A Comprehensive Overview of Direct Oral Anticoagulants for the Management of Venous Thromboembolism

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A Comprehensive Overview of Direct Oral Anticoagulants for the Management of Venous Thromboembolism Anthony J. Comerota MD, Eduardo Ramacciotti MD, PhD

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Cite this article as: Anthony J. Comerota MD, Eduardo Ramacciotti MD, PhD, A Comprehensive Overview of Direct Oral Anticoagulants for the Management of Venous Thromboembolism, Am J Med Sci, http://dx.doi.org/10.1016/j. amjms.2016.03.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A Comprehensive Overview of Direct Oral Anticoagulants for the Management of Venous Thromboembolism Anthony J. Comerota, MD,1 Eduardo Ramacciotti, MD, PhD2* 1

Director, Jobst Vascular Institute, 2109 Hughes Dr Suite 400, Toledo, OH 43606 USA;

[email protected] 2

Bristol-Myers Squibb Company, 345 Park Ave, New York, NY 10154 USA;

[email protected] *Present address: Visiting Professor, Thrombosis and Hemostasis, Loyola University Medical Center, 2160 1st Ave, Maywood, Illinois 60153 USA, and Full Professor Vascular Surgery, Albert Einstein Israeli Hospital, Avenida Albert Einstein, 627/701 – Morumbi, São Paulo - SP, 05652900, Brazil Corresponding author: Anthony J. Comerota, MD, FACS, FACC, Director, Jobst Vascular Institute 2109 Hughes Dr Suite 400, Toledo, OH 43606 USA Phone: 419-291-2080; Fax: 419-479-6980; E-mail: [email protected] Short title: DOAC management of venous thromboembolism

Conflicts of Interest and Source of Funding: Anthony J. Comerota has been a consultant to Bayer, Daiichi-Sankyo, Bristol-Myers Squibb Company and Pfizer Inc. and has received honoraria for consulting services. Eduardo Ramacciotti was an employee of Bristol-Myers Squibb Company when work on this manuscript began. Professional medical writing and editorial

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assistance were provided by Robert Coover, MPH, CMPP, and Dana Fox, PhD, CMPP, at Caudex, funded by Bristol-Myers Squibb Company and Pfizer Inc. Key terms: venous thromboembolism, anticoagulants, hemorrhage

Abbreviations used in manuscript: aPCC, activated PCC aPTT, activated partial thromboplastin time bid, twice daily Cmax, maximum plasma concentration CRNM, clinically relevant nonmajor DOACs, direct oral anticoagulants DVT, deep vein thrombosis HR, hazard ratio INR, international normalized ratio LMWH, low-molecular-weight heparin MI, myocardial infarction PCC, prothrombin complex concentrate PD, pharmacodynamics PK, pharmacokinetics PT, prothrombin time rFVIIa, recombinant factor VIIa tmax, maximum plasma concentration UFH, unfractionated heparin VTE, venous thromboembolism VKAs, oral vitamin K antagonists

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Abstract Venous thromboembolism (VTE) is a prevalent, potentially fatal health problem. Although standard anticoagulant therapy is effective, compared to the newer direct acting oral anticoagulants (DOACs) it has disadvantages. Heparin and its derivatives must be administered parenterally, while use of oral vitamin K antagonists is complicated by unpredictable pharmacokinetics and pharmacodynamics, drug-food and drug-drug interactions, and the requirement for frequent laboratory monitoring. Randomized phase 3 trials have demonstrated that patients will receive similarly effective anticoagulation with the direct oral anticoagulants (DOACs) dabigatran, edoxaban, rivaroxaban, and apixaban compared with warfarin, with similar or reduced risk of bleeding. Extended therapy trials have consistently demonstrated superior effectiveness for DOAC treatment compared with placebo in preventing VTE recurrence. This article presents a comprehensive review of the pharmacokinetics, pharmacodynamics, and accumulated clinical trial evidence for each DOAC for acute and extended VTE therapy, and considers the potential implications these agents have for the clinical management of VTE.

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Introduction Venous thromboembolism (VTE) is a prevalent and potentially fatal health problem affecting over 900,000 people in the United States and over 1 million people in Europe annually.1,2 Recent studies have shown that VTE-related deaths exceed those caused by acute myocardial infarction (MI) and stroke.1,2 An estimated 28% of patients will not survive past 1 month, with pulmonary embolism (PE) associated with higher fatality rates than deep vein thrombosis (DVT); this exceeds the case fatality rate reported for MI.3 Although age is a risk factor, VTE is a common problem affecting all segments of the population. Those surviving VTE potentially face significant morbidities, including postthrombotic syndrome and chronic thromboembolic pulmonary hypertension. Recurrent events increase long-term morbidity.

Since the classic study by Barritt and Jordan,4 anticoagulation has been the mainstay of therapy, initially with unfractionated heparin (UFH) being converted to vitamin K antagonists (VKAs). This was the standard of care until low-molecular-weight heparin (LMWH) compounds were developed, offering incremental benefits over standard UFH, and in some instances VKAs,5–8 including rapid absorption from subcutaneous tissue, the possibility of initiating treatment in the outpatient setting, and an apparent improvement in thrombus resolution. Moreover, compared with UFH, there is a reduced risk of heparin-induced thrombocytopenia and osteopenia when used over the long term.9,10

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Fondaparinux, a pentasaccharide, shares many of the advantages of LMWH, but with its long half-life, requires only once-daily injection.11,12 The LMWHs and fondaparinux require parenteral administration, although monitoring is not generally required.

Until recently, VKAs have been the only oral anticoagulants available for the management of VTE. Unfortunately, VKAs have a number of disadvantages that complicate patient care: unpredictable pharmacokinetics (PK) and pharmacodynamics (PD); food and drug interactions; and they function within a narrow therapeutic window, which requires frequent laboratory monitoring.13,14 As a result, the management of patients receiving VKAs is often cumbersome, and even with expert management, many patients are frequently outside the therapeutic range.15 This is a major concern because time spent within the therapeutic range is inversely correlated with the incidence of thromboembolic or hemorrhagic events.16

The most recent advance in the management of patients with VTE is the development of the direct oral anticoagulants (DOACs), which directly inhibit factor Xa or factor IIa, factors strategically positioned in the coagulation cascade (Figure 1). Factor Xa is located at the intersection of the intrinsic and extrinsic coagulation pathways prior to its interaction with factor II (prothrombin). Factor IIa (thrombin) forms the basic structure of thrombus, and activates fibrinogen, which is the final step in the coagulation cascade. The DOACs directly bind to activated factors X and II. These new fixed-dose oral agents, unlike VKAs, do not require laboratory monitoring or dose adjustment and have a low potential for food and drug interactions. Additionally, these agents reach peak concentration within 1–4 hours after 5

ingestion,17-22 which is in sharp contrast to the extended time required for warfarin to achieve a therapeutic international normalized ratio (INR). This extended timing necessitates parenteral anticoagulation with either UFH or LMWH for a minimum overlap of therapy for 5 days. Despite these conveniences, and the similar or lower bleeding risk observed in clinical trials of DOACs versus standard therapy, clinicians are concerned because the DOACs are not monitored and their anticoagulant effect cannot be reversed by methods customary with warfarin use. The DOACs approved for use include the following:

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The direct thrombin inhibitor, dabigatran

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The factor Xa inhibitors: rivaroxaban, apixaban, and edoxaban. Other agents in this class are in preliminary stages of development.

