Overview of the Direct Oral Anticoagulants

Transcription

1 Original Article Nedaa Skeik, MD Abhishek Sethi Michele Shepherd, PharmD From: Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, MN Address for correspondence: Nedaa Skeik, MD Minneapolis Heart Institute 920 E 28th Street, #300 Minneapolis, Minnesota Tel: Nedaa.Skeik@allina.com Overview of the Direct Oral Anticoagulants ABSTRACT Over the past 6 decades, warfarin has proven efficacious in reducing stroke risk in patients with atrial fibrillation and reducing the risk of recurrent venous thromboembolism in patients with acute deep vein thrombosis or pulmonary embolism. However, there have been multiple challenges with using warfarin including delayed onset of action, need for bridging and monitoring as well as many drug-drug and drug-food interactions. Hence, long years of research have led to the development of direct oral anticoagulants. Of the 4 direct oral anticoagulants currently approved by the Food and Drug Administration, 1 is a direct thrombin inhibitor (dabigatran) and the other 3 are direct factor Xa inhibitors (apixaban, rivaroxaban and edoxaban). Direct oral anticoagulants have been found to be at least as effective as warfarin with fewer bleeding complications. This paper provides an overview of the evolution of anticoagulation therapies and an extensive literature review of the new direct oral anticoagulants. KEY WORDS anticoagulation, direct oral anticoagulant, bleeding n INTRODUCTION In the 1920s, cattle in Canada and the northern United States suffered from severe internal bleeding that was associated with diet. It was discovered that spoiled sweet clover hay (Melilotus alba and Melilotus officinalis) contained a hemorrhagic factor, a coumarin compound that was isolated and named dicoumarol, that reduced the activity of prothrombin. 1,2 A related derivative, warfarin, was initially used as a rodenticide and eventually moved to clinical application. Warfarin acts as an inhibitor of vitamin K epoxidase reductase, which catalyzes the reduction of oxidized vitamin K. 3 The latter is essential for the carboxylation of coagulation proteins for factors II, VII, IX, and X. 4,5 Based on multiple clinical trials, warfarin was proven to reduce stroke risk in patients with atrial fibrillation (AF) and to reduce recurrent venous thromboembolism (VTE) after the initial event. 6 However, warfarin has multiple pitfalls including delayed therapeutic onset, interindividual variability in anticoagulant effect, significant drug-drug and drug-food interactions, dietary restrictions, and an increased need for monitoring. 4,7 Research to develop more convenient new anticoagulation therapies with better efficacy and fewer side effects has been ongoing for decades. Based on their mechanism of action, the direct oral anticoagulants (DOACs) can be divided into 2 groups: direct thrombin (factor IIa) and direct FXa inhibitors. 4 The effects of DOAC are seen within a few hours of ingestion, generally require no monitoring, and have fewer drug-drug interactions when compared with warfarin. Furthermore, they have been proven to be at least as effective as warfarin with fewer bleeding complications. 8,9 The Food and Drug Administration (FDA) has approved idarucizumab as a specific antidote to dabigatran and is currently considering andexanet alfa as a reversal agent for the available anti-xa agents. This paper will review the novel anticoagulant therapies and highlight management of bleeding caused by these agents. Ó by the Minneapolis Heart Institute Foundation n DIRECT THROMBIN INHIBITORS Thrombin is an important clotting factor that catalyzes the production of fibrin from fibrinogen and activates factors V, VIII, XI, and XIII. 1 3 Given that thrombin also strongly activates platelet aggregation, it has been an important target for anticoagulation therapy. Multiple intravenous thrombin inhibitors, including argatroban, hirudin, bivalirudin, lepirudin, and desirudin, have been primarily used to manage patients with heparin-induced thrombocytopenia (HIT). Dabigatran is the only oral direct thrombin inhibitor that is currently approved to reduce the risk of 38 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January 2017

