November CE Article

NOVEMBER CPE Article

Review of Direct Acting Oral Anticoagulants

Authors: Kaylee Hall, PharmD Candidate 2022; Jordan Spurling, PharmD Candidate 2022; Mark Huffmyer, PharmD, BCGP, BCACP, CACP The authors declare that there are no financial relationships that could be perceived as real or apparent conflicts of interest. Universal Activity # 0143-0000-20-011-H01-P &T 2.5 Contact Hours Expires 12/14/23 Learning Objectives: At the conclusion of this Knowledge-based article, the reader should be able to: 1.

Understand the mechanism of actions, approved indications, side effects, reversal agents, drug-drug interactions and drug-food interactions of DOACs.

Evaluate the use of DOACs in special populations.

Evaluate peri-procedural management of DOACs.

Compare and contrast DOACs to warfarin

Introduction Compared to warfarin, DOACs require less moniFor decades, warfarin, a vitamin K antagonist, was the only oral anticoagulant available on the market in the United States. While effective at treating and preventing thromboembolic events, warfarin requires close monitoring due to its narrow therapeutic index, which is further complicated by its many drug-drug and drug-diet interactions. This makes it cumbersome and costly to manage [1]. In 2010, a new oral anticoagulant with a novel mechanism of action was approved and several drugs have followed since then. Direct acting oral anticoagulants (DOACs), include dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban, so called because of their direct mechanism of action. Warfarin exhibits its affect by depleting functional vitamin K reserves and therefore, reducing the synthesis of vitamin K dependent clotting factors [2]. DOACs, sometimes referred to as non-vitamin K dependent or novel oral anticoagulants (NOACs), act directly on specific clotting factors to produce their anticoagulant effect. Since the approval of the DOACs, there has been a declining use of warfarin each toring, have less drug-drug interactions, drug-diet interactions, and can reduce the risk of hemorrhage [4]. These advantages have made DOACs the recommended treatment over warfarin for DVT/PE by the CHEST Guidelines [5] and recommended for stroke prevention in non-valvular atrial fibrillation by the American College of Cardiology [6]. In this article, we will discuss the mechanisms of action, side effects, drug-drug interactions, drug-diet interactions, reversal agents, periprocedural management and special populations of DOACs and, in addition, how they compare to warfarin. We will focus on the four most commonly prescribed DOACs, dabigatran, rivaroxaban, apixaban and edoxaban. These medications are often seen in the pharmacy and are considered to be high-risk medications by the Institute for Safe Medication Practices (ISMP) due to the risk of bleeding associated with them [7]. Understanding the DOACs, their properties and side effects can help to improve on patient care by expanding the knowledge of community pharmacists. year while the use of DOACs continue to rise [3].

Understanding the DOACs Many factors are considered in choosing the most appropriate DOAC for each individual patient. These factors include indication, drug-drug interactions, side-effects, kidney function, and other patient specific factors. Like warfarin, the DOACs have a major side effect of bleeding and bruising, though in studies comparing warfarin to the DOACs, the DOACs have been shown to have less bleeding risk [8]. In general, DOACs are eliminated both renally and hepatically to varying degrees. DOACs are faster acting than warfarin and anticoagulation effects are reversed quickly upon discontinuation. While frequent INR monitoring is needed for warfarin this is not true for the DOACs, though other parameters including kidney and liver function need to be monitored, albeit less frequently, over the course of treatment. Warfarin also has many more drug- drug and drug-food interactions compared to the DOACs. The DOACs interact with medications that affect P-glycoprotein transporters (P-gp). Rivaroxaban and apixaban also have drug interactions with CYP3A4 inhibitors/inducers.

Dabigatran Dabigatran is FDA approved to reduce the risk of stroke in patients with nonvalvular atrial fibrillation, for the treatment of DVT/PE after treatment with parenteral anticoagulants for 5-10 days and, to reduce the risk of recurrence of DVT/PE [9]. Dabigatran acts as a direct thrombin inhibitor, which inhibits the conversion of fibrinogen into fibrin. The maximum effects of dabigatran can be seen within 1-2 hours of administration, with a halflife of 12-17 hours. Dabigatran is the least reliant on the liver compared to the other DOACs and is predominantly renally eliminated (80%), thus in patients with impaired renal function, half-life and drug exposure increase. Aside from bleeding and bruising, common side effects include nausea, heartburn and abdominal pain. Dabigatran should be administered with a full glass of water and can be taken with meals to help reduce the incidence of heartburn. This capsule cannot be crushed or opened because it may lead to an increase in adverse reactions. Dabigatran is typically dosed twice daily [10].