Recently, evidence supporting the DOAC options for VTE treatment has emerged. This review summarizes the PK and PD of these agents and the accumulated clinical trial evidence for each DOAC for the management of VTE, and considers the potential implications these agents have for the clinical management of VTE.

Pharmacodynamics and Pharmacokinetics Pharmacokinetic characteristics of DOACs. Pharmacologic profiles of the DOACs are summarized in Table 1. These nonpeptidic, orally available agents directly inhibit 1 of the 2 key serine proteases in the coagulation cascade, thrombin (factor IIa) or activated factor X. Although several of the agents may have a similar mechanism of action, it is possible that 6

differences in the PD and PK properties will influence how and when specific drugs are used for patient care.

Dabigatran. Dabigatran etexilate is the prodrug of dabigatran, which is a nonpeptidic small molecule that reversibly inhibits free and clot-bound thrombin.23–25 Dabigatran also inhibits tissue factor–induced thrombin generation in human platelet-poor plasma.24 In addition, dabigatran inhibits thrombin-activated platelet aggregation and tissue factor–induced platelet aggregation.26

Dabigatran has low oral bioavailability. Dabigatran etexilate was developed to improve gastrointestinal absorption. Absorption of dabigatran etexilate in the stomach and small intestine depends on an acidic environment. To establish such an environment, dabigatran etexilate contains a tartaric acid core.27 With this acidic environment, drug absorption occurs independently of physiologic variations in gastric pH. Coadministration with food has no effect on its bioavailability.28

Dabigatran etexilate is rapidly absorbed, with a time to maximum plasma concentration (tmax) of 1.25–3 hours.29 It has a mean plasma half-life of 12–17 hours, which is independent of the dose.21,30 Thirty-five percent of dabigatran is bound to plasma proteins, and 80% is excreted unchanged by the kidneys.21 Patients with compromised renal function (creatinine clearance < 50 mL/min) have lower excretion rates, elevated plasma concentrations, and require dose reduction.31 Dabigatran is dialyzable. 7

Neither dabigatran etexilate nor dabigatran itself inhibits CYP isoenzyme systems. These hepatic enzyme systems interact importantly with antifungal agents, statins, and proton-pump inhibitors.

Edoxaban. Edoxaban is an orally active small molecule that reversibly inhibits factor Xa, which is bound within the prothrombinase complex, and attenuates prothrombinase-induced thrombin generation. It has little, if any, effect on platelet aggregation.32

Edoxaban’s maximal anticoagulant effect occurs 1–2 hours after ingestion. Its antithrombotic activity parallels the changes in clotting parameters reflected by anti-Xa activity, prothrombin time (PT), and activated partial thromboplastin time (aPTT), which return to baseline within 12 hours following ingestion.20 The coadministration of strong P-glycoprotein inhibitors increases exposure to edoxaban.33

Rivaroxaban. Rivaroxaban binds to factor Xa, rapidly inhibiting it in a reversible and competitive fashion.34 Rivaroxaban also inhibits tissue factor- or collagen-induced thrombin generation in human platelet-rich plasma.35

Rivaroxaban has little, if any, effect on platelet aggregation. Rivaroxaban prolongs PT, aPTT, and Heptest, with the maximal effect occurring within 4 hours of drug administration,19,36 and dose-dependent inhibition of factor Xa was observed in humans. However, standard laboratory testing cannot be reliably used to measure the anticoagulant effect of rivaroxaban. 8

Rivaroxaban’s rapid absorption results in a tmax of 2–4 hours. Coadministration with food increases the tmax.37

More than 90% of rivaroxaban is bound to plasma proteins, and therefore it is not dialyzable. It has a terminal half-life of 5–9 hours, which increases slightly in older individuals, most likely related to diminished renal function.37,38 Gender has no effect on PD.19,39 Rivaroxaban is metabolized in the liver via CYP3A4, CYP2C8, and CYP-independent mechanisms.37,38,40 Therefore, it is contraindicated in patients with severe liver disease and those taking antifungal agents that inhibit CYP3A4 and P-glycoprotein, or agents that induce these enzyme systems.37

Apixaban. Apixaban is a reversible inhibitor of factor Xa. It inhibits Xa bound within the prothrombinase complex as well as free Xa, and has no effect on platelet aggregation. Apixaban is rapidly absorbed, reaching maximum plasma concentration (Cmax) approximately 3–4 hours after ingestion. Approximately 87% of apixaban is protein-bound; therefore, it will not be eliminated with dialysis.41 It has a half-life of approximately 12 hours.18

In humans, apixaban produces a concentration-dependent increase in PT, aPTT, and modified PT, and apixaban increased Heptest in a human model.18,42,43 At the expected therapeutic dose of apixaban, changes observed in clotting tests are small, with a high degree of variability, but may have value in qualitative assessment (ie, if apixaban is present or not). Plasma concentration-dependent increases in anti-Xa activity were observed in the dose range 9

tested with the Rotachrom® Heparin chromogenic assay, although this test is not recommended for monitoring apixaban’s anticoagulant effects.44,45

Apixaban is metabolized through several pathways involving the liver and the kidneys. One such pathway is the CYP3A4-dependent pathway.46 However, inhibition or induction of the CYP enzyme system by apixaban is minimal.

Approximately 25% of an orally administered dose of apixaban is recovered in urine, with approximately 55% being excreted through the feces.41 Its multiple elimination pathways suggest that patients with mild or moderate hepatic or renal impairment can be treated with apixaban.