2 SKEIK ET AL stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF) as well as to manage patients with VTE or who are at risk for VTE. 1,4 n DABIGATRAN In October of 2010, dabigatran was the first DOAC to receive FDA approval to reduce stroke and SE risk in patients with NVAF. Later, it received approval for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE; 5 10 days after initial therapy with parenteral anticoagulation), reduction of recurrent risk after initial anticoagulation therapy for DVT and PE and finally reduction of DVT and PE risk in patients undergoing total hip replacement (THR; Table 1). 5 It is not currently indicated to reduce DVT risk in patients undergoing total knee replacement (TKR). Idarucizumab is a monoclonal antibody that received FDA approval in 2015 as a specific antidote for dabigatran. 5 Pharmacology and Dosage Dabigatran etexilate is a prodrug that is hepatically converted to its active form, dabigatran (Tables 1,2). 4,6 Binding to plasma proteins is approximately 35% here]. Maximum serum concentration (T max )isreached1to3 hours post-administration and the half-life is 12 to 17 hours in healthy patients. 5 Dabigatran s duration of action is about 24 hours in patients with normal renal function, but can be up to 5 days in patients with renal insufficiency. 4 A total of 80% of dabigatran is excreted via the renal system. Dabigatran is available as 75-, 110-, and 150-mg capsules. For nonvalvular atrial fibrillation, the dosage is based on the patient s creatinine clearance (CrCl; 150 mg twice daily in patients with a CrCl.30 ml/min or 75 mg twice daily if CrCl is ml/min). The 75- mg dosage was not clinically studied and was based on pharmacokinetic data. For the initial and extended management of VTE, the dosage is 150 mg twice daily if CrCl.30 ml/min. For prophylaxis of DVT and PE after THR, the dosage is 110 mg for the first day, then 220 mg daily for 28 to 35 days after surgery. 5 Dabigatran has not been clinically studied and thus is not FDA approved, for NVAF with CrCl,15 ml/ min. It is not indicated for initial or extended management of VTE and DVT prophylaxis after THR with CrCl 30 ml/min. 5 Dabigatran is a substrate of the efflux permeability glycoprotein (P-gp) transporter, which pumps dabigatran into the intestinal lumen and the proximal tubules of the kidney. Inhibitors of P-gp (eg, amiodarone, dronedarone, quinidine, systemic ketoconazole, and verapamil) prevent excretion of dabigatran and increase the dabigatran plasma concentration and the risk of bleeding. 4,6 While patients with NVAF and CrCl,30 ml/min or with VTE and CrCl,50 ml/min should avoid using P-gp inhibitors with dabigatran, dabigatran dosage should be reduced to 75 mg twice daily in patients with NVAF and CrCl 30 to 50 ml/min. In contrast, P-gp inducers (eg, rifampin, carbamazepine, and St. John s wort) promote the excretion of dabigatran resulting in lower plasma levels and thus should not be used with dabigatran. 4,6 Concurrent use of dabigatran and antiplatelet therapy should be considered only if risk of thrombosis outweighs the risk of bleeding. Common side effects of dabigatran include bleeding, dyspepsia, abdominal pain, gastrointestinal (GI) bleeding, and thrombocytopenia. Severe hypersensitivity reaction is very rare, occurring in less than 0.1% of patients. 4 In the RE-LY trial (randomized evaluation of long-term anticoagulation therapy), the discontinuation rate of dabigatran in the first and second years was 16% and 21%, and for warfarin it was 10% and 17%, respectively. 4,7 Hepatitis risk was similar for dabigatran (150 mg) and warfarin at 1.9% and 2.2%, respectively. 1,4,7 Clinical Trials NVAF. The RE-LY trial compared dabigatran to warfarin in patients with NVAF plus 1 risk factor, with the primary efficacy endpoint of stroke and SE and the primary safety endpoint of major bleeding (Table 3). Dabigatran (150 mg twice daily) was found to be superior (P,.001) and dabigatran (110 mg twice daily) was noninferior to warfarin for risk reduction of ischemic stroke and SE. 4,8 Both doses of dabigatran demonstrated a lower risk of hemorrhagic stroke (P,.001). Furthermore, the risk of major bleeding was significantly lower with dabigatran 110 mg twice daily (P ¼.003), and similar with 150 mg twice daily (P ¼.31) when compared with warfarin. 8 However, there was a trend toward a higher risk of major bleeding in patients who were 75 years or older (P ¼.07; P for interaction,.001), mostly observed for extracranial bleeding (especially GI). 10 While dabigatran 110 mg twice daily had a similar risk for GI bleeding as warfarin (P ¼.43), the risk was significantly higher with dabigatran 150 mg twice daily (P,.001). Management of VTE. The RE-COVER trial (efficacy and safety of dabigatran compared to warfarin for 6 month treatment of acute symptomatic venous thromboembolism) studied the efficacy and safety of oral dabigatran 150 mg twice daily compared with warfarin (target INR: 2 3) for 6-month treatment of acute symptomatic VTE following 5 to 10 days of JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January

3 DOACS TABLE 1 Indications and dosage of DOACs. Apixaban Edoxaban Rivaroxaban Dabigatran NVAF 5 mg orally twice daily 2.5 mg orally twice daily if 2 ofthe following: age 80 years, weight 60 kg, or Cr 1.5 mg/dl Usage if CrCl,15 ml/min is based on pharmacokinetics and not on clinical studies. Caution is advised VTE Treatment 10 mg orally twice daily for 7 days, then 5 mg orally twice daily No dose adjustment based on renal function Usage if CrCl,15 ml/min is based on pharmacokinetics and not on clinical studies. Caution is advised VTE Secondary Prevention VTE Prophylaxis in THR/TKR 2.5 mg orally twice daily CrCl,25 ml/min: no clinical studies Start hours postop THR: 2.5 mg twice daily orally for 35 days TKR: 2.5 mg twice daily orally for 12 days CrCl,30 ml/min: no clinical studies CrCl.95 ml/min: not recommended (drug may be cleared too rapidly and adequate drug levels not attained) CrCl ml/min: 60 mg orally once daily CrCl ml/min: 30 mg orally once daily CrCl,15 ml/min: not recommended Begin after 5 10 days of initial therapy with a parenteral anticoagulant CrCl.50 ml/min: 60 mg orally once daily CrCl ml/min, weight 60 kg, or on P-gp inhibitor: 30 mg orally once daily CrCl.50 ml/min: 20 mg orally daily with evening meal CrCl ml/min: 15 mg orally daily with evening meal CrCl,15 ml/min: not recommended CrCl.30 ml/min: 15 mg orally twice daily for 21 days, then 20 mg orally daily CrCl,30 ml/min: not recommended Not approved CrCl.30 ml/min: 20 mg orally daily CrCl,30 ml/min: not recommended Not approved Start 6 10 hours postop THR: 10 mg orally daily for 35 days TKR: 10 mg orally daily for 12 days Avoid in CrCl,30 ml/min CrCl.30 ml/min: 150 mg orally twice daily CrCl ml/min: 75 mg orally twice daily CrCl,15 ml/min: not recommended An initial 5 10 days of parenteral anticoagulation is required before initiating dabigatran CrCl.30 ml/min: 150 mg orally twice daily CrCl 30 ml/min: not recommended CrCl.30 ml/min: 110 mg for the first day, then 220 mg orally daily CrCl 30 ml/min or on dialysis: dosing recommendations not available CrCl,50 ml/min with concomitant use of P-gp inhibitor: avoid coadministration TKR not approved Dosage Forms Tablets: 2.5, 5 mg Tablets: 15, 30, 60 mg Tablets: 10, 15, 20 mg Capsules: 75, 110, 150 mg Close bottle immediately after use. Keep tightly closed. Keep in original container; remove only at time of use. Do not put in pillbox or medication organizer. Use within 4 months after opening bottle. Unless otherwise indicated, Table 1 lists FDA-approved indications and dosages. 40 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January 2017

