Central Journal of Family Medicine & Community Health

Cite this article: Ranger NS, Ward MA (2015) A Comparison of the Direct Oral Anticoagulants in Treatment of Acute Deep Vein Thrombosis for Primary Care Physicians. J Family Med Community Health 2(2): 1032.

Abstract

Management of acute deep vein thrombosis (DVT) is within the scope of primary care physicians. When indicated, treatment is essential to prevent life-threatening pulmonary embolism (PE). Parenteral anticoagulation followed by warfarin has been considered the standard of care. Four pivotal trials have established a role for direct oral anticoagulants (DOACs) in acute treatment of DVT. Dabigatran, rivaroxaban, apixaban, and edoxaban have been shown to have similar efficacy compared to warfarin in the management of acute DVT. These new agents offer similar, or superior, bleeding risks and have distinctive properties that may affect clinicians’ prescribing have distinctive properties that practices. Here we summarize the key findings of these four trials and offer some insights as to which agents may be better suited to specific clinical scenarios.

*Corresponding authorNathalie S. Ranger, Department of Family Medicine, Queens University, Kingston, Ontario, Canada, Email:

Submitted: 22 January 2015

Accepted: 06 April 2015

Published: 08 April 2015

Copyright© 2015 Ranger NS et al.

OPEN ACCESS

Keywords•Deep vein thrombosis•Pulmonary embolism•Dabigatran•Rivaroxaban•Apixaban•Edoxaban

Research Article

A Comparison of the Direct Oral Anticoagulants in Treatment of Acute Deep Vein Thrombosis for Primary Care PhysiciansNathalie S. Ranger1* and Michael A. Ward1,2

1Department of Family Medicine, Queens University, Canada 2Department of Family and Community Medicine, University of Toronto, Canada

INTRODUCTIONThe annual incidence of acute deep vein thrombosis (DVT)

in the general population remains 0.1 to 0.2%. As such, a family physician with an average sized practice can expect to see 2 to 4 cases of DVT per year [1]. Approximately one-third to one-half of untreated lower extremity DVTs will result in a pulmonary embolism (PE). The mortality rate of untreated PE is approximately 30% [2]. This can be reduced to between 3 to 8% if treatment is initiated [2]. In survivors, the risk of persistent pulmonary hypertension (PPH) is 0.57 to 3.8% after acute PE and over 10% after recurrent PE [3]. PPH can progress and lead to potentially fatal right-sided heart failure [3]. The post-thrombotic syndrome, a painful condition that can result in chronic leg swelling, skin hyper-pigmentation, and venous ulcers, is also a worrisome complication of DVT occurring in about 40% of patients [4].

Clinical scoring tools were developed to aid in the diagnosis of DVT in the outpatient setting. The most commonly used algorithm is the “Well’s score” (Table 1) [5]. It incorporates signs and symptoms, risk factors, and likelihood of an alternate diagnosis to generate a pre-test probability of DVT and guide further management. DVT can be effectively ruled out in low risk patients with a normal high-sensitivity D-dimer assay [6]. However, if imaging is deemed necessary, based on a higher initial risk category or a positive D-dimer test, the patient should

be sent for compression ultrasonography for direct visualization and diagnosis [7].

Until recently, the sole option for treatment of proximal leg DVTs was the combination of a short-term parenteral anticoagulant (typically a low molecular weight heparin [LMWH]) followed by a mid- or long-term oral anticoagulant (typically a vitamin K antagonist [VKA] such as warfarin). The decision to treat or simply follow distal (below the knee) DVTs with serial ultrasound should be made on an individual basis after consideration of each patient’s unique clinical risk [8]. Patients considered to be at high risk for DVT may have anticoagulation initiated before results of imaging are available [8].

When the decision is made to treat DVT, anticoagulation is considered the standard of care. The short-term goal is preventing clot extension and PE while the long-term goal is prevention of recurrence [9]. Primary care physicians are often responsible for initiating and/or monitoring VKA anticoagulation with the goal of maintaining an international normalized ratio (INR) between 2.0 and 3.0. Reliable outpatient parenteral anticoagulation may be difficult to organize in some clinical settings, and warfarin initiation and continuation is both labour-intensive and subject to significant patient-to-patient variability [10]. Warfarin is continued mid- or long-term, with duration depending on presence of risk factors to explain the DVT, whether these are transient or persistent, and whether or not it is a recurrent DVT [4]. It is generally accepted that all patients with proximal DVT

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should be treated for a minimum of three months (‘mid-term’), with extension to at least six months (‘long-term’) if idiopathic DVT or active cancer and indefinite duration if it is a recurrent DVT (with annual re-assessment) [9].

