188

The New or Non–Vitamin K Antagonist Oral Anticoagulants: What Have We Learned Since Their Debut Brandon J. McMahon, MD1

Hau C. Kwaan, MD, FRCP1

1 Division of Hematology/Oncology, Feinberg School of Medicine,

Northwestern University, Chicago, Illinois

Address for correspondence Hau C. Kwaan, MD, FRCP, Northwestern University, Olson Pavilion, 710 North Fairbanks Court, Chicago, IL 60611 (e-mail: [email protected]).

Abstract

Keywords

► ► ► ► ► ►

anticoagulants warfarin rivaroxaban apixaban edoxaban dabigatran

One of the major advances in the management of thrombosis is arguably the introduction of the new non–vitamin K antagonist oral anticoagulants (NOACs). These are small molecules, designed to directly inhibit specific steps in the coagulation pathway, with dabigatran (Pradaxa), inhibiting thrombin and rivaroxaban (Xarelto), apixiban (Eliquis), edoxaban (Lixiana), and betrixaban being factor Xa inhibitors. They have several advantages over vitamin K antagonists such as warfarin, with more predictable bioavailability, fewer drug interactions, and improved safety, especially intracranial hemorrhage. Yet, since their debut, several issues have arisen with their increasing usage, with concerns over monitoring and reversal, being predominant. Issues addressed in this article include their efficacy, bleeding risk, and the recognition of a vulnerable population where monitoring is needed. The current approach to reversing the drug action is updated. The change in the approach to future drug design is also discussed.

Since the regulatory approval of rivaroxaban in Canada in September 2008, other “new” (or non–vitamin K antagonist) oral anticoagulants (NOACs) were rapidly added to our antithrombotic armamentarium, including inhibitors of thrombin, dabigatran (Pradaxa, Boehringer Ingelheim, Ingelheim, Germany) and factor Xa, rivaroxaban (Xarelto, Bayer, Leverkusen, Germany), apixiban (Eliquis Bristol-Myers Squibb, New York, NY), edoxaban (Lixiana Daiichi Sankyo, Tokyo, Japan), and betrixaban (Portola Pharmaceuticals, South San Francisco, CA). Though these have many improved characteristics over those of vitamin K antagonists (VKAs) such as warfarin, several issues have arisen as worldwide adoptions of these drugs increase. In this article, many of these issues are addressed.

Pharmacologic Features of Non–Vitamin K Antagonist Oral Anticoagulants The basic pharmacologic features of the NOACs are shown in ►Table 1. Warfarin mediates its anticoagulant effect by

published online February 15, 2015

Issue Theme Anticoagulant Therapy: Present and Future; Guest Editor: Job Harenberg, MD.

blocking vitamin K–dependent posttranslational modifications on coagulation factors II, VII, IX, and X. Its impact on multiple factors helps explain its narrow therapeutic margin. The NOACs have been designed to have a directed effect on one of the key components of coagulation.1,2 Thrombin is the target for dabigatran, whereas for rivaroxaban, edoxaban, apixaban, and betrixaban, the target is factor Xa. Unlike unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux, the Xa inhibitors exert their effect directly, and not through an antithrombin-mediated mechanism. Each of the NOACs achieves their pharmacologic effect quickly, but has variable half-lives, with dabigatran and betrixaban having the longest and rivaroxaban the shortest. In man, 66% of rivaroxaban is excreted by the kidneys.3 Apixaban has the least dependence on renal function for elimination, while betrixaban is eliminated mostly in the bile.4,5 An important feature of dabigatran is its low bioavailability, and absorption being pH sensitive, resulting in its formulation together with tartaric acid.6 Concomitant use of proton pump inhibitors may result in decreased absorption.7

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0035-1544159. ISSN 0094-6176.

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Semin Thromb Hemost 2015;41:188–194.