4 SKEIK ET AL TABLE 2 Drug Interactions with DOACs. Apixaban Edoxaban Rivaroxaban Dabigatran P-gp inhibitors NVAF þ CrCl ml/min: consider dabigatran 75 mg twice daily NVAF þ CrCl ml/min: avoid VTEþ CrCl,50 ml/min: avoid Can lead to increased exposure to dabigatran and risk of bleeding P-gp inducers Avoid use Can lead to reduced exposure to dabigatran and may decrease efficacy Anticoagulants, antiplatelets, NSAIDs, SSRIs, SNRIs May increase bleeding risk Combined P-gp and strong CYP3A4 inhibitors Avoid use Can lead to increased exposure of rivaroxaban (from 30% 160%) and increase bleeding risk Combined P-gp and strong CYP3A4 inducers Avoid use Can lead to decreased exposure (up to 50%) and may decrease efficacy Combined P-gp and moderate CYP3A4 inhibitor CrCl ml/min: avoid use unless benefit. risk Anticoagulants, antiplatelets, NSAIDs, SSRIs, SNRIs May increase bleeding risk P-gp inhibitors NVAF: no dose reduction recommended with concomitant use VTE treatment: 30 mg orally once daily Anticoagulants, antiplatelets, NSAIDs May increase bleeding risk P-gp inducers Avoid use Combined P-gp and strong CYP3A4 inhibitors.2.5 mg twice daily: reduce dose by 50% 2.5 mg twice daily: avoid use Can lead to increased exposure to apixaban and increase the risk of bleeding Combined P-gp and strong CYP3A4 inducers Avoid use Can lead to decreased exposure to apixaban and may decrease efficacy Anticoagulants, antiplatelets, NSAIDs, SSRIs, and SNRIs May increase bleeding risk NSAID, nonsteroidal anti-inflammatory drug; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. parenteral anticoagulation. 8 Dabigatran was found to be noninferior (P,.001) to warfarin for recurrent VTE and VTE-related death without a significant increase in major bleeding risk (hazard ratio [HR] 0.82; 95% confidence interval [CI], ). The RE-MEDY (a phase III, randomised, multicenter, double-blind, parallel-group, active controlled study to evaluate the efficacy and safety of oral dabigatran etexilate [150 mg twice daily] compared to warfarin [INR ] for the secondary prevention of venous thromboembolism) and RE-SONATE (twice-daily oral direct thrombin inhibitor dabigatran etexilate in the long-term prevention of recurrent symptomatic proximal venous thromboembolism in patients with symptomatic deep-vein thrombosis or pulmonary embolism) trials investigated the extended use of dabigatran 150 mg twice daily versus warfarin (RE- MEDY) or placebo (RE-SONATE) in preventing recurrent VTE for those patients who completed at least 3 months of anticoagulation. The RE-MEDY trial found that dabigatran was noninferior to warfarin (P ¼.01) with a lower risk of major or clinically relevant bleeding. 9 In the RE-SONATE trial, the recurrent VTE risk was significantly lower with dabigatran than placebo (P,.001), but there was an increase in major or clinically relevant bleeding risk in the dabigatran group (HR, 2.92; 95% CI, ). 9 The RE-NOVATE (a phase III randomised, parallel group, double-blind, active controlled study to investigate the efficacy and safety of orally administered 220 mg dabigatran etexilate capsules [110 mg administered on the day of surgery followed by 220 mg once daily] compared to subcutaneous 40 mg enoxaparin once daily for days, in prevention of venous thromboembolism in patients with primary elective total hip arthroplasty surgery) and RE- MODEL (thromboembolism prevention after knee surgery). Two different dose regimens of orally administered dabigatran etexilate capsules [150 or 220 mg once daily starting with a half dose (ie, 75 or 110 mg) on the day of surgery] compared to subcutaneous enoxaparin 40 mg once daily for 6-10 days) trials investigated 2 doses of dabigatran (150 or 220 mg twice daily) compared with subcutaneous (SQ) enoxaparin 40 mg once daily to prevent DVT in patients undergoing THR or TKR. 4,11,12 Patients received prophylaxis for 28 to 35 days or for 6 to 10 days, respectively. Both dabigatran doses were found to be noninferior to enoxaparin in reducing DVT risk (RE-NOVATE: P,.0001 for 220 mg, P,.0001 for 150 mg; RE-MODEL: P ¼.0003 for 220 mg, P ¼.017 for 150 mg), with no significant difference in major bleeding rates (RE-NOVATE: P ¼.44 for 220 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January

5 DOACS TABLE 3 Clinical trials. Evidence for NVAF DOAC vs. warfarin Evidence for VTE Management (DOAC versus LMWH/VKA) Evidence for VTE Risk Reduction after Initial Treatment Evidence for VTE Prophylaxis for THR (DOAC versus enoxaparin) Evidence for VTE Prophylaxis for TKR (DOAC versus enoxaparin) Apixaban Edoxaban Rivaroxaban Dabigatran ARISTOTLE (mean CHADS2 score: 2.1) Superior: hemorrhagic stroke Superior: major bleeding ICH and fatal bleed: lower Superior: cardiovascular mortality ENGAGE AF-TIMI 48 (mean CHADS2 score: 2.8) CrCl 15 95: noninferior for stroke or systemic embolism Superior: hemorrhagic stroke Superior: major bleeding Superior: cardiovascular mortality ROCKET-AF (mean CHADS2 score: 3.5) Noninferior: all stroke Major bleed: similar ICH and fatal bleeding: lower GI and need for transfusion: higher RE-LY (mean CHADS2 score: 2.1) Superior: ischemic and hemorrhagic stroke Major bleeding: similar (higher in age 75 years) ICH and fatal bleeding: lower GI: higher Superior: cardiovascular mortality AMPLIFY Noninferior: recurrent VTE/mortality Major bleeding: lower Hokusai-VTE study Noninferior: recurrent VTE Superior: fatal and intracranial bleeding, clinically relevant bleeding EINSTEIN Non-inferior: recurrent VTE/mortality Major bleeding: lower (pooled analysis) RE-COVER Noninferior: recurrent VTE/mortality Major bleed: similar Clinically relevant nonmajor and any bleed: lower AMPLIFY-EXT Superior versus placebo with similar major bleeding Not approved for this indication (not studied) EINSTEIN-EXT Superior versus placebo with higher major bleeding RE-MEDY Noninferior versus warfarin, similar major bleeding RE-SONATE Superior versus placebo, higher major bleeding ADVANCE 3 Superior with no difference in bleeding Not approved for this indication STARS J-V (hip replacement) Superior with no difference in bleeding RECORD 1 and RECORD 2 Superior with no difference in bleeding RE-NOVATE I and RE-NOVATE II Noninferior STARS J-IV (hip fracture) Similar with no difference in bleeding ADVANCE 2 Superior with no difference in bleeding Not approved for this indication STARS E-3 Superior with no difference in bleeding RECORD 3 and RECORD 4 Superior with no difference in bleeding Not approved for this indication RE-MODEL/RE-MOBILIZE Noninferior 42 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January 2017

