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New oral anticoagulants for patients with nonvalvular atrial fibrillation

Holden, Amber PA-C; Azimi, Nassir MD, FACC, FSCAI; Forest, Christopher P. MSHS, DFAAPA, PA-C

Journal of the American Academy of PAs: November 2015 - Volume 28 - Issue 11 - p 28–34
doi: 10.1097/01.JAA.0000471615.92278.1c
CME: Cardiology

ABSTRACT Four new oral anticoagulants have been approved for reducing stroke risk in patients with nonvalvular atrial fibrillation. Compared with warfarin, these agents offer a more predictable dose response with fewer food and drug interactions and no regular blood monitoring, although some of the drugs have an increased risk of major gastrointestinal bleeding. This article reviews the new drugs.

Amber Holden practices at Rancho Family Medical Group in Temecula, Calif. Nassir Azimi is chair of medicine and co-chair of the endovascular committee at Sharp Grossmont Hospital in La Mesa, Calif., a partner in the La Mesa Cardiac Center, a member of the San Diego County Cardiovascular Advisory Committee, and a clinical faculty member at Midwestern School of Medicine in Glendale, Ariz. Christopher P. Forest is an assistant professor of clinical family medicine and director of research at the University of Southern California's Keck School of Medicine and practices urgent care and family medicine in Los Angeles, Calif. Dr. Azimi discloses that he receives payment to speak about rivaroxaban and dabigatran. The other authors have disclosed no potential conflicts of interest, financial or otherwise.

Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of November 2015.

Box 1

Box 1

With the advent of new oral anticoagulants that do not require monitoring the international normalized ratio (INR), primary care providers can be more confident about reduced risk of intracranial hemorrhage and increased compliance in patients with atrial fibrillation (AF). Within the last 5 years, four new agents have been approved for AF. Compared with warfarin, these agents offer a more predictable therapeutic response with fewer food and drug interactions and decreased overall cost to the healthcare system.1 Before selecting a new agent, providers must understand the nature of AF and the rationale for each of these anticoagulants.

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Primary care providers play an integral role in managing anticoagulation and preventing stroke in patients with AF. Since the introduction of warfarin in 1954, oral antithrombotic options have changed little until recently. The FDA approved dabigatran in 2010, rivaroxaban in 2011, apixaban in 2012, and edoxaban in 2015.

These medications are approved for nonvalvular AF, more specifically AF not secondary to rheumatic mitral stenosis or a prosthetic heart valve. These new oral anticoagulants have simplified the management of AF by eliminating some of the challenges associated with warfarin.

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AF is recognized as the most common sustained cardiac dysrhythmia in the United States, affecting an estimated 5 million patients.2 The prevalence of AF is expected to more than double by 2030, to an estimated 12 million patients.2 Epidemiologic data demonstrate that 75% of patients with AF are over age 65 years, and the incidence of AF increases with age.3 Although age is the most common risk factor, other comorbidities include hypertension, coronary artery disease (CAD), valvular heart disease, and heart failure. Of major concern to healthcare providers is that patients with untreated AF are five times more likely to have a stroke than patients without this condition.4

Box 2

Box 2

The CHADS2 score is used to estimate the risk of stroke in patients with AF by evaluating the following risk factors: Congestive heart failure, Hypertension, Age 75 years or older, Diabetes, and a history of prior Stroke or transient ischemic attack. The more inclusive CHA2DS2VASc score in the 2014 American Heart Association (AHA) Guidelines for AF adds three additional risk factors: the presence of Vascular disease, Age 65 to 74 years, and Sex Category female. These guidelines recommend treatment if the patient has a risk score greater than or equal to 2; however, any concomitant risk factor may warrant anticoagulation to decrease risks associated with stroke.5 In addition to CHA2DS2VASc, two other indications for therapy are confirmed cardiac thrombus and mitral valve stenosis. Effective management of AF consists of preventing stroke and systemic embolism with antithrombotic therapy and controlling ventricular rate or rhythm (Figure 1).



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Warfarin was introduced as a pesticide in 1948 and approved by the FDA in 1954 for use as an anticoagulant in humans. The drug is commonly used for stroke prevention in patients with AF and is the only FDA-approved oral anticoagulant for AF in patients with mitral stenosis or prosthetic heart valves. Pooled data from six trials show that for every 37 patients treated with warfarin over 1 year, one stroke is prevented.5 Initial dosing is 2 to 5 mg daily depending on patient age and risk factors. The maintenance dose depends upon a variable patient response as measured by INR.