The New Non–Vitamin K Antagonist Oral Anticoagulants

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Table 1 Pharmacologic Features of NOACs Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Betrixaban

Target

Thrombin

Xa

Xa

Xa

Xa

Peak level (h)

2–3

3

3

1–2

3–4

T½, (h)

12–17

5–9

9–14

10

20

Bioavailability (%)

6

80

>50

62

34

Renal excretion (%)

80

66

25

50

17

Hepatic clearance (%)

20

28

75

50

80

General Efficacy Nonvalvular Atrial Fibrillation Most of the NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) have been evaluated in large phase III studies for use in nonvalvular atrial fibrillation to reduce stroke and/or systemic embolization.8–11 Results were favorable with regard to efficacy, as all were found to be noninferior to warfarin for the primary endpoint. In the cases of dabigatran 150 mg bid and apixaban 5 mg BID, there was a reduction in stroke or systemic embolization compared with warfarin that met statistical significance.8,9 The use of NOACs outside the setting of clinical trials (i.e., in general practice) thus far has been favorable as well. For example, stroke/systemic embolization rates were comparable in almost 5,000 patients on dabigatran compared with 9,000 patients on warfarin in one study, with an important reduction in intracranial hemorrhage and mortality for those treated with dabigatran.12 Betrixaban showed similar or lower rates of bleeding compared with warfarin in a limited phase II study (Explore-Xa).4 This novel anticoagulant is long acting and is currently undergoing a clinical trial (APAX) designed for hospitalized severely ill patients.

Venous Thromboembolism There have been six phase III studies involving over 27,000 patients comparing the safety and efficacy of the NOACs to standard therapy with VKAs in acute venous thromboembolism (VTE).13–20 In the case of edoxaban and dabigatran, there was an initial overlap of parenteral anticoagulation (LMWH/UFH). Monotherapy was used initially with apixaban and rivaroxaban, with no initial parenteral anticoagulation. There was some variability in duration of treatment: in the dabigatran and apixaban trials, patients were treated for 6 months, and in the rivaroxaban and edoxaban trials, patients were treated for 3, 6, or 12 months (at the discretion of the treating physician). Noninferiority to VKA therapy was demonstrated with each of the NOACs. In a pooled meta-analysis of all six phase III studies,21 the rate of recurrent VTE in DOAC-treated patients was 2.0 versus 2.2% in the VKA groups, and no significant heterogeneity between studies was noted. Extended treatment following initial therapy has also been evaluated with dabigatran, apixaban, and rivaroxaban.13,14,16 Continued use of these agents following a standard course of anticoagulation for an acute VTE event

resulted in a significant reduction in recurrent thrombosis compared with placebo. Dabigatran was also compared with extended warfarin therapy in this setting, and was found to be noninferior for the purpose of reducing thrombotic recurrence. Betrixaban in a phase II study showed efficacy and bleeding rates similar to that of warfarin and was well tolerated.4,5 However, at the time of this writing, it is not yet approved by regulatory agencies.

NOACs and Bleeding Risk Balancing the need for treatment or prevention of thrombosis with anticoagulant use and their inherent propensity to cause or worsen bleeding is extremely challenging. Patients are constantly reevaluated for bleeding versus thrombotic risk to assess need for continued anticoagulation. Major bleeding with chronic use of VKAs has been estimated to be approximately 1 to 3 per 100 patient years, but reaching as much as 6.5% per year in those felt to be in high-risk categories.22,23 To date, rates of bleeding with use of NOACs have been demonstrated to be at least comparable to VKAs and, in many instances, statistically lower than warfarin (►Table 2). Combined, these targeted agents have demonstrated lower overall bleeding rates broadly across all major categories. A metaanalysis of 12 randomized studies in over 100,000 evaluable patients reported a statistically significant reduction in major bleeding (RR, 0.72; 95% confidence interval [CI], 0.62–0.85), fatal bleeding (RR, 0.53; 95% CI, 0.43–0.64), intracranial bleeding (RR, 0.43; 95% CI, 0.37–0.50), clinically relevant nonmajor bleeding (RR, 0.78; 95% CI, 0.68–0.90), and total bleeding (RR, 0.76; 95% CI, 0.71–0.82) with use of NOACs versus VKA.24 Although not statistically lower, gastrointestinal bleeding events were comparable to VKA treatment. When used in nonvalvular atrial fibrillation, all of the targeted agents had a statistically significant reduction in ICH compared with warfarin.8–11 A possible explanation for this is the fact that the brain has higher levels of tissue factor, and the reduction of Factor VIIa that results from use of VKA translates into higher complication rates in the brain due to downregulation of the extrinsic pathway. In all six published phase III studies evaluating NOACs in treatment of acute VTE, major bleeding rates were found to be similar to, if not lower than, VKA therapy. Major bleeding rates were lower than VKAs with apixaban (AMPLIFY study) Seminars in Thrombosis & Hemostasis