Rivaroxaban Rivaroxaban is FDA approved to reduce the risk of stroke in patients with nonvalvular atrial fibrillation, for prophylaxis of DVT/PE in patients after hip/knee replacement, DVT/PE treatment and recurrence and, is the only DOAC currently FDA approved, for the prevention of major cardiovascular events in patients with CAD and PAD [9]. Rivaroxaban works by the inhibition of factor-Xa, which inhibits the conversion of prothrombin to thrombin. The maximum effects of rivaroxaban can be seen within 2 hours of administration, with a half-life of 5-9 hours. Rivaroxaban is 66% renally eliminated and 28% eliminated in the feces, causing increases in exposure in both renal and hepatic impairment. Doses of 15mg or greater should be taken with food to ensure adequate absorption. Tablets can be crushed and administered in applesauce if there is difficulty swallowing. Rivaroxaban dosing is dependent on indication and renal function but is typically dosed once or twice daily. [11]

Apixaban Apixaban is FDA approved to reduce the risk of stroke in patients with nonvalvular atrial fibrillation, for prophylaxis of DVT/PE in patients after hip/knee replacement and DVT/PE treatment and recurrence [9]. Apixaban, like rivaroxaban, is a factor-Xa inhibitor and has a similar side effect profile. The maximum effect of apixaban can be seen within 34 hours of administration, with a half-life of 8-15 hours. Apixaban is excreted in both the urine (26%) and the feces; however, among the DOACs it is least reliant on the kidneys. It can be taken without regards to meals and can be crushed and administered in applesauce if there is difficulty swallowing. Apixaban is typically dosed twice daily. [12]

Edoxaban Edoxaban is FDA approved to reduce the risk of stroke in patients with nonvalvular atrial fibrillation and for treatment of DVT/PE after treatment with parenteral anticoagulation for 5-10 days [9]. Like dabigatran, edoxaban requires a heparin lead-in prior to use for treatment for acute DVT/PE. Edoxaban is a factor-Xa inhibitor similar to rivaroxaban and apixaban. The maximum effects of edoxaban can be seen within 1-2 hours of administration, with a half-life of 8-10 hours. Edoxaban is excreted about 50% in the urine. Edoxaban should not be used in patients with a CrCL >95ml/min, which may limit clinical utility. Edoxaban can be taken without regard to meals and may be crushed and mixed into applesauce or water if there is difficulty swallowing. Edoxaban is typically dosed once daily. [13]

Betrixaban Betrixaban is the newest DOAC and was recently FDA approved in 2017 for VTE prophylaxis in acutely ill medical patients [14]. For the purpose of this arti-

Approval year in the US Mechanism of Action

Time to peak therapeutic effect Half-life 1954

Competitive inhibition of vitamin K epoxide reductase complex 1 (VKORC1) 5-7 days 2010

Direct Thrombin Inhibitor

1-2 hours

20-60 hours 12-17 hours

Renal elimination

Drug interactions Primarily hepatic metabolism Extensive 80%

P-gp Rivaroxaban 2011

Direct Factor Xa Inhibitor

2-4 hours

5-9 hours 33%

P-gp, CYP3A4 Apixaban 2012

Direct Factor Xa Inhibitor Edoxaban 2015

Direct Factor Xa Inhibitor

3-4 hours

8-15 hours 25%

P-gp, CYP3A4 1-2 hours

10-14 hours 35-39%

P-gp

Table 2: DOAC Dosing

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism) Dabigatran

CrCl

30 ml/min: 150 mg BID CrCl 15-30 ml/min: 75mg BID CrCl <15 ml/min: avoid use Rivaroxaban

CrCl > 50 ml/min: 20 mg once daily with evening meal CrCl 15-50 ml/min: 15 mg once daily with food CrCl <15: avoid use