Trials of DOACs for Treatment of VTE A schematic of the trial designs with the DOACs for treatment of VTE is presented in Figure 2.47 Acute treatment is defined as the therapy initiated at the time of diagnosis and continued for 5–7 days, which is the necessary time for overlap of heparin with VKAs to become sufficiently therapeutic. Long-term therapy is defined as treatment extending 3–12 months from the initiation of anticoagulation, and is thought to be the proper duration of anticoagulation for most patients with an initial thromboembolic event.48 Extended therapy is generally suggested for those who have had PE or proximal DVT not provoked by surgery or other transient risk factors and who are at low or moderate risk of bleeding. Extended treatment is recommended for patients who have had recurrent VTE.48 10

The acute treatment trials evaluating dabigatran and edoxaban differed from those evaluating rivaroxaban and apixaban (Table 2). The trial designs of the 2 former agents treated patients initially with LMWH for at least the first 5 days, after which either dabigatran or edoxaban was initiated in patients in the experimental group. On the other hand, in the rivaroxaban and apixaban studies, the DOACs were the only agents used initially and over the long term in the experimental arms.

Anticoagulation with VKAs has been the standard for long-term treatment of VTE. The duration of therapy is variable, depending on the etiology, thrombus burden, and other prothrombotic risk factors that coexist.

However, the overall balance between reduced risk of recurrence and the bleeding risk of extended VKA treatment continues to be a source of debate. Extended (indefinite) treatment with VKAs requires laboratory monitoring and dose adjustment, and patients continue to be at risk for food and drug interactions, which may compromise efficiency or increase bleeding risk. The DOACs are single-dose, do not require monitoring, and have been shown to be associated with lower risk of bleeding when used initially and long term for VTE.49-56 The findings suggest that DOACs might also be appropriate for extended therapy of VTE beyond that originally accepted as the appropriate duration for the patient’s initial thrombotic event. The pharmacologic characteristics of the DOACs position them to be particularly attractive for longterm administration, especially if safety is proved. Studies have been performed to evaluate 11

extended therapy for VTE with dabigatran versus VKA and placebo, rivaroxaban versus placebo, and apixaban versus placebo (Table 3).

Initial and Long-term Treatment Trials Dabigatran. The RE-COVER49 and RE-COVER II56 studies had similar trial designs evaluating patients with acute DVT (Table 2). Both were designed as noninferiority trials comparing the same initial therapy of parenteral anticoagulation (UFH or LMWH, or fondaparinux) followed by randomization for long-term treatment to either dabigatran 150 mg twice-daily or warfarin, targeting an INR of 2.0–3.0. The RE-COVER trial randomized 2,564 patients, and 2,589 were randomized in RE-COVER II. Results were essentially identical. 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 < 0.001 for noninferiority). Major bleeding occurred in 1.6% versus 1.9% of the dabigatran- and warfarin-treated patients, respectively (P = 0.38). The secondary safety endpoint of any bleeding occurred in 16.1% of the dabigatran group and 21.9% of the warfarin patients (P < 0.001 for superiority).

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 < 0.001 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 dabigatran patients versus 22.1% of the warfarin patients.

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Dabigatran was the first DOAC studied to assess the risks and benefits of extended therapy. This is the only DOAC to be compared with both an active control (VKA) and placebo for prevention of VTE recurrence. The active-controlled study was RE-MEDY, and the placebocontrolled study was RE-SONATE.53 Both included a randomized, double-blind design for patients who had completed at least 3 months of anticoagulation for their acute VTE. The active-controlled study was designed to evaluate whether dabigatran was noninferior to warfarin in preventing recurrent VTE. Participants in the active-controlled study (RE-MEDY) were thought to be at increased risk for VTE in the judgment of the site investigators.

The placebo-controlled study was designed to evaluate whether extended treatment with dabigatran was superior to placebo in preventing recurrent VTE. These patients were thought to be at reduced risk for recurrence compared with the active control study. Initial treatment before randomization was 3–12 months for RE-MEDY and 3–18 months for RE-SONATE.

RE-MEDY patients were randomized 1:1 in a double-blind design to either active dabigatran at a dose of 150 mg twice daily or VKA to maintain an INR of 2.0–3.0. In the RE-SONATE study, patients were randomized in a double-blind fashion to receive dabigatran 150 mg orally twice daily or placebo. Patients (N = 4,219) underwent randomization between the 2 extendedtreatment trials: 2,866 in RE-MEDY and 1,353 in RE-SONATE. In the RE-MEDY study (VKA control), treatment duration ranged from 6 to 36 months, and follow-up was reported only while patients were receiving anticoagulation. In the RE-SONATE study, patients received active

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treatment or placebo for only 6 months and were followed another 12 months after treatment concluded for study efficacy and safety endpoints.

In the RE-MEDY study, the primary efficacy outcome was recurrent VTE, which occurred in 1.8% of the dabigatran patients and 1.3% of the VKA patients. Dabigatran met the noninferiority margin for prevention of recurrent VTE (P = 0.01). Predefined subgroups were analyzed and no differences were observed. Major bleeding occurred in 0.9% of the dabigatran group and 1.8% of the warfarin group (P = 0.06). Major or clinically relevant nonmajor (CRNM) bleeding occurred in 5.6% of the dabigatran patients and 10.2% of warfarin-treated patients (P < 0.001). There were no significant differences in the risk of bleeding according to study treatment in the predefined subgroups. Of the dabigatran patients, 0.9% suffered acute ischemic coronary events during treatment compared with 0.2% of warfarin-treated patients (P = 0.02).

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 < 0.001). 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 (hazard ratio [HR] 0.61; P = 0.03). 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.

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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 = 0.001). Only 1 acute coronary event occurred in each treatment group.

Edoxaban. The Hokusai VTE study55 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 2.0–3.0. 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 < 0.001 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 = 0.004). The Hokusai study demonstrated that after at least 5 days of acute 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.

Rivaroxaban. The EINSTEIN investigators studied oral rivaroxaban for symptomatic VTE51 and symptomatic PE.52 In their first study of symptomatic VTE, 3,449 patients with symptomatic proximal DVT with or without PE were randomized to rivaroxaban or enoxaparin followed by warfarin targeting an INR of 2.0–3.0. During initial therapy with rivaroxaban, patients received 3 weeks of 15 mg twice daily, then were converted to 20 mg daily for 3–12 months. The primary 15

efficacy outcome, which was symptomatic recurrent VTE occurring during the 3- to 12-month treatment period, occurred in 3.0% of the enoxaparin-VKA group and 2.1% of the rivaroxabantreated group (HR 0.68; P < 0.001 for noninferiority, and P = 0.08 for superiority). The primary safety outcome of major and CRNM bleeding was 8.1% for both treatment groups (HR 0.97; P = 0.77).