6 SKEIK ET AL TABLE 4 Laboratory monitoring of DOACs. Direct Factor Xa Inhibitors Rivaroxaban and apixaban Heparin level (aka anti-xa) Assay used to calculate heparin levels shows reasonable linear correlation with increasing levels of direct factor Xa inhibitors Heparin (anti-xa) level of,0.1 U/mL suggests lack of significant factor Xa inhibitor activity PT/INR Value of PT (reported in seconds) shows some correlation with direct factor Xa inhibitor level; however, correlation with the calculated INR is weaker Normal PT likely rules out clinically significant levels of direct factor Xa inhibitor Due to variability of PT/INR reagents, this test is not recommended to rule out the presence of the direct factor Xa inhibitor. Heparin levels (anti-xa) should be ordered instead Edoxaban Heparin level (anti-xa) The assay used to calculate heparin levels shows reasonable linear correlation with increasing levels of direct factor Xa inhibitors A heparin (anti-xa) level of,0.1 U/mL suggests lack of significant factor Xa inhibitor activity PT/INR No good correlation with PT or aptt Direct Factor IIa Inhibitor Dabigatran level Preferred test if available (performed at Allina Health Central Lab at Allina Commons) Thrombin time (TT) Useful to rule out presence of dabigatran A normal TT may rule out clinically significant levels of dabigatran aptt Can be used if dabigatran level and TT tests are not available Less sensitive than TT and may be normal at trough drug level Elevated aptt cannot quantify the amount of dabigatran present PT/INR Less sensitive than TT and aptt Specific assays for apixaban, edoxaban, and rivaroxaban may be available in the future pending reagent availability in the USA. mg, P ¼.60 for 150 mg; RE-MODEL: P ¼.82 for 220 mg, P ¼ 1.0 for 150 mg dosage). 13,14 Use with Mechanical Heart Valves. The RE-ALIGN trial (a randomised, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement) compared the safety of dabigatran to warfarin in patients with mechanical heart valves. 15 However, because of the concerns for increased risks of major bleeding and valve thrombosis, the trial was prematurely discontinued. 4 Currently, dabigatran is contraindicated in patients with mechanical heart valves. Acute Coronary Syndrome (ACS). The RE-DEEM trial (randomized dabigatran etexilate dose finding study in patients with acute coronary syndromes post index event with additional risk factors for cardiovascular complications also receiving aspirin and clopidogrel: multi-centre, prospective, placebo controlled, cohort dose escalation study) compared step-up dabigatran doses (50, 75, 110, and 150 mg twice daily) to placebo as add-on therapy to antiplatelet agents in patients presenting with ACS. The primary outcomes were major and clinically relevant minor bleeding. The study was not powered to address cardiovascular (CV) ischemic events. Compared with placebo, dabigatran showed an increased dose-dependent risk of bleeding. Dabigatran is currently not indicated to use for ACS. Laboratory Monitoring Under normal circumstances, there is no need for dabigatran plasma concentration monitoring (Table 4). However, monitoring might be helpful in some situations (eg, bleeding, surgery, and/or compliance assessment). 4 Because dabigatran is a thrombin inhibitor, it can prolong numerous coagulation tests, such as the prothrombin time (PT), INR, activated partial thromboplastin time (aptt), thrombin clotting time (TT), and ecarin clotting time (ECT). 16 The correlation with dabigatran concentration varies among these tests. It is poor with PT/INR and fair with TT and ECT. While TT exhibits a linear correlation with the dabigatran concentration, aptt exhibits a curvilinear correlation. 16 When the TT and aptt are normal, one can almost certainly assume that dabigatran has been cleared from the system. 1,4 Management of Bleeding While dabigatran has improved care for patients with NVAF and VTE, bleeding remains a significant complication (Tables 5 7). 4 Time cannot be an antidote because the half-life of dabigatran is relatively long (12 17 hours). 17 Furthermore, protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse its anticoagulation effects. 4,17 Idarucizumab was approved by the FDA in 2015 as a specific antidote to dabigatran. It is a specific monoclonal antibody that has a stronger binding affinity for dabigatran than endog- JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January