Treatment of DVT and PE CrCl > 30 ml/min: 150 mg BID after 510 of parenteral anticoagulation 15 mg BID with food for 21 days, then 20 mg daily with food

Reduction in the risk of recurrence of DVT and PE CrCl > 30 ml/min: 150 mg BID after previous treatment 10mg daily without regard to meals, after 6 months of therapeutic anticoagulant treatment

VTE prophylaxis in total hip or knee arthroplasty CrCl > 30 ml/min: 110 mg on the first day then 220 mg daily 10 mg once daily beginning 6 to 10 hours postoperatively or when hemostasis established.

Stable coronary artery disease or peripheral artery disease CrCl ml/min: 2.5 mg BID with 81 mg Aspirin CrCl < 15ml/min: avoid use

cle, we will focus on dabigatran, rivaroxaban, apixaban and edoxaban. Special Populations

Chronic Kidney Disease and End Stage Renal Disease DOACs are largely renally eliminated and are therefore dose adjusted based on creatinine clearance (CrCl), with the exception of apixaban. Apixaban requires a dose decrease if two out of three of the following criteria are met: age years, body weight 60kg or serum creatinine 1.5mg/dL. [10, 11] In clinical efficacy and safety trials of apixaban, patients on dialysis and patients with a CrCl <15ml/min were not enrolled. However, pharmacokinetic data may suggest possible use in this patient population [12]. Retrospective studies have looked at the use of apixaban, at both 2.5mg BID and 5mg BID dosing, compared to warfarin in patients with end stage renal disease. The use of apixaban over warfarin in this patient population appears to be both safer and more effective, though a dose recommendation cannot be determined without further prospective trials [15]. Rivaroxaban and dabigatran should be monitored closely in patients with CrCl<30ml/min and avoided in patients with CrCl <15ml/min due to lack of data [11]. Edoxaban is unique when you consider that it cannot be used in patients with adequate renal function (CrCl >95ml/min), however there is no data suggesting use in patients with CrCl <15ml/min [13]. American Society of Clinical Oncology updated months has to be reconsidered based on the patient and cancer status [18]. Apixaban and dabigatran are not currently recommended by guidelines to be used in cancer patients at this moment, though prospective randomized control trials are underway.

Obesity In 2016, the International Society on Thrombosis and Haemostasis (ISTH) released guidelines on the use of DOACs in obese patients. Based on PK/PD data the ISTH does not recommend the use of DOACs in patients with a BMI >40 kg/m2or >120kg due to the risk of underdosing and limited efficacy data in this population [19]. In a retrospective study, comparing the recurrence of VTE in patients being treated with DOACs compared to warfarin showed no difference in the recurrence of VTE within 12 months [20]. Further retrospective studies investigating the use of DOACs in obese patients have been done that show evidence supporting the use of rivaroxaban and apixaban in obese patients. In obese patients, Rivaroxaban should be considered over apixaban [21] due to the low volume of distribution, which would make it less affected by body weight [22]. Further prospective trials are needed to best assess which anticoagulants and dosing are most appropriate in this patient population.

Though recommendations may be made in patients with CrCl of 15-30 ml/min, with careful moni- Hepatic Impairment toring and dose adjustments when appropriate, All DOACs are metabolized to some extent by the patients treated with DOACs with a CrCl <30 liver. Patients with hepatic impairment should be ml/min may have increased bleeding risk com- evaluated using the Child-Pugh score. Dabigatran pared to those treated with warfarin [16]. Currently, is the least metabolized by liver compared to the warfarin remains the recommended oral anticoag- other DOACs. However, it is not recommended for ulation agent in the population. Additional patient patients with severe hepatic impairment but may factors need to be considered when determining be considered in patients with mild to moderate treatment options for this patient population. impairment [23]. Rivaroxaban should be avoided in patients with moderate to severe liver impairment. Cancer-associated VTE vere hepatic impairment but may be considered in Prior to the approval of DOACs, low molecular weight heparin (LMWH) was recommended as the drug of choice for cancer associated VTE and still is by the most current 2016 CHEST guidelines [17]. The patients with mild to moderate impairment. Edoxaban can be used in patients with mild hepatic impairment but is not recommended in patients with moderate to severe impairment [24]. Apixaban is not recommended in patients with setheir guidelines in 2019 on the treatment of patients with cancer with an established VTE to pre- Pregnancy vent recurrence. Rivaroxaban is the only DOAC that The use of DOACs during pregnancy have not yet is recommended for initial treatment and can be been studied and are not recommended to be used considered for long-term use up to 6 in woman who are pregnant or considering becommonths. Edoxaban can be considered for long-term ing pregnant. LMWH is the drug of choice in this use after the initial use of LMWH. Use beyond 6 patient population per CHEST guidelines. [25]