Warfarin inhibits the synthesis of vitamin K dependent clotting factors, including factors II, VII, IX, X, and anticoagulant proteins C and S (Figure 2). The half-life of warfarin ranges from 20 to 60 hours, consistent with the half-lives of the vitamin K dependent clotting factors and anticoagulant proteins. In comparison, the half-lives of the new oral anticoagulants range from 5 to 17 hours. Warfarin's prolonged half-life and narrow therapeutic range require meticulous attention to dosing and close monitoring of laboratory values.



Because warfarin is a vitamin K antagonist, its pharmacologic action may be reversed by administration of vitamin K or fresh frozen plasma. A single dose of warfarin may last 2 to 5 days in the body, so therapy must be discontinued 5 days before surgery, compared with 1 to 2 days for the newer agents. However, if patients need urgent surgery, those taking warfarin can rely on INR monitoring and an antidote; no monitoring parameters exist to assure that the effects of the new anticoagulants have been minimized before surgery, especially in patients with renal impairment.

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Drug and food interactions

INR monitoring is required because warfarin is affected by the patient's metabolism, clotting factors synthesized by the liver, and food and drug interactions. Warfarin is cleared by hepatic metabolism via the cytochrome P450 pathway. Foods that contain high amounts of vitamin K, such as leafy green vegetables, can reduce warfarin's efficacy. Patients must maintain a consistent diet to keep levels of warfarin within therapeutic range.

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Monitoring blood levels

For patients with nonvalvular AF, the target INR for stroke prevention is between 2 and 3, a narrow therapeutic window that is difficult for patients to maintain.6 Regularly monitoring a patient's INR helps to ensure that a safe, effective dose of warfarin is being taken. In studies, the average time in therapeutic range is 64%.5 This suggests that more than 35% of the time, patients are at risk of hemorrhage or thrombosis.

Warfarin's advantages include affordability, familiarity, once-daily dosing, and the existence of an antidote. Disadvantages include numerous food and drug interactions and the need for frequent blood monitoring.

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Many of the challenges associated with using warfarin are no longer issues for patients using the new oral anticoagulants.

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This direct thrombin inhibitor is indicated for preventing stroke and systemic embolism in patients with nonvalvular AF. Dabigatran exhibits peak activity in 1 to 6 hours and has a half-life of 12 to 17 hours.

The main adverse drug reactions to dabigatran are gastrointestinal (GI) (35%), including dyspepsia and GI bleeding (6.1%).7 In comparison, 24% of patients on warfarin reported GI adverse reactions, including GI bleeding (4%).7 Because 80% of the dabigatran dose is excreted by the kidneys, the usual 150 mg twice-daily dose should be halved to 75 mg twice daily for patients with renal impairment (defined as a creatinine clearance of 15 to 30 mL/minute).

The RE-LY study examined the safety and efficacy of dabigatran relative to warfarin in 18,113 patients over 2 years.8 The study concluded that dabigatran demonstrated a statistically significant reduction in the incidence of overall stroke (RR 0.64; 95% CI 0.51 to 0.81, P<0.001) and intracranial hemorrhage (RR 0.40, 95% CI 0.27 to 0.60, P<0.001) compared with warfarin.8 The risk of hemorrhagic stroke was significantly reduced (74%) in patients treated with dabigatran compared with warfarin.5 Patients on dabigatran also had fewer episodes of life-threatening bleeding (RR 0.81, 95% CI 0.66 to 0.99, P<0.04) but more major GI bleeding (1.6% versus 1% per year; RR 1.50, 95% CI 1.19 to 1.89, P<0.001).8

Major advantages of dabigatran include superior stroke reduction, less intracranial hemorrhage, and no INR monitoring. Disadvantages include cost, twice-daily dosing, increased GI bleeding risk compared with warfarin, and lack of a reversal agent.

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The first of the factor Xa inhibitors, rivaroxaban is approved for stroke prevention in patients with nonvalvular AF. The drug reaches maximum plasma concentration and factor Xa inhibition in 2 to 4 hours. Rivaroxaban has the shortest half-life of any of the new oral anticoagulants—5 to 9 hours—and offers convenient once-daily dosing.

Adverse reactions to rivaroxaban include bleeding, increased risk of thrombotic events after premature discontinuation, and risk of spinal or epidural hematomas in patients undergoing spinal puncture.