7 DOACS TABLE 5 Management of bleeding associated with the DOACs: bleeding categories and general measures. Bleeding Category Mild Bleeding (all criteria below) Moderate Bleeding (all criteria below) Major Bleeding (1 of the below) Life-Threatening Bleeding (1 of the below) Hemoglobin Decrease and/or Transfusion Needs No significant decrease in hemoglobin No blood transfusion necessary Bleeding associated with Decrease in hemoglobin of,2 g/dl or Transfusion of,2 units of blood Symptoms Asymptomatic contained, local bleeding Symptomatic bleeding excluding critical organs Intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal, intraarticular, or pericardial Bleeding associated with Decrease in hemoglobin of 2 g/dl or Transfusion of 2 units of blood Symptomatic bleeding in a critical area or organ Intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal, intraarticular, or pericardial Bleeding associated with Decrease in hemoglobin of 5 g/d or Transfusion of 4 units of blood Potentially fatal hemorrhage Symptomatic intracranial bleed Hypotension requiring use of intravenous inotropic agents Surgical intervention necessary General Measures Mild Bleeding Moderate Major Life-Threatening Anticoagulant Drug Hold 1 or more anticoagulant doses based on bleeding severity and renal function Consider other anticoagulant if 2 doses of drug need to be interrupted and or it can no longer be used. Consider bridging agent if CHADS2 score.4 Check and monitor for Possible medication interactions Renal function to verify correct dosing Hepatic function to verify correct dosing of rivaroxaban and apixaban Restart anticoagulation when bleeding is contained and no contraindications. Laboratory Monitoring None recommended Local bleeding control Hold anticoagulant Consider activated charcoal (1 2 gm/kg) if:,2 hours since last dose of dabigatran or rivaroxaban,6 hours since last dose of apixaban For edoxaban, there are currently no data or ongoing study to evaluate if activated charcoal can be used in cases of overdose/ toxicity Check and monitor for: possible medication interactions renal function to verify correct dosing hepatic function to verify correct dosing Monitor CBC Local bleeding control 44 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January 2017

8 enous thrombin. It is currently indicated in dabigatrantreated patients requiring emergent surgery or urgent procedures, and/or presenting with life-threatening or uncontrolled bleeding. 18 Dabigatran is lipophilic and can be absorbed by charcoal if the latter is given within 2 hours of the last dabigatran dose. 4,17 Hemodialysis is another potential option for dabigatran clearance, but is not supported by concrete evidence. 4 Prothrombin complex concentrates (PCCs), which contain factors II, VII, IX, and X, have been shown to reduce bleeding in rabbits; and activated PCC (apcc) has been shown to correct bleeding time prolongation caused by dabigatran. 4,17 Recombinant factor VIIa was shown to reduce tail bleeding in a rat model with dabigatran, but only partially restored aptt. 17 These procoagulant agents should be avoided as they may increase the risk of thromboembolic events. 4 A summary of the authors institution recommendations for the management of bleeding caused by the DOACs is provided (Tables 5 7). Anticoagulant Conversion Transitioning from warfarin to dabigatran can take place whenever the INR is less than 2 (Table 8). Transitioning from dabigatran to warfarin varies depending on the CrCl of the patient. For patients with CrCl.50 ml/min, warfarin should be started 3 days before discontinuing dabigatran. For patients with CrCl 30 to 49 ml/min, warfarin should be started 2 days before stopping dabigatran. For patients with CrCl 15 to 29 ml/min, warfarin should be started 1 day before stopping dabigatran. For patients with CrCl,15 ml/min, the transition is not recommended. Transitioning from or to unfractionated heparin (UFH) infusion includes stopping one agent and starting the other at the same time. The transition from or to a direct FXa inhibitor (apixaban, rivaroxaban, or edoxaban) or low molecular weight heparin (LMWH) includes stopping one agent and starting the other at the same time of the next scheduled dose of the agent being discontinued. n FACTOR XA INHIBITORS Factor Xa acts at the convergence of the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of FXa at this point makes sense since it will impact both pathways. 4 Direct FXa inhibitors bind directly to free and clot-bound FXa to inhibit coagulation. 4,13 There have been multiple FXa inhibitors developed including rivaroxaban, apixaban, edoxaban, and betrixaban. This paper will focus on the first 3 agents since betrixaban is not yet FDA approved. 4 SKEIK ET AL n RIVAROXABAN Pharmacology and Dosage Rivaroxaban binds to free and clot-bound FXa with high affinity and selectivity (Tables 1,2). 4,14 It comes in a tablet formulation with 3 doses: 10, 15, and 20 mg. 4 Rivaroxaban has a T max of 2 to 4 hours and a half-life of 5 to 13 hours. Approximately one-third of rivaroxaban is excreted unchanged as active drug in urine and about two-thirds is excreted as inactive metabolites in urine and feces. 19 Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ABCG2 transporters. Concurrent use with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir, ritonavir, indinavir, and conivaptan) will reduce the rivaroxaban metabolism and increase plasma concentrations of rivaroxaban and thus the risk of bleeding. In contrast, concurrent use with combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John s wort) will increase the metabolism of rivaroxaban and reduce its plasma concentrations and efficacy. Combined P-gp and strong CYP3A4 inhibitors and inducers should not be used with rivaroxaban. 4,19 Concomitant use with antithrombotics, such as antiplatelet agents, may increase bleeding risk and should be considered only if the risk of thrombosis is high. 4 Side effects reported with rivaroxaban include bleeding, thrombocytopenia, agranulocytosis, hypersensitivity reaction, Stevens Johnson syndrome, and hepatitis. Contraindications include active pathologic bleeding and severe hypersensitivity reaction to the drug. 19 Clinical Trials Rivaroxaban is the first FXa inhibitor to receive FDA approval for reduction of stroke risk and SE in patients with NVAF (20 mg daily with meal if CrCl.50 ml/ min and 15 mg with meal if CrCl ml/min), treatment of patients with DVT and/or PE (15 mg twice daily with food for 21 days, then 20 mg daily with food for at least 3 months), reduction of risk of recurrent VTE after the initial therapy (20 mg daily with food, long term), and reduction in DVT risk in patients undergoing THR or TKR (10 mg daily with or without food, beginning 6 to 10 hours postoperatively for 12 [TKR] or 35 days [THR]; Table 3) ,17,19 23,27 38 There is no clinical data for use of rivaroxaban in liver impairment (Child-Pugh class B or C) and its use should be avoided in renal impairment when CrCl,15 ml/min and NVAF or CrCl,30 ml/min and VTE management In contrast to dabigatran, rivaroxaban may be given once daily in NVAF and does not require parenteral anticoagulation prior to its use in VTE. 1,4 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January

