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A review of novel oral anticoagulants

O'Leary, Geraldine M. MSN, RN, ANP-BC, FNP-BC

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doi: 10.1097/01.CCN.0000511829.26969.85
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For more than 50 years, warfarin, a vitamin K antagonist, has been the most effective oral anticoagulant available for patients requiring systemic anticoagulation.1-4 More recently, a new class of anticoagulant drugs has emerged, called novel oral anticoagulants (NOACs). These drugs are also known as direct oral anticoagulants. They require no routine lab monitoring, have fewer drug and food interactions, and a quick onset time, which may make them more suitable than warfarin for certain patients.

Currently, the NOACs approved for use in the United States are dabigatran, rivaroxaban, apixaban, and edoxaban.1,3,4Overview of NOACs provides a look at the action, indications, contraindications, and adverse reactions for each agent.5-10

Dabigatran

Dabigatran etexilate mesylate (Pradaxa), the first oral direct thrombin inhibitor approved by the FDA, is a prodrug that rapidly converts to its active compound, dabigatran, by nonspecific esterases in the plasma and liver.1,2 It inhibits thrombin from forming fibrin during the last stage in clot formation.1-4

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Table:
Overview of NOACs5-10

Dabigatran is approved in the United States for the prevention of stroke and systemic embolism in adults with nonvalvular atrial fibrillation (NVAF), the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who were treated with a parenteral anticoagulant for 5 to 10 days, to reduce the risk of recurrent DVT and PE, and as prophylaxis for DVT and PE in adult patients who have undergone elective total hip arthroplasty (THA).1,5

It has a rapid onset of action that eliminates the need for therapeutic bridging with injectable anticoagulants such as heparin and enoxaparin.2,11 Dabigatran is eliminated through the renal system, so dose adjustments are necessary for patients with significantly impaired kidney function. Each approved indication has specific dosage recommendations, dose adjustments, and dose avoidance for patients with impaired kidney function based on the creatinine clearance (CrCl) and patients requiring dialysis.2,5,11,12 Assess the patient's kidney function prior to starting dabigatran and stop the drug if acute kidney failure develops; alternative anticoagulant therapy should be considered.5 (See Characteristics of NOACs for a summary of each drug.)

Avoid the use of dabigatran in patients receiving potent P-glycoprotein (P-gp) inducers, such as rifampin, and potent P-gp inhibitors such as dronedarone or ketoconazole, as they may alter elimination and the anticoagulant effects of dabigatran.2,5,11 Dabigatran is contraindicated in patients with a history of serious hypersensitivity reaction, those with active pathologic bleeding, and those with a mechanical heart valve because it is less effective and causes more bleeding than warfarin in this population.5,13 There are no significant food interactions with dabigatran and no routine lab monitoring is required.2,5,9 Coagulation tests, including prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT) may become slightly elevated; however, they do not accurately predict the degree of anticoagulation, nor do they predict when the anticoagulant effects have worn off when discontinued.2,3

Adverse reactions to dabigatran include major bleeding events; hypersensitivity reactions such as urticaria, rash, pruritus, allergic edema, and anaphylaxis; and abdominal pain and/or discomfort, nausea, burning, and gastritis-like symptoms such as gastroesophageal reflux disease, esophagitis, or erosive gastritis.5

Currently, idarucizumab (Praxbind) has been approved for use by the FDA as a rapid-acting reversal agent for dabigatran in patients who require emergency surgery, urgent procedures, or if they experience life-threatening or uncontrolled bleeding.4,10,14 Idarucizumab is a humanized monoclonal antibody fragment that binds to dabigatran and neutralizes its anticoagulant effect.14 Adverse reactions to idarucizumab include headache, hypokalemia, delirium, constipation, pyrexia, and pneumonia.14

Rivaroxaban

Rivaroxaban (Xarelto) is the first oral direct coagulation factor Xa inhibitor approved for use in the United States.1,6 Its mechanism of action is to reversibly bind to the active site of coagulation factor Xa, which inhibits the beginning of clot formation.1,6

Rivaroxaban is approved to reduce the risk of stroke and systemic embolism in patients with NVAF, the treatment of DVT and PE, and to reduce the risk of recurrent DVT and PE after initial treatment, and primary prevention of DVT and PE in adult patients who have had elective THA or total knee arthroplasty (TKA).1,2,6

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Table:
Characteristics of NOACs2,5-8,11

Rivaroxaban has a rapid onset of action with peak concentrations within 2 to 4 hours, which eliminates the need to bridge the patient with injectable anticoagulants.2,6,11 Low doses may be given without food; however, higher doses require food to help with its absorption.2,6 Approximately 36% of rivaroxaban is eliminated in the urine and the remainder is eliminated as inactive metabolites in the urine and feces.2,6,11 As a result, dose adjustment is necessary for kidney impairment and the drug should be avoided entirely in patients with severe kidney impairment.2,6 Assess the patient's kidney function prior to starting rivaroxaban and stop the drug if acute kidney failure develops; alternative anticoagulant therapy should be considered.6 Rivaroxaban is highly protein bound (92% to 95%) and cannot be hemodialyzed.2,6