A double-blind trial compared the safety and efficacy of rivaroxaban and dose-adjusted warfarin in 14,264 patients with nonvalvular AF.9 The primary end point of stroke or systemic embolism was similar in the rivaroxaban group (1.7% per year) and the warfarin group (2.2% per year).9 This noninferiority of rivaroxaban to prevent stroke in patients with AF was statistically significant (RR 0.79, 95% CI 0.66-0.96, P<0.001).9

No significant difference was found in the incidence of overall major bleeding (rivaroxaban, 3.6%, and warfarin, 3.4%); however, fewer patients on rivaroxaban had intracranial bleeding: 0.5% compared with 0.7% in the warfarin group (RR 0.67, 95% C 0.47-0.93, P=0.02).9 Patients in the rivaroxaban group also had less fatal bleeding (RR 0.50, 95% CI 0.31-0.79, P=0.003), and more major GI bleeding, 3.2% compared with 2.2% than patients in the warfarin group (P<0.001).9

This trial showed that rivaroxaban is noninferior to warfarin for stroke prevention and demonstrated no significant difference in the risk of major bleeding. Though a statistically significant increase in major GI bleeding was noted with rivaroxaban, a statistically significant decrease in fatal bleeding and intracranial hemorrhage make this drug an attractive alternative to warfarin.

Advantages of rivaroxaban include once-daily dosing, no dietary restrictions, and no INR monitoring. Disadvantages include cost, increased GI bleeding compared with warfarin, and lack of a reversal agent.

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Another factor Xa inhibitor, apixaban is approved for reducing stroke risk and systemic embolism in patients with nonvalvular AF. Its half-life is similar to the other new oral anticoagulants. Half of the drug is cleared within 12 hours. Dosing is twice-daily and adjustments are recommended for frail patients, defined as having two or more of the following: age 80 years or greater, body weight of 60 kg (132.3 lb) or less, or serum creatinine of 1.5 mg/dL or greater. Dosing adjustments are also recommended for patients who also are taking strong dual CYP3A4 and P-glycoprotein inhibitors, such as verapamil, dronedarone, and erythromycin.

Adverse reactions to apixaban include increased risk of bleeding, increased risk of thrombotic events after premature discontinuation, and increased risk of spinal or epidural hematoma in patients with spinal or epidural puncture.

In a double-blind trial comparing the efficacy of apixaban to dose-adjusted warfarin in 18,201 patients with AF, apixaban was found superior in three areas: overall risk reduction for stroke (RR 0.79, 95% CI 0.65-0.95, P=0.01), particularly hemorrhagic stroke (RR 0.51, 95% CI 0.35-0.75, P<0.001); major bleeding (RR 0.69, 95% CI 0.60-0.80, P<0.001); and all-cause mortality (RR 0.89, 95% CI 0.80-0.99, P=0.047).10 Apixaban was the only new oral anticoagulant to result in less GI bleeding than warfarin; however, these results were not statistically significant.

The advantages of apixaban include improved efficacy over warfarin at reducing overall stroke, less major bleeding and all-cause mortality, and no INR monitoring. Disadvantages include twice-daily dosing, cost, and lack of a reversal agent.

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The newest factor Xa inhibitor, edoxaban was approved in January 2015 for reducing stroke and systemic embolism in patients with nonvalvular AF. Edoxaban exhibits peak concentration at 1 to 2 hours and has a half-life of 10 to 14 hours.11 Like rivaroxaban and warfarin, edoxaban offers the convenience of once-daily dosing. Because 50% of edoxaban is excreted by the kidneys, the usual 60 mg daily dose should be halved to 30 mg daily for patients with a creatinine clearance of 15 to 50 mL/minute; the drug should not be used in patients with creatinine clearances greater than 95 mL/minute because it increases the risk of ischemic stroke.11 The most frequently reported adverse reactions to edoxaban are bleeding and anemia. As with other anticoagulants, bleeding is the most serious and potentially life-threatening adverse reaction.

ENGAGE-AF-TIMI 48 was a multinational, double-blind study involving 21,105 patients over a mean of 2.8 years. This trial examined the efficacy and safety of edoxaban relative to warfarin and concluded that edoxaban is noninferior to warfarin at reducing overall stroke and demonstrates reduction in overall bleeding, except GI bleeding.12 The primary endpoint of incidence of stroke or systemic embolism per year was 1.18% for the edoxaban group and 1.50% for the warfarin group.12 Patients had fewer major bleeding events with edoxaban (2.75%) than with warfarin (3.43%) (RR 0.80; 95%, CI 0.71 to 0.91; P<0.001). With edoxaban and warfarin, the rates of life-threatening bleeding were 0.40% and 0.78%; intracranial hemorrhage, 0.39% and 0.85%; and major bleeding plus clinically relevant nonmajor bleeding, 11.1% and 13.02%. Major GI bleeding was higher with edoxaban (1.51% per year) than with warfarin (1.23% per year) (RR 1.23; 95% CI 1.02 to 1.50; P=0.03).12 Although increased GI bleeding remains of great concern, edoxaban is equally effective at stroke prevention and showed a statistically significant reduction in overall major bleeding, fatal bleeding, and intracranial hemorrhage compared with warfarin.