It is worthwhile noting that sparse randomized controlled trial (RCT) evidence exists supporting the routine use of anticoagulation in the treatment of acute DVT [11,12]. Indeed older, small, underpowered trials found little difference in outcome between non-steroidal anti-inflammatory drugs (NSAIDs), placebo, and anticoagulation in the management of DVT/PE [11,12]. Evidence for warfarin’s effectiveness comes primarily from older observational studies [11] showing decreased risk of PE in treated versus untreated DVT and our own collective historical clinical experience. Although one might argue that the use of anticoagulation to treat DVT is not grounded in rigorous RCT evidence, or that it is not clearly better than treatment with an NSAID (small underpowered trials), it is important to note that aspirin is not currently recommended for initial treatment of DVT. However, recent trials suggest that aspirin can be considered for extended treatment of first unprovoked DVT after completion of standard anticoagulant therapy in patients where there exists clinical equipoise as to whether or not to extend treatment [13-15].

Despite the seeming lack of RCT evidence, anticoagulation for DVT remains the standard of care. A new class of medications known as the direct oral anticoagulants (DOACs) – dabigatran [16], rivaroxaban [17], apixaban [18], and edoxaban [19] – have emerged as new options for the treatment of acute DVT [19-22], extended DVT [19,22-24], and PE [19-22]. Regulatory agencies have approved a direct thrombin inhibitor (dabigatran) and three factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) [25] for the outpatient management of DVT; currently, edoxaban has been approved in the United States but has not yet been approved for use in Canada or Europe.

Most of the DOACs are associated with a reduction in clinically significant bleeding compared to warfarin and offer the benefit of not requiring ongoing blood level monitoring [10]; this represents a substantial increase in patient satisfaction and ease

of use. Additionally, the new agents have significantly fewer drug interactions (Table 2). They are renally excreted at different rates and require once or twice yearly monitoring of renal function tests [26]. There remains some concern that no direct reversal agents are available at this time [10].

The DOACs also have a rapid onset of action. Indeed apixaban and rivaroxaban were studied as stand-alone anticoagulants and do not require the traditional bridging with a parenteral anticoagulant. This translates into an option for ‘oral-only’ treatment of acute DVT, simplifying the treatment regime considerably [10].

Four landmark trials have been published comparing the novel DOACs to warfarin for the treatment of acute DVT. They were designed as non-inferiority studies (e.g. the DOAC demonstrating at least 50% of the proven efficacy of standard therapy) [27]. We will review the salient features of each of these trials and present an unbiased view of the potential role of these new agents from a primary care perspective. We also encourage primary care clinicians to consider reviewing previously published analyses written from our specialist consultants’ perspectives [10,26,28].

METHODS

Inclusion criteria for considering studies for this critical appraisal

Study design: Criteria for inclusion in this review included: 1) published randomized controlled trials (RCTs) that compared interventions for treatment of acute VTE versus warfarin in adults (18 years of age or older), 2) trials must have used randomized allocation and single or double blinding, and 3) the results were to be presented using an intention-to-treat or modified intention-to-treat analysis with a follow-up length of three to twelve months.

The aim of this paper was to critically analyze the four landmark trials investigating DOAC use in acute DVT treatment. The literature search was completed to identify these trials in addition to any outstanding comparable trials that warranted inclusion.

Clinical feature Score

Active cancer (treatment ongoing or within previous 6 months or palliative) 1

Paralysis, paresis, or recent orthopedic casting of a lower extremity 1

Recently bedridden for longer than three days or major surgery within the past four weeks 1

Localized tenderness in the deep vein system 1

Swelling of an entire leg 1

Calf swelling 3 cm greater than the other leg, measured 10 cm below the tibial tuberosity 1

Pitting edema greater in the symptomatic leg 1

Collateral non-varicose superficial veins 1Alternative diagnosis more likely than DVT (e.g. Baker's cyst, cellulitis, muscle damage, post phlebitic syndrome, inguinal lymphadenopathy, external venous compression) -2

≤ 0 = low probability (3% prevalence of DVT)1-2 points = moderate probability (17% prevalence of DVT)3-8 points = high probability (75% prevalence of DVT)

Table 1: Wells criteria for DVT.

Adapted from Wells et al., 1997 [5].

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DOAC Interaction Contraindication to Simultaneous Use

Dabigatran[16]

KetoconazoleQuinidineAmiodaroneVerapamil RifampinSt. John’s WortClarithromycin

KetoconazoleRifampinSt. John’s Wort

Rivaroxaban[17]

KetaconazoleRifampinSt. John’s WortClarithromycin RitonavirAnticonvulsantsPhenytoinCarbamazepine Phenobarbital

Azole antifungalsKetoconazoleItrakonazoleVorikonazolePosakonazoleRitonavirRifampinSt. John’s Wort

Apixaban[18] (See rivaroxaban) (See rivaroxaban)

Edoxaban (See rivaroxaban) (Not yet approved in Canada or Europe; product monograph not currently available in United States)

Table 2: Drug interactions and contraindications to concomitant use of DOACs.

Adapted from Schulman, 2014 [10].