9 DOACS TABLE 6 Management of bleeding associated with direct factor Xa inhibitors. Bleeding Category Mild Moderate Major Life-Threatening General Approach See general measures in Table 1 Bleeding Source Recommendations See general measures in Table 5 See general measures in Table 5 Maintain adequate diuresis GI tract: GI consult GI tract: GI consult Vascular: vascular surgery and/or interventional radiology consult Local hemorrhage including hematoma: compression and surveillance imaging Transfusion Consider transfusion if symptomatic anemia or hemoglobin,7 g/dl Vascular: vascular surgery and/or interventional radiology consult. Local hemorrhage including hematoma: compression and surveillance imaging Intracranial or intraspinal bleed: neurology and neurosurgery consults Intraocular: ophthalmology consult Intramuscular or intra-articular: orthopedic consult Pericardial: cardiac surgery and cardiology consults Retroperitoneal: general surgery consult Consider transfusion if symptomatic anemia or hemoglobin,7 g/dl Labs Not recommended Check heparin levels (anti-xa) If not available, check PT (in seconds) to estimate medication clearance (see Table 4: Laboratory monitoring of DOACs ) Hemodialysis Not beneficial Not beneficial Not beneficial PCC or apcc rviia Not recommended If continuous active bleeding and Coverage with Other Anticoagulant Consider other anticoagulant if 2 doses of the drug need to be interrupted and or it can no longer be used. Consider bridging agent if CHADS2 score is.4 Resume Anticoagulant Restart anticoagulation when bleeding is contained and no further risk of bleeding. abnormal heparin levels (aka anti-xa) or PT, consider PCC. If not available, apcc or rfviia Cover with other anticoagulant (preferable low intensity unfractionated heparin) when deemed safe especially if CHADS2 score.4 Decision about restarting anticoagulation should be based on risks and benefits. See general measures in Table 5 Maintain adequate diuresis GI tract: GI consult Vascular: vascular surgery and/or interventional radiology consult Local bleed including hematoma: compression and surveillance imaging Intracranial or intraspinal bleed: neurology and neurosurgery consults Intraocular: ophthalmology consult Intramuscular or intra-articular: orthopedic consult Pericardial: cardiac surgery and cardiology consults Retroperitoneal: general surgery consult Recommend blood transfusion Check heparin levels (anti-xa) if not available, check PT (in seconds) to estimate medication clearance (see Table 4: Laboratory monitoring of DOACs ) Recommend PCC If not available, consider apcc or rfviia as soon as possible Cover with other anticoagulant (preferably low intensity unfractionated heparin) when deemed safe, especially if CHADS2 score.4 Decision about restarting anticoagulation should be based on risks and benefits. 46 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January 2017

10 SKEIK ET AL TABLE 6 Continued. Treatment Options for Major or Life-Threatening Bleeding due to Direct Factor Xa Inhibitors Dose Side Effects Considerations 4-Factor (4F)-PCC 50 units/kg IV May repeat dose in 12 hours if bleeding continues Maximum dose 5,000 units/day Dosing may change based on bleeding severity and thrombotic risk of patient Disseminated intravascular coagulation (DIC) Systemic thromboembolism Contains heparin. Contraindicated in patients with known HIT. Alternatives if 4F-PCC Unavailable Dose Side Effects Activated PCC (anti-inhibitor coagulant complex) units/kg IV May repeat dose in 12 hours if bleeding continues Maximum dose: 200 units/kg/day Dosing may change based on bleeding severity and thrombotic risk of patient Does not contain heparin Recombinant active factor VII 20 mcg/kg IV May repeat dose every 2 hours until hemostasis achieved or until treatment judged ineffective. Maximum dose 90 mcg/kg Dosing may change based on bleeding severity and thrombotic risk of patient Does not contain heparin DIC Systemic thromboembolism DIC Systemic thromboembolism JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January

11 DOACS TABLE 7 Management of bleeding associated with direct factor IIa inhibitors. Bleeding Category Mild Moderate Major Life-Threatening General Approach See general measures in Table 5 See general measures in Table 5 See general measures in Table 5 Maintain adequate diuresis See general measures Table 5 Maintain adequate diuresis Bleeding Source Recommendations GI tract: GI consult Vascular: vascular surgery and/or interventional radiology consult Local hemorrhage including hematoma: compression and surveillance imaging Transfusion Consider transfusion if symptomatic anemia or hemoglobin,7 g/dl GI tract: GI consult Vascular: vascular surgery and/or interventional radiology consult Local hemorrhage including hematoma: compression and surveillance imaging Intracranial or intraspinal bleed: neurology and neurosurgery consults Intraocular: ophthalmology consult Intramuscular or intra-articular: orthopedic consult Pericardial: cardiac surgery and cardiology consults Retroperitoneal: general surgery consult Consider transfusion if symptomatic anemia or hemoglobin,7 g/dl Laboratory Monitoring Not recommended Check dabigatran level If dabigatran level not available, check TT If TT not available, check aptt (see Table 4: Laboratory monitoring of DOACs ) Hemodialysis Not recommended Consider hemodialysis, especially if abnormal renal function; continuous active bleeding; abnormal dabigatran level, TT, or aptt Idarucizumab Not recommended. If continuous active bleeding and abnormal dabigatran level, TT or aptt (see Laboratory Monitoring), consider idarucizumab PCC or apcc, rfviia Not recommended Consider PCC only if idarucizumab is not available and active bleeding with an abnormal dabigatran level, TT or aptt (see Laboratory Monitoring ) If PCC is not available, recommend apcc or rfviia Coverage with Other Anticoagulant Consider other anticoagulant if 2 doses of dabigatran need to be interrupted and/or it can no longer be used. Consider bridging agent if CHADS 2 score.4 Cover with other anticoagulant (preferably low-intensity UFH) when deemed safe, especially if CHADS 2 score.4 GI tract: GI consult Vascular: vascular surgery and/or interventional radiology consult Local bleed including hematoma: Compression and surveillance imaging Intracranial or intraspinal bleed: neurology and neurosurgery consults Intraocular: ophthalmology consult Intramuscular or intra-articular: orthopedic consult Pericardial: cardiac surgery and cardiology consults Retroperitoneal: general surgery consult Recommend blood transfusion Check dabigatran level If dabigatran level not available, check TT If TT not available, check aptt (see Table 4: Laboratory monitoring of DOACs ) Recommend hemodialysis as soon as possible Recommend idarucizumab as soon as possible Recommend PCC as soon as possible only if idarucizumab is not available If PCC not available, recommend apcc or rfviia Cover with other anticoagulant (preferably low-intensity UFH) when deemed safe, especially if CHADS 2 score.4 48 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January 2017

