Cardiol Ther (2018) 7:1–13 https://doi.org/10.1007/s40119-018-0107-0 REVIEW A Review of the Role of Non-Vitamin K Oral Anticoagulants in the Acute and Long-Term Treatment of Venous Thromboembolism Andrew Bromley Anna Plitt Received: January 16, 2018 / Published online: March 10, 2018 The Author(s) 2018. This article is an open access publication may change physician practices in the near ABSTRACT future. Venous thromboembolism (VTE), which includes both deep vein thrombosis and pul- Keywords: Anticoagulation; NOAC; Venous monary embolism (PE), is a very common dis- thromboembolism order with high risk for recurrence and is associated with signiﬁcant morbidity and mor- tality. The non-vitamin K oral anticoagulants BACKGROUND (NOACs), which include dabigatran, rivaroxa- ban, apixaban, and edoxaban, have been shown Venous thromboembolism (VTE), which is to be noninferior to conventional anticoagulant comprised of deep venous thrombosis (DVT) therapy for the prevention of recurrent VTE and and pulmonary embolism (PE), is the third most are associated with more favorable bleeding common cardiovascular disease after myocar- risk. Evidence from the treatment of VTE with dial infarction and stroke [1, 2]. VTE occurs for traditional therapy (low molecular weight hep- the ﬁrst time in one to two adults in 1000 each arin and vitamin K antagonists) implies that year  with incidence rising to at least ﬁve in extended or indeﬁnite treatment reduces risk of 1000 persons over the age of 70 years . Nearly recurrence. Recently, mounting evidence sug- one-third of patients with VTE manifest with gests a role for the extended use of NOACs to PE, whereas the remaining two-thirds present reduce the risk of VTE recurrence. This review with DVT alone . VTE is associated with sig- summarizes the existing evidence for the niﬁcant morbidity and mortality. In the extended use of NOACs in the treatment of VTE absence of treatment, the 30-day mortality rate from phase III extension studies with dabiga- for patients with ﬁrst-time DVT is 3% and 31% tran, rivaroxaban, and apixaban. Additionally, for PE . More generally, the 30-day mortality it examines and discusses the major society rates after VTE are 10.6% and 23% at 1 year, yet guidelines and how these recommendations notably, these rates do not reﬂect the latest advances and treatment options available, Enhanced content To view enhanced content for this article go to https://doi.org/10.6084/m9.ﬁgshare. principally, the NOACs discussed in this review . Additionally, the management of VTE is associated with signiﬁcant health care costs for A. Bromley A. Plitt (&) not only the hospitalization and treatment of Mount Sinai Heart, New York, NY, USA the initial VTE, but for associated recurrences e-mail: email@example.com 2 Cardiol Ther (2018) 7:1–13 and readmissions . This review aims to sum- ACCP, its use may inﬂuence decisions regarding marize the existing evidence for the use of duration of anticoagulation. NOACs in the acute and long-term treatment of Venous thromboembolic events are known VTE, examine major society guidelines, and to be associated with factors such as recent discuss how these recommendations may surgery, extended periods of immobility, preg- change physician practices in the near future. nancy, puerperium, estrogen-based hormonal This article is based on previously conducted therapy, and active malignancy . Nearly studies and does not contain any studies with 50% of VTE patients, however, do not have any human participants or animals performed by underlying risk factors and therefore experience any of the authors. unprovoked VTE . In patients with unpro- voked VTE, the risk of recurrence is 11% at 1 year and nearly 40% at 10 years . Notably, VTE AS A CHRONIC DISEASE the risk of recurrence of deep vein thrombosis and pulmonary embolism is similar. Further- The notable long-term complications of VTE more, when DVT recurs, it usually does so as include post-thrombotic syndrome (PTS) and DVT and pulmonary embolism tends to recur as chronic thromboembolic pulmonary hyperten- pulmonary embolism [19, 20]. After a ﬁrst VTE sion (CTEPH). Post-thrombotic syndrome pre- episode, the rate of recurrence is highest in the