rivaroxaban is a substrate of CYP3A4, CYP3A5, CYP2J2, P-gp, and ATP-binding cassette G2 (ABCG2) transporters. Similar to apixaban, strong inhibitors of P-gp and CYP3A4 increase the risk of bleeding while inducers of P-gp and CYP3A4 decrease exposure to rivaroxaban and increase the risk of thromboembolic events. Concomitant use should be avoided. There is some information that risk versus benefit should be used in those receiving rivaroxaban with P-gp and moderate CYP3A4 inhibitors in patients with impaired renal function CrCl 15 to <80 mL/min; in general, concomitant use should be avoided.7

Other anticoagulants, antiplatelet agents, thrombolytics, and NSAIDs have the potential to interact with the newer anticoagulants and increase risk of bleeding, and clinical decision making is needed to assess appropriateness of therapy and compare potential risk versus potential benefit for individual patients.

Role of Pharmacists

Pharmacists have the opportunity to evaluate the appropriateness of anticoagulation therapy and monitor therapy to see if dose adjustments may be necessary. Selection of anticoagulation should be based on individualized needs, including clinical indication, individual parameters (age, height, weight), renal function, hepatic function, concurrent medications, medical history, and medication compliance. Pharmacists can work on a multidisciplinary team to provide clinical information regarding potential drug interactions and recommendations for therapy, whether it requires dose reduction or alternative drug therapy that does not have an interaction. In addition, they can educate patients about monitoring for signs and symptoms of bleeding, counsel on potential drug interactions, and help with the transition of converting between anticoagulants, if needed.

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