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Update on Direct Oral Anticoagulants and Their Uses
U p d a t e o n D i rec t O r a l A n t i c o a g u l a n t s a n d Th e i r Uses Vigyan Bang, MDa,b,*, Russell S. Zide, Chi-Cheng Huang, MDb,c,d,e,f,g
MD
a,b
,
KEYWORDS Direct oral anticoagulants Warfarin Atrial fibrillation Venous thromboembolism
HOSPITAL MEDICINE CLINICS CHECKLIST
1. Anticoagulants are beneficial for treatment of venous thromboembolism and prevention of stroke in atrial fibrillation. 2. Direct oral anticoagulants (DOACs) are a growing alternative to warfarin because of their predictable pharmacokinetics and ease of use. 3. There is an advent of rapid and safe reversal agents for DOACs for use in situations of major bleeding and preprocedurally.
INTRODUCTION
Direct oral anticoagulants (DOACs) are rapidly gaining traction as the preferred method of oral anticoagulation for patients with nonvalvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), and for prophylaxis of deep vein thrombosis (DVT). Their predictable pharmacokinetic properties allow easy dosing regimens that avoid many of the difficulties and challenges associated with vitamin K antagonist (VKA) therapy. However, the DOAC agents pose unique challenges for health care providers, who have previously developed comfortable strategies to manage VKAs and must now adapt to a new class of medications. This article reviews the indications
a General Internal Medicine, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA 01805, USA; b Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02110, USA; c Department of Hospital Medicine, Lahey Health System, 41 Mall Road, Burlington, MA 01805, USA; d Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA 01805, USA; e Lahey Medical Center, 1 Essex Center Dr, Peabody, MA 01960, USA; f Beverly Hospital, 85 Herrick Street, Beverly, MA 01915, USA; g Addison Gilbert Hospital, 298 Washington Street, Gloucester, MA 01930, USA * Corresponding author. E-mail address: [email protected]
Hosp Med Clin - (2016) -–http://dx.doi.org/10.1016/j.ehmc.2016.11.004 2211-5943/16/ª 2016 Elsevier Inc. All rights reserved.
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and dosing considerations, clinical efficacy and safety, laboratory monitoring, and reversibility considerations of DOACs. DOACs include oral direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) and direct thrombin inhibitors such as dabigatran. MECHANISM OF ACTION AND PHARMACOLOGY Direct Thrombin Inhibitors
Dabigatran etexilate, a prodrug of dabigatran, is the only commercially available oral direct thrombin inhibitor, or inhibitor of factor IIa. Dabigatran is a small, synthetic molecule that specifically and reversibly inhibits free and clot-bound thrombin by binding to the active site of thrombin.1 Inhibition of thrombin attenuates formation of fibrin, reduces thrombin generation, and may limit platelet aggregation. Oral Activated Factor X Inhibitors
Factor Xa inhibitors bind directly to the active site of factor Xa, located at the convergence of the intrinsic and extrinsic pathways in the coagulation cascade. Inhibition at this site blocks thrombin generation from both pathways, and prevents subsequent amplification of thrombin generation, and thrombin-mediated activation of coagulation and platelets.2 The DOAC plasma concentration reaches their peak at 1 to 4 hours. Therefore, the therapeutic effect of DOACs occurs more rapidly and the risk of bleeding increases proportionately. The bioavailability of most of the DOACs is between 60% and 100%. The exception is dabigatran, which has low bioavailability, therefore requiring a higher dosage. The high bioavailability of DOACs contributes to a more predictable anticoagulant response, eliminating the need for routine monitoring. The metabolism of DOACs is mainly performed by the liver. There may be interpatient variability when these drugs are given to patients with moderate hepatic disease,3 and they must therefore be used with caution in such patients. Most of the DOACs are excreted renally, with primary excretion rates ranging from 60% to 85%, except for apixaban and edoxaban, which have a much lower excretion rates. Therefore, patients with impaired renal function can have increased plasma drug concentrations. LABORATORY MONITORING OF DIRECT ORAL ANTICOAGULANTS
With the use of VKA for anticoagulation, clinicians have become accustomed to checking International Normalized Ratio (INR) values to assess how well patients are being anticoagulated and adjust VKA dosing. The DOACs challenge this paradigm by offering predictable pharmacokinetics, thus eliminating the need for routine laboratory monitoring. However, there are certain clinical scenarios when laboratory monitoring is clinically warranted, such as before urgent or emergent surgery, when assessing medication compliance, and for ensuring adequate anticoagulation in patients at the extremes of weight. A few routine laboratory tests are available that, when properly calibrated, can offer insight into the degree of anticoagulation for patients taking DOACs. For patients taking dabigatran, a normal thrombin time can be used to rule out any clinically relevant anticoagulation.4 The dilute thrombin time is the best option for assessing whether patients are appropriately or overly anticoagulated, but this test is not universally available. A normal activated partial thromboplastin time likely excludes supratherapeutic levels of dabigatran. For patients taking rivaroxaban, apixaban, or edoxaban, use of the anti-Xa activity can reliably assess the degree of anticoagulation across a wide range of drug concentrations, including subtherapeutic, therapeutic, and supratherapeutic levels.5 This
Direct Oral Anticoagulants and Their Uses
assessment is best done using a calibrated anti-Xa activity for each individual factor Xa inhibitor. However, when calibrated anti-Xa activity levels are not available, a generic chromogenic anti-Xa activity at a normal level is likely to rule out meaningful levels of any factor Xa inhibitor. A normal prothrombin time is likely to exclude supratherapeutic levels of the anti-Xa inhibitors. Perhaps more relevant to most patients is the need for regular, ongoing renal function monitoring. Each of the DOACs is, at least in part, cleared by the kidneys. Therefore, patients require periodic assessment of renal function to determine when dose adjustments are necessary or whether their use is contraindicated. The American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines on the use of DOACs outlines that renal function should be evaluated before initiation of DOACs and reassessed when clinically indicated (at least annually).6 Note that all major trials of DOACs versus warfarin for stroke prevention in AF used the Cockcroft-Gault equation to estimate renal function. Although many electronic medical records automatically calculate estimated creatinine clearance (CrCl) or glomerular filtration rates, these are often done using the Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration equations and can have significantly disparate values from the Cockcroft-Gault estimate. Therefore, clinicians should calculate the CrCl and clearly document this value at appropriate intervals and when assessing DOAC dosing. REVERSIBILITY OF DIRECT ORAL ANTICOAGULANTS
The meta-analysis of primary studies in AF showed lower rates of major bleeding with the DOACs compared with warfarin in Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)7 with dabigatran and Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)8 with apixaban. Rate of major bleeding was neutral in the Rivaroxaban Once daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF)9 with rivaroxaban. The DOACs reduced the relative risk of intracranial bleeding compared with warfarin. However, they showed higher rates of major gastrointestinal (GI) bleeding with the DOACs compared with warfarin in the same studies.10 Although several meta-analyses and major published clinical trials suggested that DOACs do not increase the risk of significant bleeding, a lack of antidote always concerned clinicians because, in emergency situations, the bleeding might need to be reversed. Bleeding associated with warfarin can be predictably managed with close monitoring of INR and reversal with fresh frozen plasma (FFP) and vitamin K. Neither FFP nor vitamin K is effective to reverse the effects of DOACs.11 Activated charcoal has been shown, in vitro, to absorb 99.9% of dabigatran suspended in acidic water. This treatment option could be useful in cases of acute intoxication. However, the efficacy of activated charcoal has not been tested in clinical practice. Desmopressin (D-arginine-deamino-vasopressin) increases the coagulation activity by stimulating the release of factor VIII and von Willebrand factor from the vascular endothelium. However, no clinical trials have evaluated the efficacy in bleeding patients on DOACs. Prothrombin complex concentrate (PCC) is a mixture of inactive factors II, IX, X, and VII. Studies on the efficacy of PCC in the reversal of the anticoagulant effect have shown inconsistent results. The activated PCC has been the most reasonable alternative for reversing dabigatran effect until recently. Clinical trials with a humanized antibody fragment directed against dabigatran (idarucizumab) and recombinant, modified factor Xa (andexanet alfa) have recently been completed.
