What's New in Anticoagulation
A trial fibrillation (AF), the most prevalent type of arrhythmia, affects an estimated 2.7 to 6.1 million people in the United States.1 Patients with AF are at a 4 to 5 times higher risk of stroke, and AF accounts for 15% to 20% of ischemic strokes in the U.S. Strokes related to AF are more severe than are strokes caused by other underlying disease.2 For many years, warfarin (vitamin K antagonist) has been the mainstay treatment of AF-related stroke. Warfarin is highly effective in reducing the risk of AF-related stroke but has substantial limitations that can outweigh those advantages—including a narrow therapeutic window and certain drug–drug and drug–food interactions.3 To overcome these limitations, recent years have seen the production of new oral anticoagulants (NOACs), such as factor Xa (rivaroxaban, apixaban, and edoxaban) inhibitors and direct thrombin inhibitors (dabigatran). Table I summarizes the approved indications and the dose adaptations of NOACs by the U.S. Food and Drug Administration and the European Commission.4
Warfarin
Warfarin, introduced in 1954, is very effective in preventing AF-related strokes. Warfarin is reversible and inexpensive, and anticoagulation with warfarin (international normalized ratio, 2–3; mean, 2.5) has been shown to decrease AF-related stroke risk by 67%. However, warfarin still remains underused by about 50% of suitable candidates receiving treatment for AF. Warfarin therapy has some limitations, such as a slow onset of action, genetic variation in metabolism, multiple food and drug interactions, and a narrow therapeutic index that makes it difficult to use in practice.5 Therefore, there is a need in AF management for novel approaches to stroke prevention with NOACs.
Dabigatran
Dabigatran is a selective and reversible, oral, direct thrombin inhibitor. The absolute bioavailability of dabigatran, after oral administration, is around 6.5% (serum half-life, 12–17 hr), which warrants twice-daily dosing.6 Renal excretion is the primary route of elimination of dabigatran (80%). The approved doses of dabigatran in the U.S. are 150 mg twice daily in patients with normal renal function and 75 mg twice daily both in patients with poor renal function (creatinine clearance [CrCl], 15–30 mL/min) and in patients with CrCl 30–50 mL/min in the presence of P-glycoprotein inhibitors. Dabigatran is contraindicated in patients with CrCl <15 mL/min or in patients who are taking P-glycoprotein inhibitors with CrCl <30 mL/min.6 Idarucizumab is a humanized monoclonal antibody fragment, derived from an immunoglobulin G-isotype molecule, which reverses the anticoagulant effects of dabigatran.7
Rivaroxaban
Rivaroxaban is an oral, direct factor Xa inhibitor with a bioavailability of 70% and a serum half-life of 5 to 9 hours in healthy volunteers and 11 to 13 hours in the elderly. Two thirds of a rivaroxaban dose undergoes metabolic degradation in the liver, of which half is eliminated renally and half is removed via the hepatobiliary route in the feces.4 The influence of renal function on rivaroxaban is considered to be moderate, and rivaroxaban is prescribed at oral dosages of 20 mg/d with evening meals (if CrCl >50 mL/min) or 15 mg/d with evening meals (if CrCl=15–50 mL/min), and is not recommended only in cases of severe renal impairment (CrCl <15 mL/min) when used for the prevention of AF-related stroke in patients with AF.4,8
Apixaban
Apixaban is another oral, direct factor Xa inhibitor, with a bioavailability of 50% and a serum half-life of 8 to 15 hours. The recommended dose is 5 mg twice daily, and the drug is mainly excreted through the liver. The dose should be reduced to 2.5 mg twice daily if patients have 2 of 3 criteria: age ≥80 yr, ≤60 kg body weight, or if the patient's serum creatinine level is ≥1.5 mg/dL or if the patient's renal impairment is severe (CrCl, 15–29 mL/min).9
Edoxaban
Edoxaban is a once-daily, oral, direct factor Xa inhibitor, which is excreted with 62% bioavailability and has a mean elimination half-life of 10 to 14 hours. Edoxaban is 50% eliminated via the renal route and 50% via the hepatobiliary route.10 Edoxaban is not recommended in patients with CrCl >95 mL/min. If patients have CrCl of 15 to 50 mL/min, the dose should be decreased to 30 mg/d (Table II).10 The oral dose of edoxaban for prevention of AF-related stroke is 60 mg/d.
Contributor Notes
★ CME Credit
Presented at the 17th Symposium on Cardiac Arrhythmias in Honor of Dr. Ali Massumi, Houston, 20 February 2016.
Section Editor: Mohammad Saeed, MD
From: Department of Cardiology (Drs. M. Razavi and Safavi-Naeini), Texas Heart Institute; and Department of Medicine, Section of Cardiology (Drs. J.E. Molina Razavi and M. Razavi), Baylor College of Medicine; Houston, Texas 77030