Table 3: RE-COVER trial results: summary [20].Dabigatran150 mg BID Warfarin Dabigatran 150 mg BID vs.

warfarin % % Hazard ratio (95% CI) P value

VTE or related death 2.4 2.1 1.10 (0.65-1.84) <0.001

Symptomatic DVT 1.3 1.4 0.87 (0.44-1.71) /

Symptomatic nonfatal PE 1.0 0.6 1.85 (0.74-4.64) /

Death related to VTE 0.1 0.2 0.33 (0.03-3.15) /Major or clinically relevant non-major bleeding 5.6 8.8 0.63 (0.47-0.84) 0.002

Major bleeding 1.6 1.9 0.82 (0.45-1.48) /

ICH 0 0.2 / /

GI bleed 4.2 2.8 / /

Dyspepsia 3.1 0.7 / <0.001

Acute coronary syndrome 0.4 0.2 / /

Myocardial infarction 0.3 0.2 / 0.69

All-cause mortality 1.6 1.7 0.98 (0.53-1.79) /

/ =Not reported

Outcome measureThe studies reviewed used a primary efficacy outcome of the

incidence of recurrent symptomatic VTE (fatal or non-fatal PE and DVT) and/or death related to VTE [20]. The primary safety outcome was major bleeding (defined as overt and hemoglobin reduction of 20 g per liter or more, requiring 2 or more units of blood transfused, occurring at a critical site, or contributing to death) [20] and/or clinically relevant non-major bleeding (defined as overt bleeding not meeting criteria for major bleeding but associated with medical intervention, assessment by a physician, study drug interruption, or discomfort/impairment in completing activities of daily living) [20].

Exclusion criteria

RCTs that did not use warfarin as a comparator intervention

were excluded. Studies published in a non-English language were also excluded.

Search methods for identification of studies

The following databases were searched: PUBMED, MEDLINE, EMBASE, The Cochrane Library, and ClinicalTrials.gov.

The PUBMED search was completed on October 6, 2014, updating a search that took place on May 20, 2014. It was searched from 2004 to the present. The PUBMED search strategy was as follows: ((“new oral anticoagulants”) AND (“deep vein thrombosis”)). This search identified the following new oral anticoagulants as currently available for use: dabigatran, rivaroxaban, apixaban, and edoxaban (approved in the United States). The search strategy utilized the term “new oral

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Table 4: EINSTEIN acute DVT trial results: summary [22].

Rivaroxaban Enoxaparin-VKA Rivaroxaban vs. enoxaparin-VKA

% % Hazard ratio (95% CI) P value

Recurrent VTE 2.1 3.0 0.68 (0.44-1.04) <0.001

Fatal PE 0.06 0 / /

Nonfatal PE 1.2 1.0 1.85 (0.74-4.64) /Combined first major or clinically relevant non-major bleeding 8.1 8.1 0.97 (0.76-1.22) 0.77

Major bleeding 0.8 1.2 0.65 (0.33-1.30) 0.21

Clinically relevant non-major bleeding 7.3 7.0 / /

Vascular events 0.7 0.8 0.79 (0.36-1.71) 0.55

All-cause mortality 2.2 2.9 0.67 (0.44-1.02) 0.06

/ =Not reported

or PE. Importantly, all patients were initially given parenteral anticoagulation, for a mean duration of 10 days, before receiving exclusive treatment with dabigatran or warfarin. The primary efficacy endpoints were time to recurrent symptomatic VTE and/or death related to VTE within 6 months after primary objective diagnosis of symptomatic proximal DVT or PE. A total of 2564 patients were randomized with 2539 included in a modified intention-to-treat analysis (patients who did not receive any study drug were excluded from analyses) and 27 were lost to follow-up. Patients on warfarin were within the INR therapeutic range (2.0 to 3.0) 60% of the time. A central committee, unaware of drug allocation, adjudicated all events. Trial outcomes are summarized in table 3.

Results of data collected during the study period showed a recurrence of VTE or death in 2.4% of patients on dabigatran versus 2.1% on warfarin (hazard ratio [HR] 1.10; 95% confidence interval [CI] 0.65-1.84; P<0.001), meeting requirements for non-inferiority. A priori criteria for superiority were not reached. Major bleeding occurred in 1.6% of patients on dabigatran and 1.9% on warfarin (HR 0.82, 95% CI 0.45-1.48). The authors suggested that dabigatran 150 mg twice daily was as effective as warfarin at reducing recurrent VTE risk, and was associated with equivalent risk of major bleeding and less non-major bleeding.

There was no significant difference in rates of acute coronary syndrome (ACS) or myocardial infarction (MI). An elevated risk of MI had been reported previously in the RE-LY trial [29]. This trial investigated dabigatran versus warfarin for prevention of stroke or systemic embolism in patients with atrial fibrillation and an average CHADS score of 2.1. A subsequent meta-analysis of trials including dabigatran supported the finding of higher risk of MI, but also showed decreased all-cause mortality with this agent [30]. This risk remains somewhat controversial and may be, in part, explained by the known cardioprotective activity of warfarin [31].