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IDARUCIZUMAB
Idarucizumab, which is a humanized monoclonal antibody fragment (Fab), binds both free and thrombin-bound dabigatran. A prospective cohort study was performed to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B).12 The primary end point was the percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, by the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. Idarucizumab normalized the test results in 88% to 98% of the patients, an effect that was evident within minutes. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33 patients, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. ANDEXANET ALFA
Andexanet is a reversal agent that is designed to neutralize the anticoagulant effects of both direct and indirect factor Xa inhibitors. Andexanet binds and removes factor Xa inhibitors, thereby enhancing the activity of endogenous factor Xa and attenuating levels of anticoagulant activity. This activity is assessed by measurement of thrombin generation and anti–factor Xa activity.13 For each factor Xa inhibitor (apixaban and rivaroxaban), a 2-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percentage change in anti–factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. Andexanet alfa reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without serious adverse or thrombotic events.14 Subsequently, a multicenter, prospective, open-label, singlegroup study evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor.15 The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Among the apixaban-treated participants, anti–factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), compared with 21% among those who received placebo (9 participants) (P<.001). Among the rivaroxaban-treated participants, anti– factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), compared with 18% among those who received placebo (14 participants) (P<.001). No serious adverse or thrombotic events were reported. In conclusion, andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older, healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. CIRAPARANTAG (PER977)
Ciraparantag, is an intravenously administered synthetic small molecule for use as a broad-spectrum reversal agent for anticoagulants, including low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), and the DOACs that is currently being studied in phase II clinical trials.
Direct Oral Anticoagulants and Their Uses
DIRECT ORAL ANTICOAGULANTS IN ATRIAL FIBRILLATION
Anticoagulation is important in stroke prevention in patients with atrial fibrillation (AF). There are multiple factors that contribute to the risk of thromboembolism in patients with AF. Several scoring systems are used for risk stratification. The 2014 ACC/ AHA/HRS guidelines recommend using CHA2DS2-VASc score.6 When using this score, 1 point is assigned for the presence of each of the following: congestive heart failure, hypertension, age (65–74 years, 1 point; 75 years, 2 points), diabetes, prior stroke or transient ischemic attack (TIA) (2 points), vascular disease (myocardial infarction [MI], peripheral arterial disease [PAD], and carotid disease), and sex (female) with a maximum of 9 points. The anticoagulation/antiplatelet therapy recommended for the groups of patients is as follows: 1 point, no therapy, acetylsalicylic acid (75 or 325 mg daily), or oral anticoagulation (OAC); and 2 points or more, OAC (VKA or DOACs). The currently US Food and Drug Administration (FDA)–approved DOACs include 1 direct thrombin inhibitor (dabigatran) and several factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). In the 2014 ACC/AHA guidelines (published before edoxaban approval), dabigatran, apixaban, and rivaroxaban are recommended for use in patients with NVAF who have had prior stroke or TIA, or are at risk by virtue of a CHA2DS2-VASc score of 2 or more. In addition, DOACS are recommended if it is not possible to maintain therapeutic INR with VKA. It must be remembered that DOACs have not been studied in patients with valvular AF, which includes mitral stenosis, mechanical or bioprosthetic valves, and mitral valve repair. DABIGATRAN
The RE-LY trial compared different dosages of dabigatran with warfarin in patients with AF.7 Enrolled patients received fixed dosages of dabigatran (110 or 150 mg twice daily) or warfarin. The primary outcome was stroke or systemic embolism. In patients with AF, dabigatran administered at a dose of 150 mg, compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. Dabigatran given at a dose of 110 mg was associated with similar rates of stroke and systemic embolism to those associated with warfarin, but lower rates of major hemorrhage. At present, dabigatran is available in 2 FDA-approved dosages: 150 mg twice a day or 75 mg twice a day (for patients with CrCl 15–30 mL/min). Subgroup analysis showed a higher risk of intracranial hemorrhage in patients greater than 75 years of age and on the higher 150 mg twice daily dose. Thus, caution should be used in patients with renal impairment or those who are greater than 75 years of age.16 DIRECT FACTOR XA INHIBITORS
At present, there are 3 factor Xa inhibitors available in the United States: rivaroxaban, apixaban, and edoxaban. RIVAROXABAN
The ROCKET AF trial randomized patients to rivaroxaban versus warfarin with the primary end point of stroke or systemic embolism.9 The primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio [HR] in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66–0.96; P<.001 for noninferiority). The risk of major bleeding was not different between the two groups (14.9% in rivaroxaban vs 14.5% in warfarin groups); however, intracranial bleeding occurred less often in the rivaroxaban group compared
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with warfarin (0.5% vs 0.7%; P 5 .02). Risk of GI bleeding was higher in the rivaroxaban group (3.2% vs 2.2%; P<.001). In patients with AF, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. At present, rivaroxaban is available in 2 FDA-approved dosages: 20 mg daily or 15 mg daily for patients with CrCl of 15 to 49 mL/min. APIXABAN
ARISTOTLE was a large noninferiority trial comparing apixaban with warfarin, with stroke or systemic embolism as the primary outcome.8 The trial was also designed for secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. The rate of the primary outcome was 1.27% per year in the apixaban group versus 1.60% per year in the warfarin group (HR with apixaban, 0.79; 95% CI, 0.66–0.95; P<.001 for noninferiority; P 5 .01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, compared with 3.09% per year in the warfarin group (HR, 0.69; 95% CI, 0.60– 0.80; P<.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (HR, 0.89; 95% CI, 0.80–0.99; P 5 .047). It concluded that, in patients with AF, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. EDOXABAN
Edoxaban is the newest approved direct factor Xa inhibitor. ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial FibrillationThrombolysis in Myocardial Infarction Study 48) compared the use of edoxaban with warfarin with regard to stroke and systemic embolism.17 Compared with warfarin, the high-dose (60 mg) edoxaban showed superiority in preventing stroke or systemic emboli (HR, 0.79; P<.001), and low-dose (30 mg) edoxaban was noninferior (HR, 1.07; P 5 .005). The rate of major bleeding, including intracranial bleeding, was lower with edoxaban compared with warfarin, regardless of the dose. However, the rate of GI bleeding was higher in the high-dose edoxaban group compared with warfarin (HR, 1.23; P 5 .03). DIRECT ORAL ANTICOAGULANTS IN VENOUS THROMBOEMBOLISM