Bariatric Surgery helps to identify cases where minimizing therapy Bariatric surgery, depending on the type of surgery performed, can significantly affect the absorption of medications. Patients who require anticoagulation therapy post-bariatric surgery are recommended to take warfarin due to the ability to monitor INR and dose adjust accordingly. DOACs are not recommended in this patient population until further studies are done [26]. cessation interval of anticoagulant is essential. Estimating risk for patients on anticoagulation depends on a variety of factors including patient indication and comorbidities, as well as the type of procedure being performed and estimated recovery time. In patients with atrial fibrillation, a CHADSVASC score is used to estimate the risk of stroke. For patients with a history of venous thromboembolism, risk is based on severity of previous The next step of estimating thromboembolic risk thromboembolism events, how recently these Pediatrics events occurred, and the patient's hypercoagulable state. Patients with mechanical heart valves are In pediatric patients, the anticoagulant most com- assessed by collecting information about additional monly used is heparins or vitamin K antagonists risk factors and assessing prosthesis. If risk factors using weight-based dosing for most indications. All are suddenly increased due to a recent embolism, DOACs are currently undergoing or planning inves- surgery may need to be postponed based on a risktigational studies to assess the benefits and risks benefit evaluation. If a patient has multiple risk facwhile also configuring age-specific formulations tors, all should be taken into account. [29] [27]. To date all studies involving DOACs have been in patient populations over the age of 18. Next, it is important to determine the schedule of therapy interruption. The schedule is dependent on the specific agent being considered. Typically, warMechanical Heart Valve Patients farin will require a longer therapy interruption, approximately 5-7 days, while DOACs require a much At the time of this writing, the only oral anticoagu- shorter interruption of about 1-4 days. Providers lation option for patients with a mechanical heart must also consider the patient's renal and hepatic valve is warfarin. None of the DOACs are currently function to determine schedule effectively. The fiindicated in this patient population. One clinical nal step to consider is whether to use bridging antitrial published in 2012 evaluated dabigatran in this coagulation. In many cases, bridging anticoagulapopulation. It was halted early due to the tion is not necessary, due to an increased risk of dabigatran group having significantly more throm- bleeding without reduction of thromboembolism botic effects and an excess of major bleeding com- rate. Bridging anticoagulation with heparin or low pared to the warfarin group [28]. molecular weight heparin may be beneficial in some patients taking warfarin who have high Periprocedural Interruptions When considering therapy interruption of a DOAC For patients on anticoagulation therapy that un- for a procedure, guidelines suggest a comprehendergo surgery, the risk of thromboembolism is in- sive approach centered on communication becreased due to the interruption of that anticoagula- tween the provider managing the DOAC, the protion therapy for the sake of the procedure. It is im- vider performing the procedure, and the paportant in these cases to estimate thromboembolic tient/caregiver concerning the continued managerisk and bleeding risk, to determine the timing of ment of the therapy. If therapy interruption is unaanticoagulation interruption, and determine voidable, the provider is advised to consider the pawhether to use bridging anticoagulation therapy. tient's renal function and DOAC bleeding risk to The first step is to estimate a patient’s bleeding determine therapy interruption timeline as well as risk. A patient’s bleeding risk is primarily deter- restarting therapy timeline. The use of routine mined by the type and urgency of the surgery be- bridging therapy is not recommended during thering performed, as well as patient specific factors apy interruption of DOACs. [31] such as patient’s age and history of bleeding. In procedures with low or no estimated bleeding, anticoagulation therapy should not be interrupted. When determining a patient's bleeding risk, it is important to keep in mind that higher bleeding risk requires higher need for perioperative hemostasis and therefore a longer period of therapy interruption. [29] Anticoagulation therapy interruption is not necessary for any procedures associated with minimal or no bleeding risk. In low bleeding risk patients, the DOAC should be restarted approximately 24 hours post-operatively. If a patient is at high risk, DOAC should be postponed to 48-72 hours after procedure or whenever hemostasis has been achieved. [31] thromboembolic risk. [30] |14| Kentucky Pharmacists Association | November/December 2020