The EINSTEIN-PE study52 was similarly designed, and randomized 4,833 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 3–12 months or open-label enoxaparin 1 mg/kg twice daily and converted to warfarin with a target INR of 2.0–3.0. The primary efficacy outcome was symptomatic recurrent VTE occurring during the 3- 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 = 0.003 for noninferiority). Major and CRNM bleeding occurred in 10.3% of the rivaroxabantreated patients versus 11.4% of the warfarin group (HR 0.90; P = 0.23). Major bleeding occurred in 1.1% of rivaroxaban-treated patients and 2.2% of the control group (HR 0.49; P = 0.003). Acute coronary events occurred in 0.6% of rivaroxaban patients and 0.9% of the standard treatment group. During the 30-day post-study treatment period, acute coronary syndromes occurred in 0.1% of both groups.

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The EINSTEIN investigators demonstrated that equal efficacy could be achieved in the treatment of acute VTE using rivaroxaban 15 mg orally twice daily for 3 weeks followed by 20 mg daily over the long term compared with conventional therapy using heparin followed by VKA. There were no differences in major and CRNM bleeding.

The EINSTEIN investigators51 additionally performed a double-blind extended-treatment study in patients with confirmed VTE who were treated for 6–12 months with therapeutic anticoagulation. This 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 or 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 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 < 0.001), resulting in a relative risk reduction of 82%.

The principal safety outcome of major bleeding occurred in 0.7% of the rivaroxabantreated patients and in no patients in the placebo group (P = 0.11). Net clinical benefit occurred in 2% of patients receiving rivaroxaban and 7.1% receiving placebo (P < 0.001). Efficacy and

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safety outcomes were consistent across the pre-specified subgroups. No patient in either group had significant elevation of hepatic enzymes/bilirubin suggestive of liver toxicity.

In summary, with a sample size of 602 patients treated with rivaroxaban, 34 recurrent events were prevented at the expense of 4 nonfatal major bleeds. CRNM bleeding occurred in 5.4% of patients on rivaroxaban; however, most of these were of mucosal origin, and 81% of these patients continued therapy with rivaroxaban.

Apixaban. The AMPLIFY investigators54 studied apixaban versus conventional therapy for patients with acute VTE. Patients (N = 5,400) 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 2.0–3.0. 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 < 0.001 for noninferiority). Major bleeding occurred in 0.6% of apixaban-treated patients versus 1.8% of those given warfarin (P < 0.0001 for superiority). There was no difference observed in the outcome in patients presenting with acute symptomatic DVT versus those presenting with acute PE. The AMPLIFY investigators demonstrated that acute DVT and PE could be treated with apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily as effectively as with conventional anticoagulation, and with a significantly better safety profile. 18

The AMPLIFY-EXTENSION 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 2,486 patients who had completed 6–12 months of anticoagulation for symptomatic VTE.50 The study drugs and placebo 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 endpoint was symptomatic recurrent VTE or death from any cause. The secondary efficacy endpoint 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 < 0.001). 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. CRNM bleeding occurred in 2.3% of patients receiving placebo, 3.0% receiving 2.5 mg of apixaban, and 4.2% of those receiving 5 mg of apixaban.

The composite outcome of symptomatic recurrent VTE, death due to VTE, MI, stroke, cardiovascular death or major bleeding occurred in 10.4% of placebo patients versus 2.4% of those receiving 2.5 mg and 2.5% of those receiving 5 mg of apixaban. Results of the prespecified subgroup analysis of efficacy and safety outcomes were consistent with the observed 19

overall treatment effects. 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 2.5mg apixaban group and 0.6% in the 5-mg apixaban group. The composite of MI, stroke, or cardiovascular death occurred once each in the 2.5- and 5-mg apixaban groups and no times in the placebo group. The 2.5 mg BID dose is currently approved by the United States FDA for extended therapy.

VTE Trials in Progress The efficacy and safety of dabigatran etexilate compared with standard care in pediatric patients with VTE is being studied in a phase 3 open-label, randomized, noninferiority trial (NCT01895777). The primary outcome of this trial is the composite of complete thrombus resolution, freedom from recurrent VTE, and freedom from mortality related to VTE, while the primary safety endpoint is freedom from major bleeding events. Eligible patients are males or females aged <18 years, with documented diagnosis of VTE initially treated with UFH or LMWH for 5–7 days and with a clinical indication for 3 months of treatment with anticoagulants for VTE. The expected completion date of this trial is March 2018.

EINSTEIN CHOICE (NCT02064439) is a multicenter, randomized, double-blind, eventdriven, phase 3 superiority trial to compare 2 doses of rivaroxaban (10 mg and 20 mg oncedaily) with 100 mg aspirin for the extended treatment (12 months) secondary prevention of symptomatic VTE in patients who have completed 6–12 months of anticoagulation for their index DVT or PE event. The primary efficacy outcome is the percentage of patients with fatal or 20

nonfatal symptomatic recurrent VTE, and the primary safety outcome is the percentage of patients with major bleeding. Male and female patients aged ≥18 are eligible for inclusion if they have confirmed symptomatic PE and/or DVT and have been treated for 6–12 months with an anticoagulant that has not been interrupted for longer than 1 week. The expected completion date of this trial is November 2016.

EINSTEIN Junior (NCT01684423) is a phase 3 trial to assess the efficacy and safety of rivaroxaban for the treatment and secondary prevention of VTE in children. The rivaroxaban dosage will be adjusted for age and body weight, and the study will be performed in 10 countries. Completion is expected in July 2016.

In the phase 3 trial addressing VTE in cancer patients (NCT02073682), edoxaban is to be compared with dalteparin for the prevention of recurrent acute VTE following an initial index event in patients with cancer. Eligible patients will have confirmed acute lower extremity proximal DVT or PE for which LMWH is indicated, as well as cancer (excluding basal-cell or squamous-cell carcinoma of the skin). Completion is expected in December 2017.

Reversing the Anticoagulant Effect of DOACs Due to the short half-lives of DOACs (approximately 12 hours), the anticoagulant effect will be significantly reduced 24 hours after the last dose; however, no specific antidote is available. Situations that may require a more rapid reversal include acute and severe bleeding and/or trauma, anticoagulant overdose, and an emergency invasive procedure or surgery.57 21

In one study, prothrombin complex concentrate (PCC) and activated PCC (aPCC) showed promise for anticoagulation reversal after a single dose of dabigatran 58; however, other in vivo research found that PCC failed to reverse dabigatran anticoagulation after 2.5 days of twicedaily dosing.59 Use of aPCC or recombinant factor VIIa (rFVIIa), or concentrates of coagulation factors II, IX, or X may be considered for bleeding reversal in the absence of clinical trial evidence. Hemodialysis can remove dabigatran because of its low protein binding, but clinical experience supporting this treatment for bleeding is limited. The antibody fragment idarucizumab is newly approved by the US Food and Drug Administration for reversal of dabigatran.60 In results of a prospective cohort study61 in patients taking dabigatran who had serious bleeding or required an urgent procedure, the median maximal percentage reversal was 100%. Hemostasis was restored in a median 11.4 hours in those who were bleeding and interoperative hemostasis observed in 92% of those having a procedure.