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Abbreviation: NOAC, non–vitamin K antagonist oral anticoagulant.

The New Non–Vitamin K Antagonist Oral Anticoagulants

McMahon, Kwaan

Table 2 Major bleeding of NOACs versus warfarin

Dabigatran

Atrial fibrillation

Acute VTE

Extended VTE

150 mg BID: RR 0.93 (0.81–1.07)

HR 0.82 (0.45–1.48)

vs. warfarin 0.52 (0.27–1.02) vs. placebo 2.92a(1.52–5.60)

110 mg BID: RR 0.80 (0.69–0.93) Rivaroxaban

HR 1.04 (0.90–1.20)

HR 0.49 (0.31–0.79)

vs. placebo 5.19a (2.3–11.7)

Apixaban

HR 0.69 (0.60–0.80)

HR 0.30 (0.17–0.55)

5 mg vs. placebo 0.25 (0.03–2.24)

Edoxaban

HR 0.47 (0.41–0.55)

HR 0.84 (0.59–1.21)

2.5 mg vs. placebo 0.49 (0.09–2.64)

Abbreviations: BID, twice a day; HR, hazard ratio; NOAC, non–vitamin K antagonist oral anticoagulant; VTE, venous thromboembolism Note: Statistically significant values are given in bold. a Major or clinically relevant nonmajor bleeding.

and rivaroxaban (EINSTEIN-PE study) (RR, 0.31; 95% CI, 0.17– 0.55 and hazard ratio (HR), 0.49; 95% CI, 0.31–0.79, respectively), which reached statistical significance. Many of the NOACs were evaluated for extended use of anticoagulation for VTE prevention following standard treatment duration. Bleeding rates were expectedly higher in the case of rivaroxaban and dabigatran when compared with placebo. However, major and clinically relevant nonmajor bleeding was considerably lower with extended use of dabigatran 150 mg bid compared with warfarin using a target INR of 2.0 to 3.0 (RR, 0.54; 95% CI, 0.41–0.71).14 Surprisingly, despite having placebo as the control arm in the AMPLIFY-EXT study, bleeding rates were comparable to placebo with both apixaban 2.5 mg and 5 mg dosing.13 In the meta-analysis of six phase III studies for acute treatment of VTE, treatment with a NOAC was associated with a 39% relative risk reduction in major (RR, 0.61; 95% CI, 0.45–0.83) and clinically relevant nonmajor bleeding (RR, 0.73; 95% CI, 0.58–0.93). An important statistical reduction in ICH (RR, 0.37; 95% CI, 0.21–0.68) and fatal bleeding (RR, 0.36; 95% CI, 0.15–0.84) was also seen, and while major gastrointestinal bleeding was also less, this did not meet statistical significance.21

“Real-World” Experiences Safety of NOACs in multiple phase III studies was extremely favorable. Whether this translates into improvements in general practice has been a concern since these agents became FDA approved. Thus far, concerns have been alleviated based on early experience in patients outside of clinical studies. In the RELY study (dabigatran in atrial fibrillation), while rates of ICH were lower than that treated with warfarin, rates of GI bleeding were higher in those treated with dabigatran at 150 mg bid dosing (1.6 vs. 1.1/100 patient years).8 Following its approval in October 2010, there was an initial rate of bleeding reported in general use that was much higher than expected. After further investigation from the FDA MiniSentinel database, it was felt that this was related to increased vigilance of the new drugs compared with standard treatments. The database was evaluated over a 1-year period that covered the immediate time following dabigatran approval (October 2010–December 2011), and overall bleeding rates were comparable, if not in favor of dabigatran. Over 100,000 Seminars in Thrombosis & Hemostasis