Rivaroxaban is a substrate for hepatic cytochrome P450-3A4 enzyme and the P-gp transport system. Strong inducers or inhibitors of this enzyme should not be used concurrently. These include rifampin, carbamazepine, phenytoin, ketoconazole, clarithromycin, and ritonavir.2,6,11,15 No significant food interactions exist. Because rivaroxaban has a predictable anticoagulant effect, there is no need for routine lab monitoring. Coagulation tests including PT, INR, and PTT may become prolonged but are not predictive of the degree of anticoagulation.2,6

The most common adverse reaction of rivaroxaban is bleeding. Other adverse reactions include musculoskeletal pain, pruritus, upper abdominal pain, and syncope.6 Currently, there is no approved reversal agent for rivaroxaban. However, andexanet alfa is in late-phase clinical development and has demonstrated the ability to reverse the anticoagulant effects of rivaroxaban by binding to the anticoagulant and keeping it in the vascular space, allowing endogenous factor Xa to be restored.10,16

Apixaban

Apixaban (Eliquis) is another factor Xa inhibitor approved by the FDA to reduce the risk of stroke and systemic embolism associated with NVAF, treat DVT and PE, reduce the risk of recurrent DVT and PE after initial treatment, and prevent DVT and PE in adult patients who have had elective THA or TKA.1-3,7 As with rivaroxaban, apixaban inhibits both free and clot-bound factor Xa.2,7 It also has a rapid onset of action, with peak concentrations 3 to 4 hours after administration, and does not require therapeutic bridging with injectable anticoagulants.2,7

Elimination is through renal (25% to 27%), biliary, and direct intestinal excretion.2,7,11 As a result, dose adjustment is necessary when two or more of the following are present: low body weight (60 kg [132.3 lb] or less), older age (age 80 or older), and significant kidney impairment (serum creatinine 1.5 mg/dL or greater).2,7 Because apixaban has extensive protein binding, hemodialysis will not clear a significant amount of drug from circulation.2,7

Like rivaroxaban, apixaban is a substrate for hepatic cytochrome P450-3A4 enzyme and the P-gp transport system, so concurrent use of strong inducers should be avoided.1,2,7,11,15 Concurrent use of strong inhibitors (ketoconazole, clarithromycin, ritonavir) require a lower dose or avoidance.1,2,7,11,15 There are no significant food interactions with apixaban.2,7 No regular lab monitoring of anticoagulation is necessary due to the predictable anticoagulant effect.1,2,7

Adverse reactions of apixaban include bleeding, gastrointestinal symptoms such as nausea and hepatic transaminitis, syncope, rash, and anaphylactic reactions.7 Currently, there is no reversal agent for excessive bleeding in patients taking apixaban.7 However, andexanet alfa also being tested for use with apixaban and clinical trials are promising.10

Edoxaban

Similar to rivaroxaban and apixaban, edoxaban (Savaysa) is an oral direct inhibitor of factor Xa that is approved to reduce the risk of stroke in patients with NVAF and treat DVT and PE after initial treatment with a parenteral anticoagulant.8,13,17 It has a rapid onset of action, with peak concentrations 1 to 2 hours after administration, and does not require therapeutic bridging with injectable anticoagulants.8,18

Approximately 50% of edoxaban is eliminated renally, and as a result, dose adjustment is necessary for kidney impairment.8,19 Do not use edoxaban in patients with a CrCl greater than 95 mL/min because of an increased risk of ischemic stroke compared with warfarin.8,19

Similar to the other Xa inhibitors, concurrent use of P-gp inducers such as rifampin should be avoided. Dose reduction should occur when patients are taking a P-gp inhibitor such as verapamil, clarithromycin, erythromycin, and ketoconazole, based on CrCl and weight in patients treated for DVT or PE.8,10 Again, as with the other Xa factor inhibitors, no regular lab monitoring of anticoagulation is necessary.8,10,17,19

Possible adverse reactions of edoxaban include anemia, bleeding, rash, and abnormal liver function tests. The most common form of major bleeding associated with edoxaban is gastrointestinal.8 Currently, there is no reversal agent for excessive anticoagulant effects of edoxaban.8,10,18,19 However, there has been a phase 1 study using ciraparantag. In a phase 1 study, researchers test a new drug in a small group of individuals for the first time to evaluate its safety, determine a safe dosage range, and identify adverse reactions. In this study, ciraparantag restored hemostasis within 30 minutes of administration, which shows promise for future development of a reversal agent.10

Nursing considerations

While NOACs have many benefits for patients, a major drawback (with the exception of dabigatran) is the lack of reversal agents. When caring for patients in the critical care setting, invasive procedures or surgery are often necessary to stabilize the patient. Without a way to control bleeding, these necessary procedures put the patient taking a NOAC at greater risk for a major bleeding event.