12 SKEIK ET AL TABLE 7 Continued. Bleeding Category Mild Moderate Major Life-Threatening Resume Anticoagulant Restart anticoagulation when bleeding is contained and no further risk of bleeding Decision about restarting anticoagulation should be based on risks and benefits Treatment Options for Major or Life-Threatening Bleeding due to Dabigatran Decision about restarting anticoagulation should be based on risks and benefits Dose/Administration Side Effects Considerations Idarucizumab 5 gm IV divided in two 2.5-gm doses Administer as 2 consecutive infusions by hanging vials or as consecutive bolus injections of both vials one after another via syringe A preexisting IV line may be used but must be flushed with saline prior to infusion. No other infusion should be administered via the same IV access There is limited data to support administration of an additional 5-gm dose in 24 hours Dosing may change based on bleeding severity and thrombotic risk of patient Headache Hypokalemia Delirium Constipation Pyrexia Pneumonia Serious adverse reactions have been reported in patients with hereditary fructose intolerance due to sorbitol excipient Idarucizumab is also indicated for reversal of dabigatran-related anticoagulation prior to emergency surgery/urgent procedures Idarucizumab is a specific reversal agent for dabigatran with no impact on the effect of other anticoagulants or antithrombotic therapies. Dabigatran can be reinitiated 24 hours after administration of idarucizumab when clinically appropriate. JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January

13 DOACS NVAF. The ROCKET-AF trial (rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin k antagonism for prevention of stroke and embolism trial in atrial fibrillation) compared rivaroxaban (20 mg once daily with CrCl.50 ml/min or 15 mg daily with CrCl ml/min) versus warfarin (target INR: 2 3) for reducing the risk of stroke and SE in patients with NVAF and at least 2 CHADS 2 risk factors. 8 Patients enrolled in ROCK- ET-AF were generally sick and had high rate of comorbidities. 8 The mean CHADS 2 score was 3.5; 55% of enrolled patients had had a prior stroke or TIA. Compared with warfarin, rivaroxaban was found to be noninferior for the primary efficacy outcome, a composite of stroke or SE (P,.001), and had a similar risk for major or clinically relevant nonmajor (CRNM) bleeding (P ¼.44 for primary safety outcomes). 8 However, intracranial hemorrhage (ICH) and fatal bleeding occurred less often with rivaroxaban (P ¼.02 and.003, respectively). 8 Based on further analysis of subgroups within the ROCKET-AF population, lower-dose rivaroxaban (15 mg) was found to be equally effective for thromboprophylaxis in patients with NVAF and renal insufficiency (CrCl ml/min; P ¼.76). 39 Although patients with renal insufficiency experienced higher bleeding rates than those with normal renal function, rivaroxaban, and warfarin resulted in similar bleeding risks (P ¼.76), with less fatal bleeding events in the rivaroxaban group (P ¼.047). 39 Furthermore, a history of prior stroke did not significantly alter the primary efficacy (composite of stroke or SE) or safety (major or CRNM) outcomes of rivaroxaban compared with warfarin (P ¼.047 and.23, respectively). 40 Management of VTE. The EINSTEIN study group (oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic deep-vein thrombosis or pulmonary embolism) compared rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily with meal for 3, 6, or 12 months) to enoxaparin to bridge to warfarin (INR: 2 3) in patients who presented with DVT alone (EINSTEIN-DVT study) or PE with or without DVT (EINSTEIN-PE study). 4,24 Pooled analysis of both EINSTEIN studies showed that rivaroxaban was noninferior to enoxaparin/warfarin for efficacy (recurrent VTE or related mortality, 95% CI: ), without significant differences in primary safety outcome (clinical relevant bleeding rates, 95% CI: ). 24 There was 46% relative-risk reduction in major bleeding with rivaroxaban compared with enoxaparin/warfarin. 24,41,42 In addition, EINSTEIN-EXT found that extended treatment (6 12 months) of rivaroxaban was superior to placebo for recurrent VTE prevention (P,.001), but with an increased risk of bleeding. 24,25 The RECORD trials (regulation of coagulation in orthopedic surgery to prevent dvt and pe, controlled, double-blind, randomized study of BAY in the extended prevention of VTE in patients undergoing elective hip replacement) compared rivaroxaban with enoxaparin to reduce risk of DVT in patients undergoing THR (RECORD 1 and 2) and TKR (RECORD 3 and 4). 10,20 23 In all 4 RECORD studies, rivaroxaban was shown to be superior to enoxaparin for total VTE prevention (composite outcome of symptomatic DVT, nonfatal PE, and all-cause mortality) with no significant increase in major bleeding. 10,43 The MAGELLAN study (multicenter, randomized, parallel-group efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically ill patients comparing rivaroxaban with enoxaparin) looked at rivaroxaban versus enoxaparin in hospitalized medical patients requiring VTE prophylaxis. 44 Standard ( days) and extended courses ( days) of rivaroxaban were noninferior (P ¼.003) and superior (P ¼.02), respectively, to enoxaparin for VTE prevention. However, both rivaroxaban treatment groups had increased bleeding risks compared with the enoxaparin group (P,.001 for both). 44 Rivaroxaban is not currently indicated for DVT prophylaxis in patients admitted to medical units. Acute Coronary Syndrome. The ATLAS ACS 2- TIMI 51 study (a randomized, double-blind, placebocontrolled, event-driven multicenter study to evaluate the efficacy and safety of rivaroxaban in subjects with a recent acute coronary syndrome) assessed rivaroxaban (5 and 2.5 mg twice daily) versus placebo as add-on therapy to antiplatelet agents in patients with ACS. 45 Compared with placebo, rivaroxaban reduced the risk of the composite endpoint of death from CV causes, MI, or stroke. However, rivaroxaban increased the risk of major bleeding and ICH but not the risk of fatal bleeding. 45 Due to concerns of increased risk of bleeding, rivaroxaban did not receive FDA approval for this indication. Rivaroxaban has been not clinically studied in patients with prosthetic heart valves and should not be considered in this patient population. Laboratory Monitoring Currently, there is no specific test to monitor the anticoagulation effects of any of the FXa inhibitors, including rivaroxaban (Table 4). The activated PTT and PT/INR assays give variable results and are therefore unsuitable for accurate monitoring. 46 However, PT in seconds shows some correlation with the level of direct FXa inhibitors such as rivaroxaban and apixaban. 50 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January 2017