Clinical trials have been designed to study the efficacy of DOACs in VTE for shortterm, long-term, and extended-term treatment. Short-term treatment is defined as the therapy initiated at the time of diagnosis and continued for 5 to 7 days, which is the necessary time for overlap for VKA to become sufficiently therapeutic. Longterm therapy is defined as treatment extending 3 to 12 months from the initiation of anticoagulation, and is thought to be the proper duration of anticoagulation for most patients with an initial thromboembolic event. Extended treatment is recommended for patients who have had recurrent VTE and are at low or moderate risk of bleeding. DABIGATRAN
The RE-COVER18 and RE-COVER II19 studies had similar trial designs evaluating patients with acute VTE. Both were designed as noninferiority trials comparing the same initial therapy, consisting of parenteral anticoagulation (UFH or LMWH, or
Direct Oral Anticoagulants and Their Uses
fondaparinux) followed by randomization for long-term treatment to either dabigatran 150 mg twice daily or warfarin. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed VTE and related deaths for both studies. In the RE-COVER trial, the primary outcome of recurrent VTE at 6 months was 2.4% in the dabigatran-treated patients versus 2.1% in the warfarin group (P<.001 for noninferiority). Major bleeding occurred in 1.6% versus 1.9% of the dabigatran-treated and warfarin-treated patients, respectively (P 5 .38). As might be anticipated, the results from RE-COVER II were virtually identical to those observed in RE-COVER. The primary efficacy outcome of recurrent VTE was 2.3% and 2.2% in the dabigatran and warfarin groups, respectively (P<.001 for noninferiority). Major bleeding occurred in 1.2% and 1.7% of patients in the dabigatran and warfarin groups. Any bleeding occurred in 15.6% of the patients on dabigatran versus 22.1% of the patients on warfarin. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Dabigatran was the first DOAC studied to assess the risks and benefits of extended therapy and compared an active control (VKA) with placebo for prevention of VTE recurrence. The active-controlled study was RE-MEDY20 and the placebocontrolled study was RE-SONATE.20 The active-controlled study was designed to evaluate whether dabigatran was noninferior to warfarin in preventing recurrent VTE. The placebo-controlled study was designed to evaluate whether extended treatment with dabigatran was superior to placebo in preventing recurrent VTE. In the active-controlled RE-MEDY study, the primary efficacy outcome was recurrent VTE, which occurred in 1.8% of the patients on dabigatran and 1.3% of the patients on VKA. Dabigatran met the noninferiority margin for prevention of recurrent VTE (P 5 .01). Major bleeding occurred in 0.9% of the dabigatran group and 1.8% of the warfarin group (P 5 .06). Major or clinically relevant nonmajor (CRNM) bleeding occurred in 5.6% of the patients on dabigatran and 10.2% of warfarin-treated patients (P 5 .001). Of the patients on dabigatran, 0.9% had acute ischemic coronary events during treatment, compared with 0.2% of warfarin-treated patients (P 5 .02). In the placebo-controlled RE-SONATE trial, the primary efficacy outcome for recurrence during the first 6 months occurred in 0.4% of the dabigatran group and 5.6% of the placebo group (HR, 0.08; P 5 .001). After the extended 12-month follow-up, the recurrence rate was 6.9% in the dabigatran group compared with 10.7% in the placebo group (HR, 0.61; P 5 .03). Protection from recurrent VTE was provided during administration of dabigatran; however, once active drug was terminated, the rate of recurrence in the dabigatran group was similar to the rate of recurrence in the matching placebo group. There was no difference in major bleeding between the dabigatran and placebo groups. Major or CRNM bleeding occurred in 5.3% of patients in the dabigatran group compared with 1.8% in the placebo group (P 5 .001). Only 1 acute coronary event occurred in each treatment group. RIVAROXABAN
The EINSTEIN investigators21 studied oral rivaroxaban for symptomatic VTE and symptomatic pulmonary embolism (PE).22 In their first study, patients with symptomatic proximal DVT with or without PE were randomized to rivaroxaban or enoxaparin followed by warfarin, targeting an INR of 2.0 to 3.0. During initial therapy with rivaroxaban, patients received 15 mg twice daily for 3 weeks, then were converted to 20 mg daily for 3 to 12 months. The primary efficacy outcome of symptomatic recurrent VTE occurring during the 3-month to 12-month treatment period, occurred in 3.0% of the
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enoxaparin-VKA group and 2.1% of the rivaroxaban-treated group (HR<0.68; P 5 .001 for noninferiority and P<.08 for superiority). The primary safety outcome of major and CRNM bleeding was 8.1% for both the treatment groups (HR<0.97; P<.77). The EINSTEIN-PE study22 was similarly designed, and it randomized 4833 patients with confirmed symptomatic PE, with or without DVT. Patients were similarly treated after randomization with either rivaroxaban 15 mg twice daily for 3 weeks and converted to 20 mg daily for 3 to 12 months or with open-label enoxaparin 1 mg/kg twice daily and converted to warfarin with a target INR of 2.0 to 3.0. The primary efficacy outcome was symptomatic recurrent VTE occurring during the 3-month to 12-month treatment period. The primary safety outcome was major and CRNM bleeding. Results revealed a 2.1% recurrence rate in the rivaroxaban-treated patients versus a 1.8% recurrence rate in patients receiving conventional therapy (HR<1.12; P<.003 for noninferiority). Major and CRNM bleeding occurred in 10.3% of the rivaroxaban-treated patients versus 11.4% of the warfarin group (HR<0.90; P<.23). The EINSTEIN investigators21 additionally performed a double-blind extended-treatment study in patients with confirmed VTE who were treated for 6 to 12 months with therapeutic anticoagulation. This study was an event-driven superiority trial assuming a primary outcome of 3.5% in the placebo group and a 70% risk reduction with rivaroxaban. Patients were then randomized and assigned to receive continued treatment with rivaroxaban 20 mg daily for 6 to 12 months or with placebo. The primary efficacy outcome was symptomatic recurrent VTE and the primary safety outcome was major bleeding. The net clinical benefit was calculated for both the groups and was defined as the composite of symptomatic recurrent VTE or major bleeding. The primary efficacy outcome occurred in 1.3% of the rivaroxaban group compared with 7.1% of the placebo group (P 5 .001), resulting in a relative risk reduction of 82%. The principal safety outcome of major bleeding occurred in 0.7% of the rivaroxaban-treated patients and in no patients in the placebo group (P 5 .11). Net clinical benefit occurred in 2% of patients receiving rivaroxaban and 7.1% receiving placebo (P<.001). Efficacy and safety outcomes were consistent across the prespecified subgroups. APIXABAN
The AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) investigators23 studied apixaban versus conventional therapy for patients with acute VTE. Patients (N 5 5400) with symptomatic proximal DVT or PE were randomized to apixaban 10 mg twice daily for 7 days and converted to 5 mg twice daily for a period of 6 months versus conventional anticoagulation with enoxaparin 1 mg/kg twice daily and warfarin targeting an INR of 2.0 to 3.0. The primary efficacy outcome was a composite of recurrent symptomatic VTE or death related to VTE. The primary safety outcome was major bleeding. The primary efficacy outcome occurred in 2.3% of the apixaban-treated patients versus 2.7% of those treated with conventional anticoagulation (P<.001 for noninferiority). Major bleeding occurred in 0.6% of apixaban-treated patients versus 1.8% of those given warfarin (P<.0001 for superiority). There was no difference observed in the outcomes in patients presenting with acute symptomatic DVT versus those presenting with acute PE. The AMPLIFY-EXT (Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment) investigators evaluated 2 doses of apixaban (5 mg twice daily and 2.5 mg twice daily) versus placebo in a randomized, double-blind study of 2486 patients who had completed 6 to 12 months of anticoagulation for symptomatic VTE.24 The study drugs and placebo
Direct Oral Anticoagulants and Their Uses
drugs were assigned in a 1:1:1 ratio and given for a period of 12 months. Outcome analysis was observed during the 12-month treatment period. The primary efficacy end point was symptomatic recurrent VTE or death from any cause. The secondary efficacy end point was a composite of symptomatic recurrent VTE, death related to VTE, MI, stroke, or death secondary to any cardiovascular disease. The primary safety outcome was major bleeding. The secondary safety outcome was the composite of major or CRNM bleeding. Symptomatic recurrent VTE or death from any cause occurred in 11.6% of patients receiving placebo, 3.8% receiving the 2.5-mg dose of apixaban, and 4.2% receiving the 5-mg dose of apixaban (P<.001). Major bleeding occurred in 0.5% of the placebo group and 0.2% and 0.1% of the 2.5-mg and 5-mg apixaban dose groups, respectively, resulting in no significant difference. The composite outcome of symptomatic recurrent VTE, death caused by VTE, MI and stroke, cardiovascular death, or major bleeding occurred in 10.4% of patients taking placebo versus 2.4% of those receiving 2.5 mg and 2.5% of those receiving 5 mg of apixaban. During the 30-day follow-up after active drug was discontinued, symptomatic recurrent VTE occurred in 0.2% of patients in the placebo group, 0.4% in the 2.5-mg apixaban group, and 0.6% in the 5-mg apixaban group. The composite outcome of MI, stroke, or cardiovascular death occurred once each in the 2.5-mg and 5-mg apixaban groups and did not occur in the placebo group. The 2.5-mg twice daily dose is currently approved by the UFDA for extended therapy. EDOXABAN
The Hokusai VTE study25 design was similar to the RE-COVER study design in that all patients had initial therapy with parenteral anticoagulation (enoxaparin or UFH). After a minimum of 5 days of parenteral anticoagulation, patients were treated with oral edoxaban 60 mg daily or VKA targeting an INR of 2.0 to 3.0. The primary efficacy outcome of symptomatic VTE within 12 months from randomization occurred in 3.5% of patients receiving warfarin and 3.2% of patients receiving edoxaban (P 5 .001 for noninferiority). The primary safety outcome of a first major or CRNM event occurred in 8.5% of patients receiving edoxaban versus 10.3% of those receiving warfarin (P<.004). The Hokusai study showed that after at least 5 days of treatment with parenteral heparin, edoxaban at 60 mg daily was as effective as warfarin in reducing recurrent VTE, but was associated with fewer major or CRNM bleeding events. DIRECT ORAL ANTICOAGULANTS IN PREGNANCY
Because warfarin is a category X drug in pregnancy (contraindicated: animal or human studies showed fetal abnormalities), heparin and LMWH have been the only choices for anticoagulation during pregnancy. Although dabigatran, rivaroxaban, and edoxaban are category C in pregnancy (risk not ruled out: animal studies showed adverse effect and no human studies done), apixaban is category B (no risk in other studies: animal studies showed no risk or adverse fetal effects during all 3 trimesters, no human studies done). SUMMARY
The DOACs offer an exciting alternative to warfarin for a variety of thrombotic conditions, including nonvalvular AF and VTE. Their unique properties allow more predictable dosing and ease of use, avoid the need for perioperative bridging anticoagulation, and have similar or improved efficacy and reduced side effect risk
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compared with warfarin. Although they have now become the first-line choice for treatment of VTE and AF, there is still an important role for warfarin. For example, patients with mechanical valve replacement should not be treated with any DOAC. In addition, many patients are unable to afford these medications and warfarin remains a more attractive option. In addition, in patients with severe renal dysfunction, the DOACs should be avoided because a lack of renal clearance may lead to bleeding complications. Engaging patients in a shared decision-making process to identify the most appropriate anticoagulant and ensuring safe long-term management are essential for high-quality, patient-centered care. The nuances of anticoagulation with DOACs will continue to evolve with their increased use and the incumbency of additional information, providing a challenging aspect to this innovative nemesis to warfarin. REFERENCES
1. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009;48(1):1–22. 2. Alexander JH, Singh KP. Inhibition of factor Xa: a potential target for the development of new anticoagulants. Am J Cardiovasc Drugs 2005;5(5):279–90. 3. DeWald TA, Becker RC. The pharmacology of novel oral anticoagulants. J Thromb Thrombolysis 2014;37:217–33. 4. Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014; 64(11):1128–39. 5. Samama MM, Meddahi S, Samama CM. Pharmacology and laboratory testing of the oral Xa inhibitors. Clin Lab Med 2014;34(3):503–17. 6. January CT, Wann LS, Alpert JS, et al, ACC/AHA Task Force Members. 2014 AHA/ ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2014;130(23):2071–104. 7. Connolly SJ, Ezekowitz MD, Yusuf S, et al, RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. 8. Granger CB, Alexander JH, McMurray JJ, et al, ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. 9. Patel MR, Mahaffey KW, Garg J, et al, ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. 10. Sardar P, Chatterjee S, Lavie CJ, et al. Risk of major bleeding in different indications for new oral anticoagulants: insights from a metaanalysis of approved dosages from50 randomized trials. Int J Cardiol 2015;179:279–87. 11. Bouillon K, Bertrand M, Maura G, et al. Risk of bleeding and arterial thromboembolism in patients with non-valvular atrial fibrillation either maintained on a vitamin K antagonist or switched to a non-vitamin K-antagonist oral anticoagulant: a retrospective, matched-cohort study. Lancet Haematol 2015;2:e150–9. 12. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. REVERSE AD trial. N Engl J Med 2015;373:511–20.