To reduce the risk of bleeding from a minor invasive or surgical procedure, dabigatran should be held for 1 or 2 days if the patient's CrCl is 50 mL/min or greater and 3 to 5 days if the CrCl is less than 50 mL/min.5 Rivaroxaban, apixaban, and edoxaban should be held for 1 day.6-8 Minor bleeding can usually be managed conservatively with supportive care and NOAC cessation.4,20

For moderate bleeding, initial measures may require volume resuscitation with fluids and/or packed red blood cells, identification of the bleeding source, and attempts at local hemostatic control.4,20 Although they have not been shown to be effective at reversing NOAC effects, consider fresh frozen plasma and cryoprecipitate.2,4

In the case of life-threatening bleeding and/or emergency procedures, such as exploratory laparotomy, thoracotomy, or craniotomy, immediate reversal is required.11,17,21 Idarucizumab can completely reverse the effects of dabigatran within minutes of administration.14 It can be given as two consecutive infusions or as a bolus injection by injecting both vials consecutively via a syringe. A preexisting I.V. line can be used after flushing with 0.9% sodium chloride solution prior to infusion. No other infusion should be administered at the same time.14

Adverse reactions to idarucizumab include thromboembolic risk and hypersensitivity reactions. Patients with hereditary fructose intolerance due to sorbitol excipient may have serious adverse reactions (hypoglycemia, hypophosphatemia, metabolic acidosis, and acute liver failure), including fatal reactions, when receiving parenteral administration of sorbitol.14

If the patient is taking any of the other NOACs that do not have a reversal agent, supportive care should begin with identifying the bleeding source, hemodynamic and lab monitoring, hemodynamic support with vasoactive therapy, and volume resuscitation with I.V. fluids and packed red blood cell transfusions, if needed.2,4,19 If the patient has ingested one of these agents within the previous 1 to 2 hours, oral administration of activated charcoal may be of benefit, but because of its narrow window of use, it is not often seen in the clinical setting.2,20

Hemodialysis is another option for emergent removal of anticoagulants. Dabigatran (about 60%) can be eliminated from the bloodstream through hemodialysis, but rivaroxaban and apixaban may not be effectively cleared because of their extensive protein-binding nature.2,20 The use of three-factor or four-factor prothrombin complex concentrates should be considered if available, as they have been shown to reverse or partially reverse the anticoagulation effect of these agents.2,20,21 The use of recombinant activated factor VIIa decreases bleeding time in animal models, but there are currently no studies to determine whether this is effective in humans.20,21

For low-risk procedures, such as dental extractions, cataract surgery, and skin biopsy, holding a single dose of the NOAC prior to the procedure will be sufficient to control bleeding.19,20,21

Moderate-risk procedures such as endoscopy with biopsy, angiography, catheter ablation, and many common ICU procedures such as central venous catheter placement (internal jugular and femoral vein), thoracentesis/paracentesis, and bronchoscopy with biopsy will require stopping dabigatran for 1 to 2 days prior to the procedure in patients with normal kidney function and up to 5 days for those with decreased kidney function (CrCl less than 50 mL/min).5 For the Xa inhibitors, patients should stop taking the drug 1 day prior to the procedure in patients with normal kidney function and 2 days for those with impaired kidney function (CrCl less than 30 mL/min); apixaban should be stopped 1 day prior to procedures with a minor risk of bleeding and 2 days prior to procedures with a moderate to high risk of bleeding.6-8

With all of the NOACs, take precautions if a patient requires spinal or epidural anesthesia. These patients are at risk for developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.5-8 Indwelling epidurals or intrathecal catheters should not be removed earlier than 12 to 24 hours after their last dose of NOAC, however the time frame will vary based on the specific NOAC drug given and the patient's age and individual risk factors. The next dose of NOAC should not be administered earlier than 2 to 6 hours after the removal of the catheter. The risk of paralysis may also be increased by traumatic or repeated epidural or spinal puncture.5-8

Monitor patients frequently for signs and symptoms of neurologic impairment such as midline back pain, numbness, tingling, or weakness of the lower extremities, and bowel and/or bladder dysfunction. Instruct the patient to immediately report any of these symptoms.6 If neurologic compromise is noted, inform the patient's healthcare provider immediately as urgent treatment is necessary.

Patient teaching

With all anticoagulants, teach patients about the risks of bleeding and bruising, including the increased risk of injury associated with falls, and the importance of reporting any unusual bleeding from their nose or gums, or blood in their urine or stool. Discuss precautions such as using an electric shaver to avoid nicks and avoiding extreme sports. It is important that patients understand they must continue to take their medication and should not stop abruptly because that could increase their risk for stroke.5-8 If they miss a dose, they should take the dose as soon as possible that same day. Drug administration may be resumed at the usual time the next day. However, if they miss an entire day, they should not double up on doses.19

The use of NOACs is increasing. It is important for nurses to understand the actions, indications, contraindications, adverse reactions, and reversal agents for each drug as well as the nursing considerations and teaching strategies needed to care for these patients.

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Keywords:

anticoagulants; direct thrombin inhibitor; direct oral anticoagulants; factor Xa inhibitor; novel oral anticoagulants; warfarin

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