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patient days, rates of GI bleeding were lower with use of dabigatran (1.6) than with use of warfarin (3.5). Episodes of ICH were also lower with dabigatran (0.8) compared with warfarin (2.4) over the same time frame. A recent study evaluated rates and types of bleeding complications with rivaroxaban in general practice.25 Over 1,700 patients were followed up for an average of 2 years, with 43% of patients reporting a total of 1,082 bleeding events, the majority (58.9%) were minor, and only 6% were considered major. When used for atrial fibrillation, major bleeding rates were 3.1 per 100 patient-years, versus 4.1 per 100 patient-years when used for VTE treatment. Case fatality rates were 5.1 and 6.3% at 30 and 90 days, respectively. The authors concluded that bleeding rates and outcomes with rivaroxaban were comparable to, if not better than, VKA in real-world use.

Use in Populations Who May Require Monitoring With the more reliable pharmacokinetics of the new generation, targeted anticoagulants, there is less need for routine laboratory testing. This has made them very attractive alternatives to VKA, and their oral bioavailability providing additional advantage over heparin/LMWHs. However, it has also raised considerable concern when applying their use broadly, to include populations of patients who may be more susceptible to bleeding complications on anticoagulation, or for that matter, may not be adequately anticoagulated with standard dosing, thereby leaving them susceptible to recurrent thrombosis. These potentially more vulnerable patient groups are listed in ►Table 3. There are emerging data regarding the efficacy and safety of the NOACs in these patients, and likely much more information will follow in the near future.

Age In the phase III studies involving dabigatran, there was a trend toward higher bleeding with older patients at both the 110-mg and 150-mg doses. Treatment by age interaction was statistically significant.26 This effect was not found with the other NOACs. Higher bleeding rates with age in patients on dabigatran may be due to the drug’s higher reliance on renal elimination compared with the direct Xa inhibitors. Importantly, while rates of bleeding with dabigatran use appear to

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The New Non–Vitamin K Antagonist Oral Anticoagulants

• Extremes of weight (100 kg) • Active malignancy • Presence of renal and/or hepatic impairment • Polypharmacy • Bleeding or high risk of bleeding • Recurrent thrombotic events especially while on anticoagulation • Compliance issues

patients enrolled exceeded 100 kg. For example, in the EINSTEIN studies, over 14% were >100 kg, and in the AMPLIFY study, this number was 19%.15,16 Van Es et al reported in their meta-analysis that weight >100 kg did not affect endpoints, with subgroup analysis of these patients still showing comparable efficacy, and meeting criteria for noninferiority compared with VKA.21 However, as overall numbers of obese patients enrolled in the studies were relatively low, and prevalence of the disease is high, caution with use in extremely under- or overweight individuals must be used until more clinical data are available, and reliable testing methods are accessible.

Renal Impairment increase with age, the rates are still comparable to those seen with VKA. In addition, the incidence of intracranial hemorrhage in those older than 75 years remained lower with dabigatran compared with warfarin. A meta-analysis of randomized controlled trials of apixaban, rivaroxaban, and dabigatran evaluated bleeding risk in patients older than 75 years.27 A total of 10 trials were included, which involved more than 25,000 elderly patients. There was no difference in major bleeding or clinically relevant nonmajor bleeding with NOAC and conventional treatment (OR, 1.02). Also, results from this meta-analysis showed NOACs were more efficacious in both atrial fibrillation for reducing rates of stroke and systemic embolization, as well as in the acute management of VTE.27 Similar findings were reported in a pooled analysis of all phase III studies evaluating the safety/efficacy of NOACs compared with VKA in treatment of acute VTE. Treatment with these agents was associated with a reduction in VTE recurrence in those 75 years of age or older, which reached statistical significance (RR, 0.56; 95% CI, 0.38–0.82).21 While there was a significant risk for bleeding with both VKA- and NOAC-treated patients 75 years of age or older, major bleeding was still statistically lower in those who received a NOAC (RR, 0.49; 95% CI, 0.25–0.96).