There was a trend towards a higher incidence of gastrointestinal (GI) bleeding in the dabigatran group, as seen in the RE-LY trial [29], but this did not reach statistical significance.

Subjective complaints of dyspepsia were more frequently observed in the dabigatran group than in the warfarin group, perhaps reflecting the acidic nature of the gut milieu as the drug is absorbed [29].

Dabigatran is currently approved for acute DVT treatment in Canada, the United States, and Europe.

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor [17]. The EINSTEIN-DVT trial [22] included two studies of rivaroxaban versus warfarin – the first arm examined treatment of acute DVT while the second arm examined the continued treatment of VTE. The first arm of this trial met inclusion criteria and will be described here. The acute DVT study was a single-blind, open-label, event-driven, non-inferiority RCT comparing oral rivaroxaban only (15 mg twice daily for three weeks followed by 20 mg once daily) for three, six, or twelve months versus standard treatment with subcutaneous enoxaparin (1 mg/kg) followed by oral warfarin or acenocoumarol (both vitamin K antagonists [VKAs]). Enoxaparin was started within 48 hours of diagnosis and discontinued when the patient’s INR was greater than or equal to 2.0 for two consecutive days. All patients in the warfarin group received a minimum of 5 days of parenteral enoxaparin. All participants had symptomatic DVT without symptomatic PE.

Primary efficacy data were evaluated using an intention-to-treat analysis. The primary efficacy outcome was symptomatic, recurrent VTE defined as the combination of DVT or nonfatal or fatal PE. The primary safety outcome, analyzed according to modified intention-to-treat, was clinically relevant bleeding defined as the combination of major or clinically relevant non-major bleeding. A total of 3449 patients were enrolled with a completion rate of 99.0% (33 lost to follow-up). Patients on a VKA were within the INR therapeutic range (2.0 to 3.0) 57.7% of the time. Central, blinded adjudication committees evaluated all suspected outcome events. Trial outcomes are summarized in table 4.

Patients in the rivaroxaban group developed symptomatic VTE recurrence totaling 2.1% versus 3.0% in the enoxaparin-VKA group (HR 0.68; 95% CI 0.44-1.04; P<0.001), establishing non-inferiority of rivaroxaban. For the principal safety outcome, first major or clinically relevant non-major bleeding occurred in 8.1% of patients on rivaroxaban versus 8.1% on standard therapy (HR 0.97, 95% CI 0.76-1.22; P=0.77).

The study’s authors suggested that rivaroxaban was as effective as standard therapy for treatment of acute DVT, with

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a similar safety profile (bleeding risk). Since this was an event-driven study, the duration of treatment was shorter for 5.9% of the patients in the rivaroxaban group versus 5.5% of patients in the standard therapy group. Total duration of treatment (three, six, or twelve months) for individual patients was determined at the discretion of the treating physician, and there were no significant differences between numbers of patients in each treatment group.

There were no increased vascular events or increased all-cause mortality in the rivaroxaban group versus VKA group in this study.

Based on the results of this trial and other safety data [32], rivaroxaban was the first DOAC approved for acute treatment of DVT in Europe, Canada, and the United States. It was also the first exclusively oral treatment approved for VTE management until very recently [17,18].

Apixaban

Apixaban is another oral factor Xa inhibitor [18]. The AMPLIFY trial [21] was a double-blind, non-inferiority RCT comparing apixaban 10 mg twice daily for seven days followed by 5 mg twice daily for six months versus standard treatment (subcutaneous enoxaparin 1 mg/kg twice daily followed by oral warfarin) in patients with symptomatic DVT and/or PE. Enoxaparin or placebo and injections were discontinued once given for at least five days (median duration of 6.5 days) with warfarin or placebo initiated concurrently and discontinued when a blinded INR of 2.0 or greater was reached. Warfarin dose was adjusted to a therapeutic INR between 2.0 to 3.0.

Patients had objectively confirmed symptomatic proximal DVT or PE (with or without DVT). The primary efficacy outcome was the adjudicated combination of incidence of recurrent symptomatic VTE (nonfatal or fatal PE or DVT) or death related to VTE. The primary safety outcome was major bleeding (see definition in Methods section). The secondary safety outcome was composite of major bleeding and clinically relevant non-

major bleeding. If non-inferiority was reached with respect to the primary efficacy outcome, an a priori decision had been made to test for superiority according to a pre-specified order: primary safety outcome, primary efficacy outcome, and secondary safety outcome. A total of 5400 patients were randomized with 5395 included in the intention-to-treat analysis (five excluded due to absent source documentation) and 28 were lost to follow-up. Patients on warfarin were within the INR therapeutic range (2.0 to 3.0) 61% of the time. An independent, blinded committee adjudicated all suspected outcome events. Trial outcomes are summarized in table 5.