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13. Lu G, DeGuzman FR, Hollenbach SJ. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19:446–51. 14. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015;373(25):2413–24. 15. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al, ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016;375(12):1131–41. 16. Hart RG, Diener HC, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 2012;43(6):1511–7. 17. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369(22):2093–104. 18. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342–52. 19. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129:764–72. 20. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709–18. 21. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–510. 22. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–97. 23. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799–808. 24. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699–708. 25. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406–15.
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a,b
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KEYWORDS Direct oral anticoagulants Warfarin Atrial fibrillation Venous thromboembolism
HOSPITAL MEDICINE CLINICS CHECKLIST
1. Anticoagulants are beneficial for treatment of venous thromboembolism and prevention of stroke in atrial fibrillation. 2. Direct oral anticoagulants (DOACs) are a growing alternative to warfarin because of their predictable pharmacokinetics and ease of use. 3. There is an advent of rapid and safe reversal agents for DOACs for use in situations of major bleeding and preprocedurally.
INTRODUCTION
Direct oral anticoagulants (DOACs) are rapidly gaining traction as the preferred method of oral anticoagulation for patients with nonvalvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), and for prophylaxis of deep vein thrombosis (DVT). Their predictable pharmacokinetic properties allow easy dosing regimens that avoid many of the difficulties and challenges associated with vitamin K antagonist (VKA) therapy. However, the DOAC agents pose unique challenges for health care providers, who have previously developed comfortable strategies to manage VKAs and must now adapt to a new class of medications. This article reviews the indications
a General Internal Medicine, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA 01805, USA; b Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02110, USA; c Department of Hospital Medicine, Lahey Health System, 41 Mall Road, Burlington, MA 01805, USA; d Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA 01805, USA; e Lahey Medical Center, 1 Essex Center Dr, Peabody, MA 01960, USA; f Beverly Hospital, 85 Herrick Street, Beverly, MA 01915, USA; g Addison Gilbert Hospital, 298 Washington Street, Gloucester, MA 01930, USA * Corresponding author. E-mail address: [email protected]
Hosp Med Clin - (2016) -–http://dx.doi.org/10.1016/j.ehmc.2016.11.004 2211-5943/16/ª 2016 Elsevier Inc. All rights reserved.
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and dosing considerations, clinical efficacy and safety, laboratory monitoring, and reversibility considerations of DOACs. DOACs include oral direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) and direct thrombin inhibitors such as dabigatran. MECHANISM OF ACTION AND PHARMACOLOGY Direct Thrombin Inhibitors
Dabigatran etexilate, a prodrug of dabigatran, is the only commercially available oral direct thrombin inhibitor, or inhibitor of factor IIa. Dabigatran is a small, synthetic molecule that specifically and reversibly inhibits free and clot-bound thrombin by binding to the active site of thrombin.1 Inhibition of thrombin attenuates formation of fibrin, reduces thrombin generation, and may limit platelet aggregation. Oral Activated Factor X Inhibitors
Factor Xa inhibitors bind directly to the active site of factor Xa, located at the convergence of the intrinsic and extrinsic pathways in the coagulation cascade. Inhibition at this site blocks thrombin generation from both pathways, and prevents subsequent amplification of thrombin generation, and thrombin-mediated activation of coagulation and platelets.2 The DOAC plasma concentration reaches their peak at 1 to 4 hours. Therefore, the therapeutic effect of DOACs occurs more rapidly and the risk of bleeding increases proportionately. The bioavailability of most of the DOACs is between 60% and 100%. The exception is dabigatran, which has low bioavailability, therefore requiring a higher dosage. The high bioavailability of DOACs contributes to a more predictable anticoagulant response, eliminating the need for routine monitoring. The metabolism of DOACs is mainly performed by the liver. There may be interpatient variability when these drugs are given to patients with moderate hepatic disease,3 and they must therefore be used with caution in such patients. Most of the DOACs are excreted renally, with primary excretion rates ranging from 60% to 85%, except for apixaban and edoxaban, which have a much lower excretion rates. Therefore, patients with impaired renal function can have increased plasma drug concentrations. LABORATORY MONITORING OF DIRECT ORAL ANTICOAGULANTS
With the use of VKA for anticoagulation, clinicians have become accustomed to checking International Normalized Ratio (INR) values to assess how well patients are being anticoagulated and adjust VKA dosing. The DOACs challenge this paradigm by offering predictable pharmacokinetics, thus eliminating the need for routine laboratory monitoring. However, there are certain clinical scenarios when laboratory monitoring is clinically warranted, such as before urgent or emergent surgery, when assessing medication compliance, and for ensuring adequate anticoagulation in patients at the extremes of weight. A few routine laboratory tests are available that, when properly calibrated, can offer insight into the degree of anticoagulation for patients taking DOACs. For patients taking dabigatran, a normal thrombin time can be used to rule out any clinically relevant anticoagulation.4 The dilute thrombin time is the best option for assessing whether patients are appropriately or overly anticoagulated, but this test is not universally available. A normal activated partial thromboplastin time likely excludes supratherapeutic levels of dabigatran. For patients taking rivaroxaban, apixaban, or edoxaban, use of the anti-Xa activity can reliably assess the degree of anticoagulation across a wide range of drug concentrations, including subtherapeutic, therapeutic, and supratherapeutic levels.5 This
Direct Oral Anticoagulants and Their Uses
assessment is best done using a calibrated anti-Xa activity for each individual factor Xa inhibitor. However, when calibrated anti-Xa activity levels are not available, a generic chromogenic anti-Xa activity at a normal level is likely to rule out meaningful levels of any factor Xa inhibitor. A normal prothrombin time is likely to exclude supratherapeutic levels of the anti-Xa inhibitors. Perhaps more relevant to most patients is the need for regular, ongoing renal function monitoring. Each of the DOACs is, at least in part, cleared by the kidneys. Therefore, patients require periodic assessment of renal function to determine when dose adjustments are necessary or whether their use is contraindicated. The American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines on the use of DOACs outlines that renal function should be evaluated before initiation of DOACs and reassessed when clinically indicated (at least annually).6 Note that all major trials of DOACs versus warfarin for stroke prevention in AF used the Cockcroft-Gault equation to estimate renal function. Although many electronic medical records automatically calculate estimated creatinine clearance (CrCl) or glomerular filtration rates, these are often done using the Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration equations and can have significantly disparate values from the Cockcroft-Gault estimate. Therefore, clinicians should calculate the CrCl and clearly document this value at appropriate intervals and when assessing DOAC dosing. REVERSIBILITY OF DIRECT ORAL ANTICOAGULANTS