Limited data are available regarding the efficacy of reversal strategies for edoxaban. It has been shown that PCC, aPCC, and rFVIIa reverse the effect of edoxaban on the PT.62 Recombinant factor VIIa and aPCC reversed the effect on aPTT, but had minimal effect on intrinsic factor X activity.63

Activated oral charcoal may be an option for reducing absorption of rivaroxaban. Likewise, PCC, aPCC, or rFVIIa may be considered in cases of emergent bleeding, but have not been evaluated in clinical studies. A small study in healthy volunteers showed that PCC immediately 22

and completely reversed the anticoagulant effect of rivaroxaban as measured by PT and endogenous thrombin potential; however, this has yet to be confirmed in patients with bleeding events.59

As with rivaroxaban, apixaban is not expected to be dialyzable because of its high level of protein binding. Administered 2 or 6 hours after apixaban, 50 g of activated charcoal was shown to decrease the half-life of apixaban by 8 hours (to roughly 5 hours).64 Administration of PCC, aPCC, or rFVIIa may be considered for reversal of apixaban-induced anticoagulation but has not been evaluated in clinical trials. In vitro results using blood from healthy volunteers indicated that laboratory-measured alterations in hemostasis induced by apixaban were variably compensated or even reversed by rFVIIa, PCC, and aPCC.65

Andexanet alfa (PRT064445) has high affinity binding for factor Xa inhibitors, thereby reducing free drug concentration and allowing native factor Xa to participate in coagulation.66 A phase 3 trial has found bolus administration of andexanet alfa to result in a 92% reversal of anti-factor Xa activity in patients treated with rivaroxaban and 94% reversal of anti-factor Xa activity in patients treated with apixaban.67 Early research with a synthetic small-molecule anticoagulant antidote (PER977) has shown that it is capable of reversing the anticoagulant effects of rivaroxaban and apixaban ex vivo, and in a rat model, decreasing bleeding induced by all 4 of the currently approved DOACs.68,69 A phase 1 trial has recently found 100 to 300 mg of PER977 to restore hemostasis within 10 to 30 minutes after administration in patients who had previously taken 60 mg edoxaban.70 23

Until the widespread availability of specific antidotes to reverse the DOACs’ anticoagulant effect, some may consider that there is a potential safety advantage in the use of warfarin, the activity of which can be reversed by administration of vitamin K. However, existing data have thus far not borne out a survival advantage for warfarin. Majeed et al.71 compared the management and prognosis of major bleeding in patients treated with dabigatran or warfarin in 5 phase 3 trials; of the 27,419 patients enrolled, 1,034 had bleeding events. Major bleeding events in patients on dabigatran were associated with older age, poorer renal function, and concurrent use of platelet inhibitors. Following the first major bleed, the 30-day mortality was lower in dabigatran-treated patients (9.1%) than in warfarin-treated patients (13.0%; odds ratio [OR] 0.68; P = 0.057). Bleeding events with dabigatran were associated with shorter stays in the intensive care unit (mean 1.6 days) compared with patients treated with warfarin (2.7 days; P = 0.01).

There are no comparative analyses of bleeding events occurring in patients while in the oral factor Xa inhibitors versus warfarin trials. However, there are uniform observations that rivaroxaban, apixaban, and edoxaban are safer than warfarin.72 With their half-lives being similar to or shorter than dabigatran, and their more complete reversal with PCC, one would expect fewer serious consequences of their bleeding events versus warfarin. The important issue of periprocedural bleeding in patients requiring invasive procedures or surgery while anticoagulated with dabigatran or warfarin was addressed by Healey et al. 73 This is one of the largest descriptions of periprocedural anticoagulant interruption with warfarin in 24

comparison with the DOAC dabigatran in a head-to-head evaluation. Anticoagulation interruption was significantly shorter in the dabigatran group. Among patients requiring urgent surgery, bleeding rates were statistically equivalent but numerically higher in warfarin-treated patients (21.6%) compared with dabigatran-treated patients (17.7%).

Summary The randomized trials of the DOACs have uniformly demonstrated that patients will receive similarly effective anticoagulation with DOACs compared with warfarin, with a similar or reduced risk of bleeding. There are no direct comparisons between the DOACs. Available data failed to reveal differences in efficacy or safety, although trends between trials are beginning to surface. The occurrence of primary outcomes and serious complications was low in these trials; therefore, without substantially larger sample sizes, it would be unlikely that significant differences would be detected. However, the observation of noninferiority for efficacy and superiority for safety in the DOAC-treated patients was notably consistent.

Extended treatment of VTE is becoming increasingly recognized as an important patient management option, especially in patients with unprovoked VTE. The benefits of DOACs are being clarified compared with no anticoagulation; however, only 1 study compared the DOAC dabigatran to warfarin for extended care. Dabigatran was equally as effective, and, as might be anticipated, was safer than warfarin. In the placebo-controlled trials, dabigatran, rivaroxaban, and apixaban consistently showed a greater than 80% reduction in risk of VTE recurrence. Dabigatran was associated with a significantly higher risk of bleeding versus placebo; use of 25

rivaroxaban demonstrated a trend toward more bleeding, whereas patients on apixaban had nearly the same risk of bleeding as those on placebo. Because comparison studies versus warfarin for extended therapy were not performed with rivaroxaban or apixaban, efficacy and safety versus warfarin have not been established.

The DOACs demonstrated uniformly reduced bleeding risks, with a notable reduction in the risk of intracranial bleeds. However, there were differences in rates of gastrointestinal bleeding, especially in the RE-COVER trial in which dabigatran was used. While it could be suggested that this might be due to a difference between drug classes (factor IIa inhibitors versus factor Xa inhibitors), it is pertinent that dabigatran has a tartaric acid core that produces an acidic microenvironment to promote absorption. Significantly more patients taking dabigatran complained of dyspepsia, which led to higher rates of discontinuation of the study drug. Although direct comparisons of these new agents are lacking, observations have emerged that one agent may be more advantageous than another in selected clinical circumstances. Dabigatran might best be avoided in patients with a history of dyspepsia or gastrointestinal bleeding.