Results demonstrated a recurrence of symptomatic VTE or VTE-related death in 2.3% of patients on apixaban versus 2.7% on enoxaparin-warfarin (RR 0.84; 95% CI 0.60-1.18; P<0.001), indicating non-inferiority of apixaban. In terms of the principal safety outcome, major bleeding occurred in 0.6% of patients on apixaban versus 1.8% on standard therapy (RR 0.31, 95% CI 0.17-0.55; P<0.001) and met requirements for superiority.

The study’s authors suggested that oral apixaban alone was as effective as standard therapy to prevent VTE recurrence; furthermore, apixaban was deemed to have a superior safety profile with regards to major bleeding.

The authors also assessed whether efficacy of apixaban differed depending on VTE presentation (i.e. PE, limited DVT or extensive DVT) and reported that efficacy was similar amongst these groups.

Apixaban has recently been approved for the management of acute VTE and prevention of recurrent DVT and PE in the United States, Europe and Canada [18].

Edoxaban

Edoxaban is the third oral factor Xa inhibitor studied for VTE management [19]. The Hokusai-VTE trial [19] was a double-blind, double-dummy, event-driven non-inferiority RCT examining edoxaban 60 mg once daily versus warfarin in patients with

Table 5: AMPLIFY trial results: summary [21].

Apixaban Enoxaparin-warfarin Apixaban vs. enoxaparin-warfarin

% % Relative risk (95% CI) P value

Recurrent VTE or VTE-related death 2.3 2.7 0.84 (0.60-1.18) <0.001

Fatal PE <0.1 0.1 / /

Nonfatal PE (with or without DVT) 1.0 0.9 / /

DVT only 0.8 1.3 / /

Major bleeding 0.6 1.8 0.31 (0.17-0.55) <0.001*

ICH 0.1 0.2 / /

GI bleed 0.3 0.7 / /Combined major or clinically relevant non-major bleeding 4.3 9.7 0.44 (0.36-0.55) <0.001

Clinically relevant non-major bleeding 3.8 8.0 0.48 (0.38-0.60) /

MI 0.2 0.1 / /

All-cause mortality 1.5 1.9 0.79 (0.53-1.19) /*P-value for superiority/ =Not reported

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anticoagulants” rather than “direct oral anticoagulants” to reflect the longer duration of use of the former term.

The Ovid MEDLINE search was completed on September 7, 2014. It was searched from 1996 to the present. The MEDLINE search strategy was as follows: ((“Administration, Oral”[Mesh]) AND (“Anticoagulants”[Mesh]) AND (“Venous Thromboembolism” [Mesh])).

The EMBASE search was completed on October 6, 2014. It was searched from 1980 to the present. The search strategy was as follows: ((“dabigatran/ct AND dabigatran/po [Clinical Trial,Oral Drug Administration]” [Mesh]) AND (venous thromboembolism/ OR deep vein thrombosis/ OR lower extremity deep vein thrombosis/ OR upper extremity deep vein thrombosis/” [Mesh])). Three more searches were completed using the identical search terms but each replaced “dabigatran” with “rivaroxaban,” “apixaban,” or “edoxaban,” respectively.

The Cochrane Library search was completed on October 6, 2014. It was searched from 2004 to the present. The search strategy was as follows: ((“dabigatran”) AND (“deep vein thrombosis”)). Three more searches were completed using the identical search terms but each replaced “dabigatran” with “rivaroxaban,” “apixaban,” or “edoxaban,” respectively.

The ClinicalTrials.gov search was completed on October

6, 2014. It was searched from its start date to the present. The search strategy was as follows: ((“dabigatran”) AND (“deep vein thrombosis”)). Three more searches were completed using the identical search terms but each replaced “dabigatran” with “rivaroxaban,” “apixaban,” or “edoxaban,” respectively.

Data collection and analysis

A total of 213 articles were found. Each full text article was examined according to the criteria for review (see ‘Inclusion criteria for considering studies for this critical appraisal’ and ‘Exclusion criteria’). The article was read in its entirety or until exclusion criteria were met. Articles were included if they presented a robust RCT of an intervention to treat acute DVT using a direct oral anticoagulant in comparison to standard treatment and reported both primary efficacy and safety outcomes. Required duration of follow-up was at least three to twelve months.

RESULTS

Dabigatran

Dabigatran is an oral direct factor IIa (thrombin) inhibitor [16]. The RE-COVER trial [20] was a double-blind, double-dummy non-inferiority RCT of oral dabigatran (150 mg twice daily) versus oral warfarin in patients with symptomatic DVT and/

Table 6: Hokusai-VTE trial results: summary [19].