The meta-analysis of primary studies in AF showed lower rates of major bleeding with the DOACs compared with warfarin in Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)7 with dabigatran and Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)8 with apixaban. Rate of major bleeding was neutral in the Rivaroxaban Once daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF)9 with rivaroxaban. The DOACs reduced the relative risk of intracranial bleeding compared with warfarin. However, they showed higher rates of major gastrointestinal (GI) bleeding with the DOACs compared with warfarin in the same studies.10 Although several meta-analyses and major published clinical trials suggested that DOACs do not increase the risk of significant bleeding, a lack of antidote always concerned clinicians because, in emergency situations, the bleeding might need to be reversed. Bleeding associated with warfarin can be predictably managed with close monitoring of INR and reversal with fresh frozen plasma (FFP) and vitamin K. Neither FFP nor vitamin K is effective to reverse the effects of DOACs.11 Activated charcoal has been shown, in vitro, to absorb 99.9% of dabigatran suspended in acidic water. This treatment option could be useful in cases of acute intoxication. However, the efficacy of activated charcoal has not been tested in clinical practice. Desmopressin (D-arginine-deamino-vasopressin) increases the coagulation activity by stimulating the release of factor VIII and von Willebrand factor from the vascular endothelium. However, no clinical trials have evaluated the efficacy in bleeding patients on DOACs. Prothrombin complex concentrate (PCC) is a mixture of inactive factors II, IX, X, and VII. Studies on the efficacy of PCC in the reversal of the anticoagulant effect have shown inconsistent results. The activated PCC has been the most reasonable alternative for reversing dabigatran effect until recently. Clinical trials with a humanized antibody fragment directed against dabigatran (idarucizumab) and recombinant, modified factor Xa (andexanet alfa) have recently been completed.
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IDARUCIZUMAB
Idarucizumab, which is a humanized monoclonal antibody fragment (Fab), binds both free and thrombin-bound dabigatran. A prospective cohort study was performed to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B).12 The primary end point was the percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, by the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. Idarucizumab normalized the test results in 88% to 98% of the patients, an effect that was evident within minutes. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33 patients, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. ANDEXANET ALFA
Andexanet is a reversal agent that is designed to neutralize the anticoagulant effects of both direct and indirect factor Xa inhibitors. Andexanet binds and removes factor Xa inhibitors, thereby enhancing the activity of endogenous factor Xa and attenuating levels of anticoagulant activity. This activity is assessed by measurement of thrombin generation and anti–factor Xa activity.13 For each factor Xa inhibitor (apixaban and rivaroxaban), a 2-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percentage change in anti–factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. Andexanet alfa reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without serious adverse or thrombotic events.14 Subsequently, a multicenter, prospective, open-label, singlegroup study evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor.15 The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Among the apixaban-treated participants, anti–factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), compared with 21% among those who received placebo (9 participants) (P<.001). Among the rivaroxaban-treated participants, anti– factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), compared with 18% among those who received placebo (14 participants) (P<.001). No serious adverse or thrombotic events were reported. In conclusion, andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older, healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. CIRAPARANTAG (PER977)
Ciraparantag, is an intravenously administered synthetic small molecule for use as a broad-spectrum reversal agent for anticoagulants, including low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), and the DOACs that is currently being studied in phase II clinical trials.
Direct Oral Anticoagulants and Their Uses
DIRECT ORAL ANTICOAGULANTS IN ATRIAL FIBRILLATION
Anticoagulation is important in stroke prevention in patients with atrial fibrillation (AF). There are multiple factors that contribute to the risk of thromboembolism in patients with AF. Several scoring systems are used for risk stratification. The 2014 ACC/ AHA/HRS guidelines recommend using CHA2DS2-VASc score.6 When using this score, 1 point is assigned for the presence of each of the following: congestive heart failure, hypertension, age (65–74 years, 1 point; 75 years, 2 points), diabetes, prior stroke or transient ischemic attack (TIA) (2 points), vascular disease (myocardial infarction [MI], peripheral arterial disease [PAD], and carotid disease), and sex (female) with a maximum of 9 points. The anticoagulation/antiplatelet therapy recommended for the groups of patients is as follows: 1 point, no therapy, acetylsalicylic acid (75 or 325 mg daily), or oral anticoagulation (OAC); and 2 points or more, OAC (VKA or DOACs). The currently US Food and Drug Administration (FDA)–approved DOACs include 1 direct thrombin inhibitor (dabigatran) and several factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). In the 2014 ACC/AHA guidelines (published before edoxaban approval), dabigatran, apixaban, and rivaroxaban are recommended for use in patients with NVAF who have had prior stroke or TIA, or are at risk by virtue of a CHA2DS2-VASc score of 2 or more. In addition, DOACS are recommended if it is not possible to maintain therapeutic INR with VKA. It must be remembered that DOACs have not been studied in patients with valvular AF, which includes mitral stenosis, mechanical or bioprosthetic valves, and mitral valve repair. DABIGATRAN
The RE-LY trial compared different dosages of dabigatran with warfarin in patients with AF.7 Enrolled patients received fixed dosages of dabigatran (110 or 150 mg twice daily) or warfarin. The primary outcome was stroke or systemic embolism. In patients with AF, dabigatran administered at a dose of 150 mg, compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. Dabigatran given at a dose of 110 mg was associated with similar rates of stroke and systemic embolism to those associated with warfarin, but lower rates of major hemorrhage. At present, dabigatran is available in 2 FDA-approved dosages: 150 mg twice a day or 75 mg twice a day (for patients with CrCl 15–30 mL/min). Subgroup analysis showed a higher risk of intracranial hemorrhage in patients greater than 75 years of age and on the higher 150 mg twice daily dose. Thus, caution should be used in patients with renal impairment or those who are greater than 75 years of age.16 DIRECT FACTOR XA INHIBITORS