Table 3 represents the amount of time necessary to hold each DOAC perioperatively in accordance with the patient’s creatinine clearance. [32]

Reversal Agents experiencing either, administration of reversal While anticoagulation therapy is highly efficacious, complications such as bleeding are not uncommon. agent is typically not warranted, and the bleed can be cared for routinely [34]. Estimates of the effect of anticoagulants find an Warfarin is reversed most effectively by a vitamin K1 approximately 2-fold increase in bleeding rates for infusion administered. In less emergent situations, patients on warfarin compared with patients only oral Vitamin K1 can be given in a tablet form when taking aspirin [33]. For this reason, use of accurate patient is nonbleeding and has an INR above 4.5 bleeding risk assessment tools incorporating indi- [35]. While Vitamin K1 is a quick and cost-effective vidual risk factors are essential in clinical prescrib- reversal agent for warfarin, it will not reverse or ing. Despite these assessment tools, it is possible have any effects on DOACs. for patients to experience a hemorrhage while taking an anticoagulant. For this reason, there are effective reversal agents to combat this adverse event [33]. There are two reversal agents approved by the FDA in the United States for DOAC-induced bleeding: Idarucizumab and Andexanet alfa. A third agent called ciraparantag, used for the reversal of rivaroxIn the event of a minor bleed, such as a nosebleed aban, apixaban, edoxaban, dabigatran and hepalasting less than 25 minutes, general supportive rins, is currently awaiting phase 3 trials [36]. measures may be used such as discontinuation of the offending agent and investigational analysis of hemorrhage source. For major bleeding events, such as blood in the stool, more intensive management may be called for. Management of major bleeding includes prompt control of the hemorrhages by mechanical compression, surgical or endoscopic hemostasis, radiological interventional procedures, transfusion of blood components and hemodynamic support with fluid replacement as well as the use of adjunctive hemostatic agents (i.e., antifibrinolytics or desmopressin) [33]. Indarucimab is effective for reversal of dabigatran induced bleeding and is effective within 4 hours of administration with 67.7% of patients stopped bleeding within 24 hours. Some patients may require an additional dose, so the pharmacist must ensure that prescribers have stopped all other antiplatelet drugs, NSAIDs, and anticoagulation agents. Andexanet alfa is approved for reversal of life-threatening bleeding for factor Xa inhibitors such as rivaroxaban and apixaban. The black box warning for Andexanet alfa includes arterial and venous thromboembolic events, ischemic events Use of a reversal agent is warranted when a patient (including myocardial infarction and ischemic has a life-threatening bleed or is undergoing an in- stroke), cardiac arrest, and sudden death. Due to vasive emergency procedure. If the patient is not these adverse effects, it is important to monitor pa-

tients for thromboembolic effects and initiate anticoagulation therapy as soon as appropriate. Andexanet alfa is a biologic that will need reconstituting which will take time. Cost may also be a barrier to using Andexanet alfa. [37]

Conclusion Prior to the 2010 approval of dabigatran, warfarin was the only available oral anticoagulant available in the United States. Since then, the DOACs have had an expanding role in clinical practice due to the ease of dosing, lack of monitoring and shorten half-life compared to warfarin. The use of these DOACs is still be investigated in many special populations, including obese patients, pediatrics and bariatrics, but may be a considerable option in the future. As the DOACs become more prevalent it is important to remember they are considered a highrisk medication and they require healthcare professionals to stay up to date on their uses in clinical, ambulatory and community settings. References

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CPE Monitor

We encourage you to check CPE Monitor to ensure you have received all 15 hours required for licensure in Kentucky. If you have any questions regarding credits, please contact the KPhA staff immediately.