Edoxaban Heparin-warfarin Edoxaban vs. heparin-warfarin

% % Hazard ratio (95% CI) P valueRecurrent VTE or VTE-related death (while on treatment) 1.6 1.9 0.82 (0.60-1.14) <0.001 (for non-

inferiority)Fatal PE (during overall study period) 0.1 0.1 / /Nonfatal PE with or without DVT (during overall study period) 1.2 1.4 / /

Combined first major or clinically relevant non-major bleeding 8.5 10.3 0.81 (0.71-0.94) 0.004 (for

superiority)

Major bleed 1.4 1.6 0.84 (0.59-1.21) 0.35 (for superiority)

Fatal ICH 0 0.1 / /Nonfatal ICH 0.1 0.3 / /GI bleeding <0.1 <0.1 / /

Clinically relevant non-major bleeding 7.2 8.9 0.80 (0.68-0.93) 0.004 (for superiority)

ACS 0.5 0.3 / /All-cause mortality 3.2 3.1 / // =Not reported

Table 7: Summary of conclusions from individual landmark RCTs of DOACs.

DOAC Trial Conclusion

Dabigatran RECOVER[20] Efficacy: non-inferior to standard therapySafety: similar safety profile (equivalent risk of major bleeding and less non-major bleeding)

Rivaroxaban EINSTEIN-DVT[22] Efficacy: non-inferior to standard therapySafety: similar safety profile (with respect to overall bleeding risk)

Apixaban AMPLIFY[21] Efficacy: non-inferior to standard therapySafety: superior (significantly less major bleeding)

Edoxaban HOKUSAI-VTE[19] Efficacy: non-inferior to standard therapySafety: similar safety profile (major bleeding), but superior for overall bleeding risk

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symptomatic DVT and/or PE. Both groups received parenteral anticoagulation initially, with either open-label enoxaparin or unfractionated heparin (UFH) daily for at least five days (median duration of 7 days). Edoxaban or placebo was started after discontinuation of the parenteral anticoagulant (edoxaban was given as a 30 mg once daily dose if the patient had a creatinine clearance of 30 to 50 mL per minute, body weight of 60 kg or less, or if taking a potent P-glycoprotein inhibitor medication). In the edoxaban and warfarin groups, 17.8% and 17.4% of patients took the 30 mg dose, respectively. Warfarin or placebo was initiated concurrently with heparin and discontinued when a blinded INR of 2.0 or greater was reached. Warfarin dose was adjusted to a therapeutic INR between 2.0 to 3.0. Treatment was completed for a minimum of three months and maximum of twelve months, with duration at the discretion of the treating physician. Patients were contacted every three months after discontinuing the study drug and all patients were contacted at month 12, regardless of their actual duration of treatment. The overall study period was considered to be twelve months. The primary efficacy outcome was the adjudicated combination of time to recurrence of symptomatic VTE (nonfatal or fatal PE or DVT) or death related to VTE. The primary safety outcome was the incidence of adjudicated clinically relevant bleeding (composite of major bleeding and clinically relevant non-major bleeding). A total of 8292 patients were randomized with 8240 patients included in the modified intention-to-treat analysis (including 11 patients lost to follow-up), as patients who did not receive any study drug were excluded from analyses. Patients on warfarin were within the INR therapeutic range (2.0 to 3.0) 63.5% of the time.

An independent, blinded committee adjudicated all suspected outcome events. Trial outcomes are summarized in (Table 6).

Recurrent VTE or VTE-related death occurred in 1.6% of patients on edoxaban compared to 1.9% of patients on warfarin (HR 0.82; 95% CI 0.60-1.14; P<0.001), establishing non-inferiority of edoxaban. With regards to the primary safety outcome, the composite of first major or clinically relevant non-major bleeding occurred in 8.5% of patients on edoxaban versus 10.3% on warfarin (RR 0.81, 95% CI 0.71-0.94; P=0.004) and met requirements for superiority. It was suggested that oral edoxaban, preceded by enoxaparin or UFH, was as effective as standard therapy to prevent VTE recurrence with better safety outcomes regarding bleeding.

The authors noted that efficacy of edoxaban was preserved regardless of whether patients initially presented with PE, limited DVT, or extensive DVT. They also observed recurrence rates during the overall study period when some patients were no longer receiving medication, and found that edoxaban remained non-inferior to standard therapy.

At this time, edoxaban is approved in Japan and the United States for the treatment and prevention of recurrent VTE [25], but is still awaiting approval in Canada and Europe.

DISCUSSIONThe completion of these four landmark trials provides

convincing evidence that DOACs can be considered as a first-

Table 8: Summary of DOAC dosing and characteristics to consider before prescribing.

DOAC Trial DosageInitial Heparin UseRequired

Contraindications

Dabigatran[16] RECOVER 150 mg BID Yes

Mechanical heart valveActive bleeding or high riskSevere renal impairmentConcurrent use of other anticoagulantsConcurrent use of drugs that are strong inhibitors of P-glycoprotein (P-gp)Pregnancy/lactation<18 years old

Rivaroxaban[17] EINSTEIN-DVT15 mg BID x 21 days; then 20 mg daily

No

Mechanical heart valveActive bleeding or high riskSevere renal impairmentConcurrent use of other anticoagulantsConcurrent use of drugs that are strong inhibitors of both CYP3A4 and P-glycoprotein (P-gp)Pregnancy/lactation<18 years old

Apixaban[18] AMPLIFY10 mg BID x 7 days; then 5 mg BID

No

Mechanical heart valveActive bleeding or high riskSevere renal impairmentConcurrent use of other anticoagulantsConcurrent use of drugs that are strong inhibitors of both CYP3A4 and P-glycoprotein (P-gp)Pregnancy/lactation<18 years old

Edoxaban HOKUSAI-VTE 60 mg daily Yes Not currently approved for use in Canada or Europe. No product monograph currently available in United States.