At present, there are 3 factor Xa inhibitors available in the United States: rivaroxaban, apixaban, and edoxaban. RIVAROXABAN
The ROCKET AF trial randomized patients to rivaroxaban versus warfarin with the primary end point of stroke or systemic embolism.9 The primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio [HR] in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66–0.96; P<.001 for noninferiority). The risk of major bleeding was not different between the two groups (14.9% in rivaroxaban vs 14.5% in warfarin groups); however, intracranial bleeding occurred less often in the rivaroxaban group compared
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with warfarin (0.5% vs 0.7%; P 5 .02). Risk of GI bleeding was higher in the rivaroxaban group (3.2% vs 2.2%; P<.001). In patients with AF, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. At present, rivaroxaban is available in 2 FDA-approved dosages: 20 mg daily or 15 mg daily for patients with CrCl of 15 to 49 mL/min. APIXABAN
ARISTOTLE was a large noninferiority trial comparing apixaban with warfarin, with stroke or systemic embolism as the primary outcome.8 The trial was also designed for secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. The rate of the primary outcome was 1.27% per year in the apixaban group versus 1.60% per year in the warfarin group (HR with apixaban, 0.79; 95% CI, 0.66–0.95; P<.001 for noninferiority; P 5 .01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, compared with 3.09% per year in the warfarin group (HR, 0.69; 95% CI, 0.60– 0.80; P<.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (HR, 0.89; 95% CI, 0.80–0.99; P 5 .047). It concluded that, in patients with AF, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. EDOXABAN
Edoxaban is the newest approved direct factor Xa inhibitor. ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial FibrillationThrombolysis in Myocardial Infarction Study 48) compared the use of edoxaban with warfarin with regard to stroke and systemic embolism.17 Compared with warfarin, the high-dose (60 mg) edoxaban showed superiority in preventing stroke or systemic emboli (HR, 0.79; P<.001), and low-dose (30 mg) edoxaban was noninferior (HR, 1.07; P 5 .005). The rate of major bleeding, including intracranial bleeding, was lower with edoxaban compared with warfarin, regardless of the dose. However, the rate of GI bleeding was higher in the high-dose edoxaban group compared with warfarin (HR, 1.23; P 5 .03). DIRECT ORAL ANTICOAGULANTS IN VENOUS THROMBOEMBOLISM
Clinical trials have been designed to study the efficacy of DOACs in VTE for shortterm, long-term, and extended-term treatment. Short-term treatment is defined as the therapy initiated at the time of diagnosis and continued for 5 to 7 days, which is the necessary time for overlap for VKA to become sufficiently therapeutic. Longterm therapy is defined as treatment extending 3 to 12 months from the initiation of anticoagulation, and is thought to be the proper duration of anticoagulation for most patients with an initial thromboembolic event. Extended treatment is recommended for patients who have had recurrent VTE and are at low or moderate risk of bleeding. DABIGATRAN
The RE-COVER18 and RE-COVER II19 studies had similar trial designs evaluating patients with acute VTE. Both were designed as noninferiority trials comparing the same initial therapy, consisting of parenteral anticoagulation (UFH or LMWH, or
Direct Oral Anticoagulants and Their Uses
fondaparinux) followed by randomization for long-term treatment to either dabigatran 150 mg twice daily or warfarin. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed VTE and related deaths for both studies. In the RE-COVER trial, the primary outcome of recurrent VTE at 6 months was 2.4% in the dabigatran-treated patients versus 2.1% in the warfarin group (P<.001 for noninferiority). Major bleeding occurred in 1.6% versus 1.9% of the dabigatran-treated and warfarin-treated patients, respectively (P 5 .38). As might be anticipated, the results from RE-COVER II were virtually identical to those observed in RE-COVER. The primary efficacy outcome of recurrent VTE was 2.3% and 2.2% in the dabigatran and warfarin groups, respectively (P<.001 for noninferiority). Major bleeding occurred in 1.2% and 1.7% of patients in the dabigatran and warfarin groups. Any bleeding occurred in 15.6% of the patients on dabigatran versus 22.1% of the patients on warfarin. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Dabigatran was the first DOAC studied to assess the risks and benefits of extended therapy and compared an active control (VKA) with placebo for prevention of VTE recurrence. The active-controlled study was RE-MEDY20 and the placebocontrolled study was RE-SONATE.20 The active-controlled study was designed to evaluate whether dabigatran was noninferior to warfarin in preventing recurrent VTE. The placebo-controlled study was designed to evaluate whether extended treatment with dabigatran was superior to placebo in preventing recurrent VTE. In the active-controlled RE-MEDY study, the primary efficacy outcome was recurrent VTE, which occurred in 1.8% of the patients on dabigatran and 1.3% of the patients on VKA. Dabigatran met the noninferiority margin for prevention of recurrent VTE (P 5 .01). Major bleeding occurred in 0.9% of the dabigatran group and 1.8% of the warfarin group (P 5 .06). Major or clinically relevant nonmajor (CRNM) bleeding occurred in 5.6% of the patients on dabigatran and 10.2% of warfarin-treated patients (P 5 .001). Of the patients on dabigatran, 0.9% had acute ischemic coronary events during treatment, compared with 0.2% of warfarin-treated patients (P 5 .02). In the placebo-controlled RE-SONATE trial, the primary efficacy outcome for recurrence during the first 6 months occurred in 0.4% of the dabigatran group and 5.6% of the placebo group (HR, 0.08; P 5 .001). After the extended 12-month follow-up, the recurrence rate was 6.9% in the dabigatran group compared with 10.7% in the placebo group (HR, 0.61; P 5 .03). Protection from recurrent VTE was provided during administration of dabigatran; however, once active drug was terminated, the rate of recurrence in the dabigatran group was similar to the rate of recurrence in the matching placebo group. There was no difference in major bleeding between the dabigatran and placebo groups. Major or CRNM bleeding occurred in 5.3% of patients in the dabigatran group compared with 1.8% in the placebo group (P 5 .001). Only 1 acute coronary event occurred in each treatment group. RIVAROXABAN
The EINSTEIN investigators21 studied oral rivaroxaban for symptomatic VTE and symptomatic pulmonary embolism (PE).22 In their first study, patients with symptomatic proximal DVT with or without PE were randomized to rivaroxaban or enoxaparin followed by warfarin, targeting an INR of 2.0 to 3.0. During initial therapy with rivaroxaban, patients received 15 mg twice daily for 3 weeks, then were converted to 20 mg daily for 3 to 12 months. The primary efficacy outcome of symptomatic recurrent VTE occurring during the 3-month to 12-month treatment period, occurred in 3.0% of the