Weight Treatment with VKAs requires frequent laboratory monitoring to ensure adequate anticoagulant effect. Degree of anticoagulation with VKAs is more dependent on genetic factors, hepatic function, dietary factors, and interaction with other medications more so than patient weight. LMWHs are dosed on the basis of patient body weight. Many of the studies evaluating the safety and efficacy of LMWH in VTE prevention and treatment excluded those  40 kg or  150 kg.28 In practice, there have been concerns raised about using weight-based doses in obesity, with potential for inadequate anticoagulation and increasing thrombotic risk. However, most of the pharmacodynamic and clinical studies have demonstrated that dosing of LMWH should be based on total body weight. As the NOACs were studied without the need for routine monitoring, and dosing is not based on patient weight, similar concerns have been raised in using these agents in obese individuals. The phase III studies did not exclude entry based on obesity; in fact, the many of the

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All of the targeted anticoagulants have some degree of renal clearance, with dabigatran having the most (80%), and apixaban the least (25–27%). Patients with severe renal dysfunction (GFR < 25–30 mL/min) were therefore excluded from the phase III studies. Despite this, there are FDA-approved dosing regimens for those with renal impairment. In those with moderate renal impairment (creatinine clearance 30–49 mL/min), use of NOAC was still as effective as VKA in VTE treatment, with a statistically lower rate of major bleeding (RR, 0.51; 95% CI, 0.26–0.99).21 It is important to note that doses were reduced if there was renal insufficiency (creatinine clearance 30–49 mL/min) in the rivaroxaban and apixaban trials. Even though there are dosing recommendations for NOACs in those with more significant renal impairment, caution would be recommended for their use in this population, as they were excluded from phase III studies, at least until more clinical data are made available and a validated monitoring assay is more widely available.

Cancer Active malignancy is a well-established risk factor for VTE and VTE recurrence. Treatment with LMWH has been demonstrated to be superior to VKA therapy in the CLOT study,29 and is therefore recommended as standard of care in this population.23 While those with malignancy were allowed entry into the NOAC studies, enrollment of these patients was universally low, ranging from 3% (AMPLIFY) to 10% (Hokusai-VTE).15,20 It is difficult to conclude much with these small numbers individually; however, a meta-analysis of all six studies of NOAC use in acute VTE treatment, with pooled analysis of 1,581 patients, demonstrated lower thrombotic recurrence in those treated with NOAC (3.4%) versus VKA (5.9%), which reached statistical significance (RR, 0.57; 95% CI, 0.77–1.06).21 Bleeding rates were higher in cancer patients than those noncancer patients, but comparable between NOACs and VKA (RR, 0.61; 95% CI, 0.45–0.83). Data on type of malignancy, stage, and active use of chemotherapy were not available, and comparator of a VKA is not currently considered standard of care for malignancy-associated thrombosis. While these results are encouraging, additional clinical investigation is needed to better clarify a role for NOAC in this setting. Evaluation of NOACs versus LMWH in malignancy-associated thrombosis in prospective studies will be helpful to elucidate potential use in this patient population. Seminars in Thrombosis & Hemostasis

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Table 3 Vulnerable populations where monitoring may be needed