One of the major advantages of the DOACs is that monitoring is not required. The DOACs will affect aPTT, PT, INR, anti-Xa activity, and bleeding times to variable degrees. Timing of testing relative to ingestion of drug impacts the results, as the half-lives of these new agents are relatively short. Peak effects occur within 2–4 hours of drug ingestion and decline rapidly thereafter. To date, there is no correlation of efficacy or safety between blood test results and 26

outcome. However, as treatment uptake of these agents increases, physicians will appreciate the ability to monitor “drug effect” in patients presenting with on-treatment complications of recurrence or hemorrhage. Therefore, monitoring and dose adjustments may need to be incorporated into future practice as our understanding of these drugs is refined.

Hundreds of thousands of patients have been studied in clinical trials evaluating the DOACs for VTE and nonvalvular atrial fibrillation. Consistent observations of similar efficacy with improved safety, improved efficacy with similar safety, or both improved efficacy and safety compared with VKAs have been reported, indicating that these agents offer a substantial advantage over conventional anticoagulation. The concerns that clinical trials do not reflect outcomes of routine patient care should be diminished by the observation of safety and efficacy in postmarketing studies74 and evidence that compliance with treatment may be better with the DOACs than with VKAs.75

Studies of treatment for acute VTE using rivaroxaban and apixaban demonstrated that the single DOAC agent replaced both initial heparin and subsequent warfarin for the treatment of acute VTE. Early efficacy in the DOAC-treated patients was similar to efficacy with conventional anticoagulation. Net clinical benefit, which includes recurrent VTE and bleeding events, favored the DOACs. Such treatment effects will further facilitate the outpatient management of VTE by eliminating the need for injections (and education of patients and/or family members on how to properly inject) and blood test monitoring. Edoxaban was shown to be superior to VKAs in patients with submassive PE following a predefined subset analysis.55 27

This is the first observation that patients with advanced VTE are more effectively treated with a DOAC than with conventional anticoagulation.

Numerous confounding conditions exist in which the utility of the DOACs needs to be clarified. These include their use in pregnancy and during breast-feeding, in the elderly and cancer patients, in those with aggressive prothrombotic states, in morbidly obese and lowbody-weight patients, and in those receiving concomitant platelet inhibitors. Therefore, additional studies are required to select the most appropriate drugs for the spectrum of patients with VTE.

One of the greatest concerns about the DOACs is the strategy for reversal of anticoagulation in case of emergency bleeding. The morbidity of bleeding complications with DOACs is no greater and often less than with warfarin because of their short half-lives. Idarucizumab is newly approved for reversal of dabigatran; direct reversal agents for factor Xa inhibitors will soon be available, and until then, PCCs are available and may be considered for reversal of these agents.

Conclusions Data from randomized phase 3 trials have demonstrated that the DOACs provide effective anticoagulation in patients with acute VTE, with similar or lesser risk of bleeding compared to standard therapy; in extended treatment the DOACs have shown the ability to reduce the risk of VTE recurrence versus placebo. Advantages shared by all four approved 28

DOACs compared with VKA therapy include the elimination of the need for routine monitoring of anticoagulant effect and the low level of drug–drug interactions, while shared disadvantages of the DOACs currently include the absence of a readily available specific antidote. Though no head-to-head trials between DOACs exist, available research provides some grounds for distinguishing among the agents. There is evidence for acute VTE treatment using either rivaroxaban or apixaban as single-agent therapy replacing both initial heparin and subsequent warfarin, while trials of dabigatran and edoxaban both incorporated initial heparin. Dabigatran is the only agent to be compared against warfarin for long-term prevention of VTE recurrence, but is also associated with a risk for gastrointestinal bleeding that may make it unsuitable in some patients. Edoxaban is the only DOAC to have been shown superior to VKAs in patients with submassive PE, following a predefined subset analysis. In the cases of all 4 of the DOACs, safety and efficacy in vulnerable patient populations remain to be clarified and represent potential targets for additional research.

29

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39

Figures FIGURE 1. Schematic of coagulation cascade and mechanism of action of anticoagulants. LMWH, low-molecular-weight-heparin; UFH, unfractionated heparin.

FIGURE 2. Design of treatment trials of DOACs for acute VTE. bid, twice daily; DOACs, direct oral anticoagulants; LMWH, low-molecular-weight heparin; qd, once daily; UFH, unfractionated heparin.

a

Acute: First ≥5 days

b

Long-term: 3-12 months

c

Extended: After a “full course” (3-12 months) of anticoagulation

TABLE 1. Pharmacokinetic characteristics of the DOACs

Cmax

Dabigatran29,31

Edoxaban22,33

Rivaroxaban37,40

Apixaban44,46

172.8 ng/mL

152 ng/mL (single

270 μg/L (20 mg

After 7 days’

(150 mg bid)30

30-mg dose); 305

qd)38

dosing: 62.3 ng

ng/mL (single 60-

mL-1 (2.5 mg bid);

mg dose)20

128.5 ng mL-1 (5 mg bid); 329.8 ng mL-1 (10 mg bid)18

Cmin

87.8 ng/mL

62 ng/mL (60 mg

26 μg/L (20 mg

After 7 days’

40

(150 mg bid)30

bid dosing, day

qd)38

10)20

dosing: 21.0 ng mL-1 (2.5 mg bid); 49.6 ng mL-1 (5 mg bid); 103.8 ng mL-1 (10 mg bid)18

tmax

1–3 h

1-2 h

2-4 h

3-4 h

t1/2

12–17 h

10-14 h

5-9 h (11–13 h in

12 h

the elderly) Protein

35%

55%

92–95%

binding Renal

Approximately 87%

80%

50%

excretion

66% (after oral

27%

administration [half is inactive drug])

Vss Bioavailability

Inter-subject

50–70 L

107 L

50 L

21 L

3–7%

62%

For the 10 mg

Approximately

dose, estimated

50% for doses up

80–100%

to 10 mg

30–40% CV

~30% CV

<30% CV21

nd

variability Effect of:

41

Age

Exposure

Exposure

increased 40–60%

increased

increased

in elderly vs young

approximately

approximately

subjects; Cmax

50% among

32% in elderly

increased 25%

elderly

subjects (no

Exposure

nd

difference in Cmax) Weight

Body weight >100

Extremes in

Body weight >120

kg: 20% lower Cmin

body weight

kg: 30% lower

vs patients 50–

(<50 kg or > 120

exposure vs

100 kg; limited

kg) had only

subjects with

clinical data

<25% influence

body weight 65–

available for

on rivaroxaban

85 kg;

plasma

body weight <50

concentrations

kg: 30% higher

patients

nd

<50 kg

exposure vs subjects 65–85 kg Sex

Exposure 40–50%

nd

No clinically

Exposure

higher in female

relevant PK

approximately

patients

differences

18% higher in

between male

female patients

and female

42

patients Renal impairment

CrCL <30 mL/min:

CrCL 30–50

CrCL 30-50

CrCL 30–50

exposure

mL/min:

mL/min:

mL/min: exposure

increased 1.6-fold

exposure

exposure

increased 29% vs

vs individuals with

increased 74% vs

increased 2.7-

individuals with

normal CrCL

individuals with

fold vs

normal CrCL; 15–

normal CrCL; <30

individuals with

29 mL/min:

mL/min:

normal CrCL; 10–

exposure

exposure

30 mL/min:

increased 44% vs

increased 72% vs

exposure

individuals with

individuals with

increased 6-fold

normal CrCL

normal CrCL

vs individuals with normal CrCL

Hepatic impairment

Moderate hepatic

Moderate

Mild or moderate

impairment

hepatic

hepatic

(Child-Pugh B): No

impairment

impairment

significant change

(Child-Pugh B):

(Child-Pugh A or

in exposure

exposure

B) did not alter

increased 2.3-

exposure

nd

fold Drug

P-gp inducers (eg,

P-gp inducers (eg,

Strong

Strong dual

43

interactions

rifampin) result in

rifampin) result in

CYP3A4/P-gp

CYP3A4/P-gp

decreased

decreased

dual inhibitors

inhibitors (eg,

exposure

exposure;

(eg,

ketoconazole,

anticoagulants

ketoconazole,

ritonavir) increase

increase bleeding

ritonavir)

exposure; strong

risk

increase

dual CYP3A4/P-gp

exposure; strong

inducers (eg,

CYP3A4/P-gp

rifampin)

dual inducers

decrease

(eg, rifampin)

exposure

decrease exposure; anticoagulants increase bleeding risk All information from prescribing information/summary of product characteristics unless otherwise noted. bid, twice daily; Cmax, maximum plasma concentration; Cmin, plasma concentration trough; CrCL, creatinine clearance; CV, coefficient of variation; CYP3A4, cytochrome P450 3A4; nd, no data; DOAC, direct oral anticoagulant; NSAID, non-steroidal anti-inflammatory drug; P-gp, Pglycoprotein; PK, pharmacokinetics; qd, once daily; t1/2, half-life; tmax, time to maximum plasma concentration; Vss, volume at steady state. 44

TABLE 2. Initial and extended treatment of VTE with DOACs: trial designs Trial

Rx before

Study drug

Comparator

Design

DOAC

No. of

Rx

patients

length (mo)

2,564 DVT only: LMWH, UFH, RE-

Dabigatran 49

COVER

Double-

1,749

Warfarin

fondaparinux × 150 mg bid

6 blind

PE

5 days with/without DVT: 786 2,589 DVT only: LMWH, UFH, RE-COVER

Dabigatran fondaparinux ×

50

II

Double-

1,750

Warfarin 150 mg bid

6 blind

PE

5 days with/without DVT: 816 8,292 DVT only: Edoxaban Hokusai-

Enoxaparin or

Double60 mg qd

VTE

51

UFH × 5 days

4,921

Warfarin

3–12 blind

PE

or 30 mg qd with/without DVT: 3,319 45

EINSTEINDVT: 3,349

Rivaroxaban DVT

52

None– 15 mg bid rivaroxaban for 21 d, used as initial

EINSTEINPE

Open-

3, 6,

label

or 12

Enoxaparin/VKA

then 20 mg

PE

qd

with/without

treatment

53

DVT: 4,833

5,400 Apixaban None–apixaban

DVT: 3,532 10 mg bid

AMPLIFY54

Enoxaparin/

Double-

used as initial

PE for 7 d, then

treatment

warfarin

6

blind with/without

5 mg bid DVT: 1,836

bid, twice daily; DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; LMWH, lowmolecular-weight heparin; PE, pulmonary embolism; qd, once daily; Rx, treatment; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

46

TABLE 3. Treatment of initial VTE with DOACs: summary of results

Drug

Trial

Desig

Study drug

n

Recurren

Major

Major +

t VTE +

bleedin

CRNM

Comparato

VTE

g

bleeding

r

death RRR, drug vs comp (%), P-value

RE-

DB

Dabigatran

Warfarin

RRR –

RRR

RRR 37%

COVER49

6 mo

150 mg bid

(after

10%

18%

5.6 vs 8.8

(after

LMWH or

2.4 vs 2.1

1.6 vs

P = 0.002

N=

LMWH or

UFH)

P < 0.001

1.9

2,564

UFH)

(NI)

P = 0.38

Dabigatra n

TTR 60.0% RE-COVER

DB

Dabigatran

Warfarin

RRR –8%

RRR

RRR 38%

II50

6 mo

150 mg bid

(after

2.3 vs 2.2

31%

5.0 vs 7.9

(after

LMWH or

P < 0.001

1.2 vs

P = nr

N=

LMWH or

UFH)

(NI)

1.7

2,589

UFH)

P = nr TTR 56.9%

Hokusai51 Edoxaban

DB

Edoxaban

Warfarin

RRR 11%

RRR

RRR 19%

3–12

60 mg qd

(after

3.2 vs 3.5

16%

8.5 vs 10.3

47

mo

or 30 mg

LMWH or

P<

1.4 vs

qd (after

UFH)

0.0001

1.6

(NI)

P = 0.35

P = 0.004

N=

LMWH or

8,292

UFH)

TTR 63.5%

EINSTEI

OLR

Rivaroxaba

Enoxaparin

RRR 32%

RRR

RRR 3%

N-

3, 6,

n 15 mg

/

2.1 vs 3.0

35%

8.1 vs 8.1

DVT52

or 12

bid for 21

VKA

P < 0.001

0.8 vs

P = 0.77

mo

d, then 20

(NI)

1.2

Rivaroxaban

mg qd

TTR 57.7%

P = 0.21

N= 3,449 EINSTEI

OLR

Rivaroxaba

Enoxaparin

RRR –

RRR

RRR 10%

N-PE53

3, 6,

n 15 mg

/

12%

51%

10.3 vs 11.4

or 12

bid for 21

VKA

2.1 vs 1.8

1.1 vs

P = 0.23

mo

d, then 20

P < 0.003

2.2

(NI)