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enoxaparin-VKA group and 2.1% of the rivaroxaban-treated group (HR<0.68; P 5 .001 for noninferiority and P<.08 for superiority). The primary safety outcome of major and CRNM bleeding was 8.1% for both the treatment groups (HR<0.97; P<.77). The EINSTEIN-PE study22 was similarly designed, and it randomized 4833 patients with confirmed symptomatic PE, with or without DVT. Patients were similarly treated after randomization with either rivaroxaban 15 mg twice daily for 3 weeks and converted to 20 mg daily for 3 to 12 months or with open-label enoxaparin 1 mg/kg twice daily and converted to warfarin with a target INR of 2.0 to 3.0. The primary efficacy outcome was symptomatic recurrent VTE occurring during the 3-month to 12-month treatment period. The primary safety outcome was major and CRNM bleeding. Results revealed a 2.1% recurrence rate in the rivaroxaban-treated patients versus a 1.8% recurrence rate in patients receiving conventional therapy (HR<1.12; P<.003 for noninferiority). Major and CRNM bleeding occurred in 10.3% of the rivaroxaban-treated patients versus 11.4% of the warfarin group (HR<0.90; P<.23). The EINSTEIN investigators21 additionally performed a double-blind extended-treatment study in patients with confirmed VTE who were treated for 6 to 12 months with therapeutic anticoagulation. This study was an event-driven superiority trial assuming a primary outcome of 3.5% in the placebo group and a 70% risk reduction with rivaroxaban. Patients were then randomized and assigned to receive continued treatment with rivaroxaban 20 mg daily for 6 to 12 months or with placebo. The primary efficacy outcome was symptomatic recurrent VTE and the primary safety outcome was major bleeding. The net clinical benefit was calculated for both the groups and was defined as the composite of symptomatic recurrent VTE or major bleeding. The primary efficacy outcome occurred in 1.3% of the rivaroxaban group compared with 7.1% of the placebo group (P 5 .001), resulting in a relative risk reduction of 82%. The principal safety outcome of major bleeding occurred in 0.7% of the rivaroxaban-treated patients and in no patients in the placebo group (P 5 .11). Net clinical benefit occurred in 2% of patients receiving rivaroxaban and 7.1% receiving placebo (P<.001). Efficacy and safety outcomes were consistent across the prespecified subgroups. APIXABAN
The AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) investigators23 studied apixaban versus conventional therapy for patients with acute VTE. Patients (N 5 5400) with symptomatic proximal DVT or PE were randomized to apixaban 10 mg twice daily for 7 days and converted to 5 mg twice daily for a period of 6 months versus conventional anticoagulation with enoxaparin 1 mg/kg twice daily and warfarin targeting an INR of 2.0 to 3.0. The primary efficacy outcome was a composite of recurrent symptomatic VTE or death related to VTE. The primary safety outcome was major bleeding. The primary efficacy outcome occurred in 2.3% of the apixaban-treated patients versus 2.7% of those treated with conventional anticoagulation (P<.001 for noninferiority). Major bleeding occurred in 0.6% of apixaban-treated patients versus 1.8% of those given warfarin (P<.0001 for superiority). There was no difference observed in the outcomes in patients presenting with acute symptomatic DVT versus those presenting with acute PE. The AMPLIFY-EXT (Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment) investigators evaluated 2 doses of apixaban (5 mg twice daily and 2.5 mg twice daily) versus placebo in a randomized, double-blind study of 2486 patients who had completed 6 to 12 months of anticoagulation for symptomatic VTE.24 The study drugs and placebo
Direct Oral Anticoagulants and Their Uses
drugs were assigned in a 1:1:1 ratio and given for a period of 12 months. Outcome analysis was observed during the 12-month treatment period. The primary efficacy end point was symptomatic recurrent VTE or death from any cause. The secondary efficacy end point was a composite of symptomatic recurrent VTE, death related to VTE, MI, stroke, or death secondary to any cardiovascular disease. The primary safety outcome was major bleeding. The secondary safety outcome was the composite of major or CRNM bleeding. Symptomatic recurrent VTE or death from any cause occurred in 11.6% of patients receiving placebo, 3.8% receiving the 2.5-mg dose of apixaban, and 4.2% receiving the 5-mg dose of apixaban (P<.001). Major bleeding occurred in 0.5% of the placebo group and 0.2% and 0.1% of the 2.5-mg and 5-mg apixaban dose groups, respectively, resulting in no significant difference. The composite outcome of symptomatic recurrent VTE, death caused by VTE, MI and stroke, cardiovascular death, or major bleeding occurred in 10.4% of patients taking placebo versus 2.4% of those receiving 2.5 mg and 2.5% of those receiving 5 mg of apixaban. During the 30-day follow-up after active drug was discontinued, symptomatic recurrent VTE occurred in 0.2% of patients in the placebo group, 0.4% in the 2.5-mg apixaban group, and 0.6% in the 5-mg apixaban group. The composite outcome of MI, stroke, or cardiovascular death occurred once each in the 2.5-mg and 5-mg apixaban groups and did not occur in the placebo group. The 2.5-mg twice daily dose is currently approved by the UFDA for extended therapy. EDOXABAN
The Hokusai VTE study25 design was similar to the RE-COVER study design in that all patients had initial therapy with parenteral anticoagulation (enoxaparin or UFH). After a minimum of 5 days of parenteral anticoagulation, patients were treated with oral edoxaban 60 mg daily or VKA targeting an INR of 2.0 to 3.0. The primary efficacy outcome of symptomatic VTE within 12 months from randomization occurred in 3.5% of patients receiving warfarin and 3.2% of patients receiving edoxaban (P 5 .001 for noninferiority). The primary safety outcome of a first major or CRNM event occurred in 8.5% of patients receiving edoxaban versus 10.3% of those receiving warfarin (P<.004). The Hokusai study showed that after at least 5 days of treatment with parenteral heparin, edoxaban at 60 mg daily was as effective as warfarin in reducing recurrent VTE, but was associated with fewer major or CRNM bleeding events. DIRECT ORAL ANTICOAGULANTS IN PREGNANCY
Because warfarin is a category X drug in pregnancy (contraindicated: animal or human studies showed fetal abnormalities), heparin and LMWH have been the only choices for anticoagulation during pregnancy. Although dabigatran, rivaroxaban, and edoxaban are category C in pregnancy (risk not ruled out: animal studies showed adverse effect and no human studies done), apixaban is category B (no risk in other studies: animal studies showed no risk or adverse fetal effects during all 3 trimesters, no human studies done). SUMMARY
The DOACs offer an exciting alternative to warfarin for a variety of thrombotic conditions, including nonvalvular AF and VTE. Their unique properties allow more predictable dosing and ease of use, avoid the need for perioperative bridging anticoagulation, and have similar or improved efficacy and reduced side effect risk
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compared with warfarin. Although they have now become the first-line choice for treatment of VTE and AF, there is still an important role for warfarin. For example, patients with mechanical valve replacement should not be treated with any DOAC. In addition, many patients are unable to afford these medications and warfarin remains a more attractive option. In addition, in patients with severe renal dysfunction, the DOACs should be avoided because a lack of renal clearance may lead to bleeding complications. Engaging patients in a shared decision-making process to identify the most appropriate anticoagulant and ensuring safe long-term management are essential for high-quality, patient-centered care. The nuances of anticoagulation with DOACs will continue to evolve with their increased use and the incumbency of additional information, providing a challenging aspect to this innovative nemesis to warfarin. REFERENCES
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