McMahon, Kwaan

The New Non–Vitamin K Antagonist Oral Anticoagulants

McMahon, Kwaan

One additional concern for use of NOACs in cancer patients is potential interaction with disease-specific drugs that may not have been fully evaluated in clinical studies to date. Since these medications are substrates for p-glycoprotein, and CYP3A4 with the Xa inhibitors, cancer-specific medications such as tamoxifen, cyclosporine, tyrosine kinase inhibitors, and tacrolimus may increase anticoagulant levels, hence potentially raising bleeding risk. Alternatively, inducers of p-glycoprotein and CYP3A4 such as dexamethasone, doxorubicin, and vinblastine may lower NOAC levels, possibly resulting in inadequate anticoagulation.30

complex concentrate (PCC) are available: the “three-factor PCC” containing prothrombin and factors IX and X and the “four-factor PCC” containing prothrombin, factors VII, IX, and X can be found. The PCCs have the advantage over fresh– frozen plasma in that lesser volume is needed as well as a higher safety index with less likelihood of carrying infectious agents.33 A study directly comparing fresh–frozen plasma with PCC showed that rapid correction of coagulopathy can be effectively accomplished with PCC, and that if INR is >5, fresh–frozen plasma should not be used because of the large volume needed.34 In a randomized study on urgent reversal of warfarin-treated patients with acute major bleeding, the four-factor PCC was found to normalize the INR within 30 minutes with less circulatory overload.33

Reversal Patients on NOACs may require reversal of the anticoagulant activity either acutely or as an elective measure (as listed in ►Table 4). Reversal is needed urgently when bleeding develops during therapy, when there is acute traumatic injury, or before a nonelective invasive procedure. Reversal is also needed when a patient develops a rapid impairment of either renal or hepatic function resulting in decrease in clearance of the NOAC. As anticoagulant therapy is most often given on a long-term basis, patient may receive a new medication that either has drug interactions with the NOAC leading to increase anticoagulant activity or an adverse effect on patient’s renal or hepatic function. In the case of warfarin, the regimen for reversal of anticoagulant effects has been well established. The reduced levels of clotting factors (V, VII, IX, and X) can be reversed by giving vitamin K, or if reversal is required quickly, by replacement of these factors through transfusion of fresh–frozen plasma. In the case of the NOACs, however, there is no approved antidote. The mainstay is the replacement of clotting factors. Various regimens using clotting factor are available.

Fresh–Frozen Plasma Though this contains (replacement) clotting factors, the volume needed for reversal of NOAC activity may be large and presents the problem of circulatory overload. Furthermore, there is a risk of transfusion-related acute lung injury (TRALI),31 allergy, and infection.32

Prothrombin Complex Concentrates These are preparations from plasma that contain varying amounts of prothrombin, factors VII, IX, and X, as well as proteins C and S. At present, two forms of prothrombin

Table 4 Conditions requiring reversal of anticoagulation • Major bleeding during therapy • Prior to an invasive procedures • Acute traumatic injury • For unexpected impairment of clearance of drug • When patient had inadvertently taken a drug with interaction • Can be elective or urgent Seminars in Thrombosis & Hemostasis

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FEIBA and Recombinant Factor VIIa In addition to the aforementioned preparations, two other agents are available, FEIBA and recombinant factor VIIa (rFVIIa). In patients with intracranial hemorrhage complicating warfarin therapy, it was found that rFVIIa gave a better correction of the INR than with PCC.35 FEIBA was originally developed to treat the bleeding seen in patients with factor VIII inhibitor, hence its name FEIBA (Factor Eight Inhibitor Binding Activity).36 FEIBA contains in vitro activated factors IX and X and prothrombin with a small amount of factor VII. The use of both FEIBA and FVIIa carries the risk of thrombosis.36–38 The risk is dose dependent and higher when more than one preparation (PCC/FEIBA/rFVIIa) is used. In addition, this risk increases in the setting of using these agents for reversal of anticoagulation in patients with thromboembolic disorders. In using these preparations, the in vitro life span should be taken into consideration. In healthy subjects, the half-lives of these clotting factors are 4.2 hours for factor VII, 16.7 hours for factor IX, 30.7 hours for factor X, and 59.7 hours for prothrombin. However, in bleeding patients in which these factors are rapidly consumed, their half-lives are considerably shorter. Likewise, the half-lives of activated factors are also shorter.