14 The anti-fxa assay is a method that involves the enzymatic cleavage of a synthetic substrate and can directly determine the amount of FXa present in the sample. This test can measure drug concentrations over a wide range (0 500 ng/ml) and show promise for monitoring rivaroxaban. However, a standardized assay is needed for routine rivaroxaban monitoring. 46 Normal PT and anti-fxa test results may indicate that a clinically significant concentration of a direct FXa inhibitor is not present. 46 Reversal and Bleeding Management Andexanet alfa is a recombinant, modified FXa molecule that acts as an FXa decoy that targets and sequesters, with high specificity, direct and indirect FXa inhibitors, including rivaroxaban (Tables 5 7). Once bound, the FXa inhibitors are then unable to bind to and inhibit native FXa, thus allowing for restoration of normal hemostatic processes. 47,48 Based on the AN- NEXA-A and ANNEXA-R studies (a randomized, double-blind, placebo controlled trial demonstrating sustained reversal of rivaroxaban-induced anticoagulation in older subjects by Andexanet alfa for Factor Xa inhibitors), andexanet alfa reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of andexanet alfa infusion without evidence of clinical toxic effect. 47,48 The ANNEXA-4 trial is an ongoing phase 4 singlearm, open-label confirmatory study to evaluate the ability of andexanet alfa to reverse the anticoagulation effect of direct and indirect oral anticoagulants in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed. Patients requiring urgent procedures are not included. 49 Similar to dabigatran, protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse its anticoagulation effects. Unlike dabigatran, rivaroxaban is not dialyzable. Charcoal may be administered within 2 hours of the last rivaroxaban ingestion in case of overdose. Until a specific antidote is FDA approved, PCC may be considered based on data showing improved bleeding times in healthy volunteer patients who received PCC while on rivaroxaban. 31 Active PCC and recombinant active factor VII (rviia) should only be considered as last resorts due to the increased risk of thromboembolic complications. 4 A summary of the authors institution recommendations for the management of bleeding caused dabigatran and the rest of the DOACs is provided (Tables 5 7). Anticoagulant Conversion Conversion from warfarin to rivaroxaban can occur when the INR is,3 (Table 8). 19 Although there is SKEIK ET AL no consensus on the conversion from rivaroxaban to warfarin, one option would be to discontinue rivaroxaban and start a bridging agent with warfarin when the next rivaroxaban dose is due. The INR should be checked no earlier than 2 days after discontinuing rivaroxaban given its lingering effect. ThebridgingagentmaybestoppedoncetheINRis therapeutic. 19 For switching among different short-acting anticoagulants such as UFH, LMWH, or another DOAC, recommendations are similar to what has been discussed for dabigatran. 19 n APIXABAN Pharmacology and Dosage Apixaban is another FXa inhibitor that comes in a tablet form with strengths of 5 and 2.5 mg, either of which is taken twice daily (Tables 1,2). 4,50 Apixaban has a T max of 3 to 4 hours and a half-life of 8 to 15 hours. 4 Renal excretion accounts for about 27% of apixaban clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces. 4 Based on pharmacodynamic and pharmacokinetic data using anti-fxa activity in subjects with end-stage renal disease (ESRD) maintained on dialysis, no dose adjustment is required based on renal function alone. However, apixaban was not studied clinically in patients with CrCl,15 ml/min. 50 Similar to rivaroxaban, apixaban is a substrate for CYP3A4 and P-gp transporters. 4 When used with P-gp and strong CYP3A4 inhibitors, apixaban plasma concentrations and the risk of bleeding increase so its dosage should be reduced by 50%. Permeability glycoprotein and strong CYP3A4 inhibitors should not be used with the 2.5-mg dosage. 50 On the other hand, concurrent use of apixaban with P-gp and CYP3A4 inducers reduce plasma apixaban concentrations and efficacy of apixaban. 50 Therefore, combined P-gp and strong CYP3A4 inducers should not be used with apixaban. Use of apixaban with antiplatelet therapy should only be considered if risk of thrombosis outweighs the risk of bleeding. Side effects that have been reported with apixaban include bleeding, nausea, skin rash, and low blood pressure. Contraindications include severe hypersensitivity, which occurs less than 0.1%, and active pathologic bleeding. Similar to rivaroxaban, there is no clinical experience with apixaban in patients with liver impairment (Child-Pugh class B or C) or severe renal impairment (CrCl,15 ml/min). Clinical Trials Apixaban was the second FXa inhibitor to receive FDA approval to reduce stroke risk in patients with NVAF (5 mg twice daily or 2.5 mg twice daily if 2 or more of the following are present [Table 3]: age 80 years, weight JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 1 n January