*Refer to drug database or product monograph for complete list of contraindicationsBID = Twice Daily.

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line option for treatment of acute DVT in the outpatient setting in primary care [8]. It is important that primary care physicians become familiar with the evidence supporting their approval for acute DVT treatment and become knowledgeable and comfortable in their clinical use. Table 7 lists the summarized conclusions from each of the four landmark trials of DOAC use in the acute treatment of DVT. Each agent has been shown to be non-inferior to warfarin in this regard and offers similar or reduced bleeding risks. Of note, a meta-analysis examining the data from nine RCTs of DOACs versus standard treatment in acute treatment of VTE concluded that each DOAC currently available in Canada has similar efficacy as standard therapy, but that rivaroxaban demonstrated a reduction in the risk of major bleeding [33]. The DOACs offer several advantages with respect to ease of use that make them an attractive alternative for outpatient treatment, including oral dosing, lack of lab monitoring requirements, and few drug-drug or food-drug interactions.

The route of administration and rapidity of onset of action are important convenience factors. The DOACs are all oral medications and their anticoagulant effect is almost immediate and similar to that of LMWH [10].

This novel group of anticoagulants does not require laboratory testing. While this may sound disconcerting to those of us accustomed to reviewing INRs, we can be reassured that the DOAC class of medications is not known to be susceptible to the numerous interactions and variability in pharmacokinetics

and pharmacodynamics that cause a wide range of individual VKA maintenance requirements [10]. This translates to better convenience for patients and physicians, and leaves less room for error that can occur with a VKA if a dosage adjustment is miscommunicated or forgotten.

If a DOAC is selected as the treatment, it is necessary to consider each particular patient’s characteristics when choosing which agent to prescribe. There are several limitations to DOAC use, which can affect the choice of DOAC and whether standard therapy is preferable.

Firstly, dabigatran and edoxaban both require initial use of parenteral heparin, which can be a barrier to starting treatment as an outpatient. Rivaroxaban and apixaban do not require initial use of heparin.

Secondly, dosing differs with each DOAC and there are several situations where dosage adjustments are necessary. Frequency of dosing is greater with dabigatran and apixaban as they are twice-daily medications (in addition to rivaroxaban for the first three weeks of treatment), so they may not be the optimal choice if medication compliance is a concern. Apixaban and rivaroxaban also require dosage changes partway through treatment, which may be confusing for some patients (see Table 8 for recommended dosage regimens).

Dosage adjustments are required for renal insufficiency and regular estimated glomerular filtration rate (eGFR) monitoring

Table 9: DOAC dosing and eGFR monitoring in renal impairment.

DOAC Renal Excretion[34] Renal Considerations eGFR Monitoring[26]

Dabigatran[16] 85% eGFR>30 mL/minute: No dosage adjustment necessary unless GFR<50 mL/minute and patient is also receiving P-gp inhibitors (e.g.amiodarone, clarithromycin, dronedarone, quinidine, verapamil, etc.), then avoid use.

eGFR ≤30 mL/minute: Avoid use (has not been studied).

Hemodialysis: Avoid use (has not been studied).

eGFR>50 mL/minute: measure eGFR every 12 months.

eGFR 30-50 mL/minute: measure eGFR every 6 months and during acute illness.

Rivaroxaban[17] 33% eGFR ≥30 mL/minute: No dosage adjustment necessary.

eGFR<30 mL/minute: Avoid use (has not been studied).

Hemodialysis: Avoid use (has not been studied).

eGFR≥50 mL/minute: measure eGFR every 12 months.

eGFR 30-49 mL/minute: measure eGFR every 6 months and during acute illness.

Apixaban[18] 27% eGFR ≥30 mL/minute: No dosage adjustment necessary.

eGFR 15-29 mL/minute: Use with caution.

eGFR<15 mL/minute and/or hemodialysis: Avoid use (has not been studied).

eGFR>50 mL/minute: measure eGFR every 12 months

eGFR 25-50 mL/minute: measure eGFR every 6 months and during acute illness.

eGFR 15-24 mL/minute: no recommendations made due to limited data.

Edoxaban 35% Not currently approved for use in Canada or Europe. No product monograph currently available in United States.

Not applicable.

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should be completed at intervals recommended according to the level of impairment (see Table 9). The DOACs should not be used in severe renal impairment. When prescribing in the elderly, there are also dosage considerations for dabigatran and apixaban (see Table 10).