Assessment of Reversal and Other Options for Reversal The initial application of these concentrates for reversal of NOAC anticoagulant activity was tested in human volunteers. In the case of dabigatran, a phase I study with 12 human volunteers who took dabigatran, the four-factor PCC did not correct the thrombin time, aPTT, or ecarin clotting time.39 However, there are anecdotal reports of successful outcome using activated PCC for dabigatran-associated bleeding.40,41 Other measures to reverse dabigatran effects include oral administration of activated charcoal to bind unabsorbed drug in the gastrointestinal tract,42,43 and hemodialysis as the drug is minimally bound to protein in blood and mainly excreted by the kidneys.44,45 There is also a specific antidote for dabigatran under development.46 This is a single chain antibody fragment, aDabi-Fab, which can bind dabigatran and reverse the anticoagulant effect both vitro and in vivo. The affinity of aDabi-Fab for dabigatran is approximately 350 times that of thrombin. The resultant complex has no effect

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Conclusion and Future Directions Experience with the use of the NOACs in the past 3 years had altered our thoughts on the development of future anticoagulants (►Table 5). The issue of “no need for monitoring” is no longer a realistic goal. Instead, limited monitoring will be desirable. Reversal of drug action should be possible with at least one antidote. It should also be one with rapid onset of action, as reversal is often required under pressing conditions. The pharmacologic characteristics should have the drug

action tailored to specific mechanism of thrombosis, that is, thrombin binding, fibrin binding, platelet binding, and/or endothelial binding. It should have the capability of both oral and parenteral administration. Its clearance should be either hepatic or renal but not both. It should have rapid onset of action (abolishing the need for bridging). The duration of action should vary with different drugs. Last but not least is that the cost should be reasonable and affordable.

References 1 Weitz JI. New oral anticoagulants in development. Thromb Hae-

most 2010;103(1):62–70 2 Eikelboom JW, Weitz JI. New anticoagulants. Circulation 2010;

121(13):1523–1532 3 Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and

4

5

6

7

8

9

10

11

12

13

Table 5 Desired characteristics of an antithrombotic drug • Limited monitoring

14

• Antidote—rapid action • Pharmacologic characteristics 

    

Action tailored to specific mechanism of thrombosis— thrombin binding, fibrin binding, platelet binding, inhibition of selectins (endothelial binding) Both oral and parenteral administration Clearance: either hepatic or renal but not both Rapid onset of action (abolishing the need for bridging) Prolonged duration of action Reasonable cost

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15

16

17

excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2009;37(5):1056–1064 Connolly SJ, Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J 2013; 34(20):1498–1505 Palladino M, Merli G, Thomson L. Evaluation of the oral direct factor Xa inhibitor - betrixaban. Expert Opin Investig Drugs 2013; 22(11):1465–1472 Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, van Ryn J. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol 2010;30(10): 1885–1889 Liesenfeld KH, Lehr T, Dansirikul C, et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011;9(11):2168–2175 Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139–1151 Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981–992 Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883–891 Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369(22):2093–2104 Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013;61(22):2264–2273 Agnelli G, Buller HR, Cohen A, et al; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368(8):699–708 Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368(8):709–718 Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369(9):799–808 Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363(26):2499–2510 Büller HR, Prins MH, Lensin AW, et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366(14):1287–1297