P=

mg qd

TTR 62.7%

N=

0.003

4,832

Apixaban

AMPLIFY5

DB

Apixaban

Enoxaparin

RRR 16%

RRR

RRR 56%

4

6 mo

10 mg bid

/

2.3 vs 2.7

69%

4.3 vs 9.7

for 7 d,

warfarin

P < 0.001

0.6 vs

P < 0.001

(NI)

1.8

N=

then 5 mg

48

5,395

bid

TTR 61.0%

P< 0.001

bid, twice daily; CRNM, clinically relevant non-major; DB, double-blind; DOACs, direct oral anticoagulants; LMWH, low-molecular-weight heparin; NI, noninferiority; nr, not reported; OLR, open-label, randomized; qd, once daily; RRR, relative risk reduction; TTR, time in therapeutic range (warfarin); UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

49

TABLE 4. Extended therapy for VTE with DOACs: trial designs Drug

Trial

Rx before

Study drug

randomizatio

Comparat

Design

or

n

No. of

Rx

patient

lengt

s

h (mo)

Dabigatran

RE-

3–12 mo of

Dabigatran

Warfarin

Double

MEDY56

VKA or

150 mg bid

INR 2.0–

-blind

6–36

1,353

6

1,197

6 or

3.0

dabigatran

Dabigatran

2,866

RE-

6–18 mo of

Dabigatran

SONATE56

VKA or

150 mg bid

Placebo

Double -blind

dabigatran EINSTEIN

6–12 mo of

Rivaroxaba

Extension5

VKA or

n 20 mg qd

2

rivaroxaban

AMPLIFY

6–12 mo of

Apixaban

Extended

standard

2.5 mg or

Therapy55

anticoagulatio

5 mg bid

Placebo

Double

Rivaroxaba -blind

12

n

Placebo

Double

2,486

12

-blind

Apixaban

n

bid, twice daily; DOACs, direct oral anticoagulants; INR, international normalized ratio; qd, once daily; Rx, therapy; VKA, vitamin K antagonist; VTE, venous thromboembolism.

50

Rivaroxaban

Dabigatran

Drug

5 mg bid

Extended55

6–12 mo

12 mo

Placebo

6 or 12

2.5 mg or

6–12 mo

AMPLIFY

Placebo

6 mo

of Tx

Length

3–12 mo 6–36 mo

6–18 mo

Pre-Tx

mo

20 mg qd

EINSTEIN

Warfarin

Placebo

Comparator

Extended52

bid

MEDY56

bid

SONATE56

150 mg

150 mg

RE-

RE-

Dose

Trial

Table 5. Extended therapy for VTE with DOACs: summary of results

bleeding

Major

mg

2.5

1.7 vs 8.8

RRR 81%

0.2 vs 0.5

3.2 vs 2.7

RRR –20%

P < 0.001

P = 0.11 RRR 51%

6.0 vs 1.2

RRR –419%

P < 0.001

5.6 vs 10.2

RRR 46%

P = 0.001

5.3 vs 1.8

RRR –192%

0.7 vs 0

nr

P = 0.06

P < 0.01 (NI) nr

0.9 vs 1.8

1.8 vs 1.3

RRR 48%

P = 1.0

P < 0.001 (Sup) RRR –44%

0.3 vs 0

nr

0.4 vs 5.6

RRR 92%

CRNM

Major +

RRR, drug vs comp (%), p-value

death

Recurrent VTE + VTE

Dabigatran

Drug

Apixaban

150 mg

150 mg

RE-SONATE56

RE-MEDY56

Dose

Trial

Warfarin

Placebo

Comparator

3–12 mo

6–18 mo

Pre-Tx

6–36 mo

6 mo

Length of Tx

1.7 vs 8.8

mg

ns

0.1 vs 0.5

RRR 75%

ns

ns

4.3 vs 2.7

RRR –62%

ns

1.2 vs 0.9

0.3 vs 3.3

rates (%)

Drug vs comp

–32

nr

RRR (%)

0.46

nr

P-value

Symptomatic, Recurrent VTE

(Sup)

P < 0.001

RRR 80%

5.0

(Sup)

P < 0.001

5 mg

2.5 mg

AMPLIFY

Extension55

Dose

Trial

Extension52

Placebo mo

6–12

Pre-Tx

Placebo

Comparator

20 mg

12 mo

Tx

Length of

6–12 mo

1.3 vs 7.1

4.2 vs 11.6

3.8 vs 11.6

(%)

comp rates

Drug vs

(0.25–0.53)

0.36

(0.22–0.48)

0.33

(95% CI)

RRR

82

64

67

RRR

Recurrent VTE + all-cause death

6 or 12 mo

nr

nr

death

All-cause

for Sup

< 0.001

thromboembolism.

not reported; ns, not significant; qd, once daily; RRR, relative risk reduction; Sup, superiority; Tx, treatment; VTE, venous

bid, twice daily; CI, confidence interval; CRNM, clinically relevant non-major; DOACs, direct oral anticoagulants; NI, noninferiority; nr,

Apixaban

Drug

Rivaroxaban

EINSTEIN

RE-COVER Dabigatran: 150 mg bid vs warfarin

HOKUSAI Edoxaban: 60 mg qd vs warfarin

RE-COVER UFH, LMWH, fonda. ≥5 days

HOKUSAI UFH, LMWH ≥5 days

AMPLIFY Apixaban: 10 mg bid. x 7 days; then 5 mg qd vs conventional anticoagulation

EINSTEIN-PE Rivaroxaban: 15 mg bid x 3 weeks; then 20 mg qd vs conventional anticoagulation

EINSTEIN-DVT Rivaroxaban: 15 mg bid x 3 weeks; then 20 mg qd vs conventional anticoagulation

LONG-TERMb

ACUTEa

AMPLIFY Extension Apixaban: 2.5 mg bid vs Apixaban: 5.0 mg bid vs placebo

EINSTEIN Extension Rivaroxaban: 20 mg qd vs placebo

RE-SONATE Dabigatran: 150 mg bid vs placebo

RE-MEDY Dabigatran: 150 mg bid vs warfarin

EXTENDEDc

Dabigatran Etexilate

Rivaroxaban Apixaban Edoxaban

Vitamin K Antagonists

ORAL

XII

XI

VIII

IX

XIIa

XIa

VIIIa

IXa Tenase complex

V

X

VIIa

Va

Xa

VII

Ia

I

IIa

II

ANTITHROMBIN

LMWH UFH

Fondaparinux

PARENTERAL

Prothrombinase complex

TISSUE DAMAGE

SURFACE CONTACT

TISSUE FACTOR

EXTRINSIC PATHWAY

INTRINSIC PATHWAY