Major advantages of edoxaban include noninferior stroke reduction, less intracranial hemorrhage, once-daily dosing, and no INR monitoring. Disadvantages include cost, increased GI bleeding compared with warfarin, and the absence of a reversal agent.

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One of the challenges with the new oral anticoagulants is the need for antidotes, for dosage adjustments in patients with renal impairment, and certain drug-drug interactions. Recent small trials suggest that experimental agents may be effective as safe, fast-acting antidotes. Idarucizumab is being studied for the reversal of dabigatran and andexanet alfa for the factor Xa inhibitors. A phase 4 study for andexanet alfa was initiated January 2015 after being granted breakthrough therapy designation by the FDA. The drug's manufacturer expects to seek accelerated FDA approval at the end of 2015.13 Having a reversal agent for the new oral anticoagulants may further boost provider confidence in using them.

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Warfarin's narrow therapeutic window, many interactions, and need for monitoring result in a high discontinuation rate, leaving many patients inadequately anticoagulated. New oral anticoagulants that are effective, convenient, and safer are needed. All oral anticoagulants can cause patient harm, and continued research is needed to improve the safety profile.

A meta-analysis of four new oral anticoagulants--dabigatran, rivaroxaban, apixaban, and edoxaban--demonstrates that using these drugs in patients with AF reduces stroke and systemic embolism 19% (RR 0.81, 95% CI 0.73-0.91; P<0.0001) compared with patients taking warfarin.14 This outcome is largely attributed to the reduction of hemorrhagic strokes using the new oral anticoagulants (RR 0.49, CI 0.38-0.64, P<0.0001).14 Although GI bleeding is more common with some of the newer drugs (RR 1.25, CI, 1.01 to 1.55, P=0.04), they reduce all-cause mortality (RR 0.90, CI 0.85 to 0.95, P=0.0003) and intracranial bleeding (RR 0.48, CI 0.39-0.59, P<0.0001).14

Overall, the new oral anticoagulants result in significant reductions in stroke, intracranial hemorrhage, and mortality. They exhibit similar or decreased rates of total major bleeding, but increased rates of GI bleeding compared with warfarin. The new drugs show promise as a relatively safe and effective alternative to warfarin for stroke prevention in patients with AF, but would benefit from an effective reversal agent.

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The new oral anticoagulants have similar drug interactions, precautions, and contraindications. Drug-drug interactions include P-glycoprotein inducers (such as rifampin and carbamazepine) and P-glycoprotein inhibitors (such as dronedarone, erythromycin, and ketoconazole). Proton pump inhibitors may reduce the absorption of dabigatran, making it less effective.5 All the studies of the new oral anticoagulants for AF disallowed triple therapy, including antiplatelet therapy for patients with comorbid conditions. In all trials of the new anticoagulants for patients with acute coronary syndrome, major bleeding increased significantly in patients on dual antiplatelet therapy. Thus, long-term triple therapy should be entered into cautiously.5

Though the new oral anticoagulants do not require INR monitoring, providers should still monitor patients for signs and symptoms of bleeding as well as their creatinine clearance, age, and weight so necessary dosing adjustments can be made. Common contraindications to these drugs include major bleeding or a hypersensitivity reaction. Use in pregnancy is controversial.

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Switching from warfarin to one of the new oral anticoagulants

Discontinue warfarin and initiate dabigatran or apixaban once the patient's INR is below 2; rivaroxaban once the patient's INR is below 3; or edoxaban once the patient's INR is 2.5 or lower.7,11,15,16

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Switching from one of the new drugs to warfarin

Because the new oral anticoagulants affect INR, initial INR measurements in a patient switching from these drugs to warfarin may not be beneficial. Switching from dabigatran to warfarin is based on creatinine clearance; switching from rivaroxaban or apixaban involves parental agents and INR monitoring.7 If continuous anticoagulation is necessary, discontinue rivaroxaban or apixaban and initiate parenteral anticoagulation with warfarin at the time of next scheduled new oral anticoagulant dose. Discontinue parenteral anticoagulants once the patient's INR reaches the therapeutic range.15,16 When switching from edoxaban to warfarin, halve the dose of edoxaban and give it with warfarin. Measure the patient's INR weekly and just before the edoxaban dose. Once the patient's INR is 2 or greater, discontinue edoxaban.11