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on coagulation or platelet function. It is presently in phase 1 clinical trial. There is one antidote for anti-Xa NOACs at the time of this writing, undergoing clinical trial.47 This compound, andexanet alfa (PRT064445), is essentially recombinant factor Xa, with modification at three locations: deletion of the a 34residue fragment (residues 46–78), replacement of the activation peptide with ArgLysArg (RKR) to form the RKRRKR linker that connects the light chain to the heavy chain, and mutation of the active-site serine to alanine (S419A). The resulting compound lacks clotting activity, but can bind direct factor Xa inhibitors. In ex vivo mixture with antiXa NOACs, the prolongation of the different clotting tests is reversed. Rabbits treated with rivaroxaban had bleeding from experimental injuries controlled by this compound. A phase 2 clinical trial of reversal of rivaroxaban in healthy subjects by andexanet alfa demonstrated that the reversal is dose dependent.48 Andexanet alfa is undergoing a phase 3 clinical trial at the time of writing this article. In addition, another drug is currently under development. This is a synthetic small molecule, PER977, that has the property of direct noncovalent binding of the active sites of all the NOACs and all forms of heparin, by forming inactive molecular complexes.49 The drug itself or these complexes do not have coagulant or anticoagulant properties. Studies by thromboelastography showed that the abnormal changes in heparinized blood can be restored to normal by this compound. In vivo studies in rats showed the reversal of the bleeding tendency as well. Safety in human (phase 1 study) is being tested any evidence of adverse effects, particularly for allergic and immunologic reactions.

McMahon, Kwaan

The New Non–Vitamin K Antagonist Oral Anticoagulants

McMahon, Kwaan

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Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129(7):764–772 Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361(24):2342–2352 Büller HR, Décousus H, Grosso MA, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369(15): 1406–1415 van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014;124(12):1968–1975 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139(11): 893–900 Kearon C, Akl EA, Comerota AJ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2, Suppl):e419S–e494S Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014;124(15):2450–2458 Beyer-Westendorf J, Förster K, Pannach S, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014;124(6):955–962 Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011;123(21):2363–2372 Sardar P, Chatterjee S, Chaudhari S, Lip GY. New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014;62(5):857–864 Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecularweight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother 2009;43(6):1064–1083 Lee AY, Levine MN, Baker RI, et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349(2):146–153 Lee AY, Peterson EA. Treatment of cancer-associated thrombosis. Blood 2013;122(14):2310–2317 Toy P, Gajic O, Bacchetti P, et al; TRALI Study Group. Transfusionrelated acute lung injury: incidence and risk factors. Blood 2012; 119(7):1757–1767 Sayah DM, Looney MR, Toy P. Transfusion reactions: newer concepts on the pathophysiology, incidence, treatment, and prevention of transfusion-related acute lung injury. Crit Care Clin 2012; 28(3):363–372, v

bin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011; 106(3):429–438 Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997;77(3): 477–480 Pinner NA, Hurdle AC, Oliphant C, Reaves A, Lobo B, Sills A. Treatment of warfarin-related intracranial hemorrhage: a comparison of prothrombin complex concentrate and recombinant activated factor VII. World Neurosurg 2010;74(6):631–635 Key NS, Negrier C. Coagulation factor concentrates: past, present, and future. Lancet 2007;370(9585):439–448 Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363(19):1791–1800 Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost 2004;2(10):1700–1708 Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124(14): 1573–1579 Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in lifethreatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med 2013;41(5): e42–e46 Schulman S, Ritchie B, Goy JK, Nahirniak S, Almutawa M, Ghanny S. Activated prothrombin complex concentrate for dabigatran-associated bleeding. Br J Haematol 2014;164(2):308–310 van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103(6):1116–1127 Woo JS, Kapadia N, Phanco SE, Lynch CA. Positive outcome after intentional overdose of dabigatran. J Med Toxicol 2013;9(2):192–195 Chen BC, Sheth NR, Dadzie KA, et al. Hemodialysis for the treatment of pulmonary hemorrhage from dabigatran overdose. Am J Kidney Dis 2013;62(3):591–594 Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 2012;46(9):e21 Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121(18):3554–3562 Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013;19(4):446–451 Crowther M, Mathur V, Kitt M, Lu G, Conley PB, Hollenbach S. A phase 2 randomized, double blind, placebo-controlled trial demonstrating reversal of rivaroxoban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for FXa inhibitors [Abstract]. Blood 2013;122:3636 Laulicht BBS, Lee C, Baker C, Jiang X, Mathiowitz E. Small molecule antidote for anticoagulants [Abstract]. Circulation 2012;126: A-11395

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