Thirdly, there are important contraindications to recognize, including use in pregnancy, children, and patients with mechanical heart valves (see Table 8). Some of these may change with further study, including DOAC use in the pediatric population, but they continue to apply at this time.

It is also important to consider drug-drug interactions between the DOACs and certain medications (see Tables 2 and 8). Dabigatran should not be used with strong P-glycoprotein inducers and inhibitors such as ketoconazole, rifampin, and St. John’s wort [26]. Quinidine, verapamil, and amiodarone may be used, but with caution. Rivaroxaban and apixaban should not be used simultaneously with strong inducers or inhibitors of P-glycoprotein and cytochrome P450 3A4 such as ketoconazole, rifampin, ritonavir, and St. John’s wort [26]. Rivaroxaban and apixaban can be used with clarithromycin and anticonvulsants with caution.

Finally, there remains no unequivocally optimal method of DOAC reversal should a major bleed occur. Several methods have been suggested, the simplest being utilization of each drug’s short half-life and withholding the next dose to wait for coagulation normalization [35]. For example, the half-life of rivaroxaban is 5-9 hours [10], while IV vitamin K reverses warfarin in 4-6 hours [36]. For life-threatening bleeds, administration of 4-factor pro-thrombin complex concentrates (PCC) (25-50 U/kg) or activated PCC (30-50 U/kg) has been suggested, with use of recombinant activated factor VII if needed [28]. However to further complicate

matters, use of PCC has not decreased mortality after warfarin-associated intracranial hemorrhage [37], so even in the setting of a VKA, it is not the “silver bullet” one may think it is. There are ongoing clinical trials investigating the efficacy of targeted reversal agents [10], including a specific factor Xa inhibitor antidote, specific dabigatran antidote, and a “universal” antidote (see Table 11) [38]. Ultimately, the availability of safe and efficacious specific antidotes will likely allay many clinicians’ reservations about using a DOAC and we will await the outcomes of those currently under study [16].

It is also difficult to quantify the level of anticoagulation achieved by a DOAC at any given time since there is no INR monitoring. This can be challenging in the case of an acute bleed where it would be helpful to judge the risk of ongoing bleeding and whether reversal efforts are effective. Although each DOAC differs, there are some measures that have been shown to correlate with serum level of the drug and possibly risk of bleeding (see Table 12) [39,40]. It is important to note, however, that these provide qualitative indices of drug level rather than quantitative indices, and the accuracy can vary depending on the assay used for the test.

While the lack of INR monitoring has been identified as a benefit of DOAC use, it can also represent a limitation, as the need for regular laboratory visits can increase the likelihood of patient adherence to the treatment regimen [10]. Without this regular monitoring and goal of staying within a target range, patients may be less motivated to regularly adhere to their medication schedule [10]. It will be very important for clinicians to emphasize the risks of non-compliance as well as the benefits of regular medication adherence.

In conclusion, DOACs represent a new class of medications

Table 10: DOAC dosing in the elderly.

DOAC Considerations in the Elderly (≥65 years)

Dabigatran[16] <80 years: 150 mg BID; consider 110 mg BID if>75 years with at least one other risk factor for bleeding (e.g. moderate renal impairment [eGFR 30-50 mL/minute], simultaneous treatment with strong P-gp inhibitors, or previous GI bleed)≥80 years: 110 mg BID

Rivaroxaban[17] No dosage adjustment required.

Apixaban[18] No dosage adjustment required (advised to use with caution if ≥75 years).

Edoxaban Not currently approved for use in Canada or Europe. No product monograph currently available in United States.

Table 11: Potential targeted reversal agents.Targeted reversal agent

PRT064445(Portola Pharmaceuticals)

aDabi-Fab(BoehringerIngelheim) PER977 (Perosphere/Daiichi Sankyo)

Target Factor Xa inhibitors Dabigatran Universal (binds factor Xa inhibitors, direct thrombin inhibitors, heparins)

Molecular structure Recombinant human factor Xa variant

Humanized antibody fragment Synthetic small molecule

Route of administration Intravenous Intravenous Intravenous

Clinical studies Rapid, almost complete reversal with 420 mg dose (apixaban, rivaroxaban); sustained effect while infused

Rapid, complete, and sustained reversal with 2000 and 4000 mg doses

Not available

Adapted from Lauw, 2014 [38].

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available to clinicians for safe and effective treatment of acute DVT in the outpatient setting. It is important that primary care physicians become familiar with the characteristics of each of these medications in order to maximize their benefits in their own patient population and clinical settings. Further study in diverse populations may broaden the possibilities for use, and approval of agents for reversal may increase the comfort with which they are prescribed in primary care.

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Ranger NS, Ward MA (2015) A Comparison of the Direct Oral Anticoagulants in Treatment of Acute Deep Vein Thrombosis for Primary Care Physicians. J Family Med Community Health 2(2): 1032.

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