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Switching from one new oral anticoagulant to another

Discontinue the current drug and start the new drug at the next scheduled dose.7,11,15,16

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Although these newer agents can appear to be cost-prohibitive, they may ultimately decrease overall disease burden. Management of AF costs the US government an estimated $26 billion (2008 US dollars) annually.17 Although most of this financial burden can be attributed to hospitalization, an estimated $6 billion (2010 US dollars) is due to pharmacologic management.17

Due to difficulties managing therapeutic levels of warfarin, the new oral anticoagulants provide a feasible alternative. The cost of these newer agents may be mitigated by the overall cost of monitoring patients' response to warfarin and the increased morbidity when patients fall out of the therapeutic range. Patients taking warfarin are more likely to permanently discontinue anticoagulation after having an acute incident such as intracranial hemorrhage, which is more common with warfarin.17

The average monthly cost for new oral anticoagulants is $244; discount programs for eligible patients may bring this cost to as little as $10.17 Generic warfarin may cost as little as $4 monthly.18

Several trials have compared the cost effectiveness of the new oral anticoagulants to warfarin. A study funded by a team grant from the Canadian Institutes of Health Research concluded that apixaban and dabigatran were the most cost-effective options compared with warfarin.19 An article comparing major randomized clinical trials for the new anticoagulants found that apixaban and dabigatran had the largest medical cost reductions compared with warfarin ($1,245 and $555, respectively); rivaroxaban increased medical costs $144.20 The article did not consider the cost of the drug or INR monitoring. A study presented at the American College of Cardiology annual conference found that the new anticoagulants reduced total medical costs largely due to fewer strokes and bleeding events in patients.21 These reviews concede that the accuracy of these data are impaired by the difficulty in making cross-model comparisons.

Factors attributing to the improved cost-effectiveness of the new oral anticoagulants include decreased rates of intracranial hemorrhage, decreased costs of managing adverse reactions, and the quality of warfarin control.

New medications such as these anticoagulants often appear to be complicated, but in light of the improved safety profile, providers can confidently use these agents and will likely find them simpler to use. All anticoagulation management should be individually tailored, considering a patient's risk factors, finances, and anticipated adherence. Providers may find it valuable to review the major advantages and disadvantages of a proposed medication with patients in order to maximize adherence.

The choice of oral anticoagulant should take into account patient characteristics, clinical trial data, and patient preferences. When adherence is an issue, rivaroxaban and edoxaban offer the advantage of once-daily dosing. Based on results of a study that included patients at higher risk for CAD, rivaroxaban is preferred in patients with CAD or previous myocardial infarction.9 In patients who are higher risk for GI bleeding, apixaban is the agent of choice because it caused less GI bleeding that the other new oral anticoagulants and warfarin. Dabigatran is preferred in patients who have a high risk of ischemic stroke and low bleeding risk. For patients concerned with out-of-pocket cost, warfarin is the least expensive anticoagulant, apart from the costs of monitoring, adherence, and potential complications.1

Patient adherence to therapy and drug efficacy make anticoagulation management challenging for clinicians. Because patients with AF generally are older, adherence and transportation to the laboratory are issues. Warfarin raises the additional concerns of INR monitoring and dietary consistency. With three published clinical trials demonstrating a decrease in intracranial hemorrhage with the new oral anticoagulants, the increased risk of managing nonvalvular AF with warfarin is attenuated.

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Primary care providers can effectively manage AF by remaining abreast of rapidly evolving treatment options. Although warfarin remains the standard of care for stroke prevention in patients with AF, with the improved safety and efficacy profiles of the new agents, these drugs may become the new gold standard in the treatment of nonvalvular AF. Current research suggests that additional options and possible antidotes for the new oral anticoagulants may soon be available. Future efforts should be directed at further improving safety profiles of newer agents and decreasing prescription cost. Warfarin is a time-tested medication for the prevention of stroke in AF that still has clinical utility and some advantages: it can be used in patients with valvular heart disease, its level of anticoagulation can be measured, and it may be safer in patients with chronic kidney disease. After evaluating the risks and benefits of oral anticoagulants, and assuming no contraindications, providers may prefer using the new oral anticoagulants in patients with nonvalvular AF.

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    anticoagulation; nonvalvular atrial fibrillation; rivaroxaban; dabigatran; edoxaban; apixaban

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