sents with signs of chronic venous insufﬁciency ﬁrst 6 months  and that risk is nearly double such as pain, edema, and ultimately, ulcer for- over the next 18 months . mation caused in part by resultant venous Factors such as residual vein thrombosis at hypertension. PTS is the most common long- ultrasound assessment, persistently elevated term sequelae of lower extremity DVT, seen in level of D-dimer, male sex, and the early devel- 20–50% of patients in the year following the opment of post-thrombotic syndrome, have all incident event, even with adequate treatment. been shown to increase the risk of VTE recur- The risk for the development of PTS is strongly rence [9, 22, 23]. The DASH scoring system, a associated with recurrent DVT [2, 9, 10]. prediction tool based on a meta-analysis of 1818 Patients with chronic thromboembolic pul- patients with unprovoked VTE, was developed monary hypertension present with progressive to estimate risk of recurrence. The scoring fac- dyspnea, exercise intolerance, and even clinical tors include abnormal D-dimer after anticoagu- signs of right heart failure such as peripheral lation therapy (2 points), age\50 years (1 edema and syncope. The incidence of CTEPH point), male sex (1 point), and in women, the following PE is 0.56–3.8% [11, 12]. These use of hormonal therapy at the time of the VTE chronic complications adversely affect quality (- 2 points). The recently validated scoring of life and contribute to a signiﬁcant ﬁnancial system was designed to highlight low-risk burden on the healthcare system [13, 14]. patients who could potentially avoid long-term Determining whether a venous throm- anticoagulation after unprovoked VTE [24, 25]. boembolic event was unprovoked or provoked by some risk factor carries prognostic signiﬁ- cance and inﬂuences treatment decisions. DEFINING TREATMENT Recently, Kearon et al.  introduced a novel concept for further stratifying provoking risk The anticoagulant treatment of VTE is tradi- factors by determining whether the risk factor is tionally marked by three different phases. Ini- transient or persistent. A persistent risk factor, tial anticoagulant therapy is the ﬁrst phase and such as metastatic cancer, would be expected to is administered in the days immediately fol- have a much higher risk of recurrence than a lowing a diagnosis of VTE . Recommended transient risk factor, such as recent surgery, after choices for initial anticoagulation include the discontinuation of therapy. Although this unfractionated heparin (UFH) or low molecular nomenclature has not yet been adopted by the weight heparin (LMWH) with subsequent introduction of a vitamin K antagonist (VKA), Cardiol Ther (2018) 7:1–13 3 as well as two of the non-vitamin K oral anti- LMWH over VKA in patient with cancer. VKAs coagulants (NOACs) rivaroxaban and apixaban were recommended over NOACs (dabigatran or . Dabigatran and edoxaban have also been rivaroxaban at that time) in both groups of used for initial therapy, however, in the studies patients given the existing evidence at that that evaluated these NOACs, patients received time. at least 5 days of parenteral anticoagulation The 2016 ACCP guidelines  take into with UFH or LMHW prior to initiating NOAC consideration the large body of evidence gath- therapy [27, 28]. ered in recent years supporting the use of Chronic or long-term treatment spans from NOACs in the treatment of acute VTE. Based on the end of the initial phase to the end of a these guidelines, NOACs are recommended over designated end point, usually 3 months. The VKAs for the ﬁrst 3 months of anticoagulation agent of choice can be the same as the initial therapy for patients with proximal DVT of the agent, or can be transitioned to a new antico- leg or PE in patients without cancer. For agulant. Extended anticoagulation therapy patients with cancer, LMWH is still the recom- refers to treatment beyond an established, mended anticoagulant. deﬁned endpoint, which is usually 3–6 months, The current guidelines recommend often with an indeﬁnite duration of therapy 3 months of anticoagulation therapy for . patients with proximal DVT of the leg or PE in Historically, the initial treatment of VTE the setting of a surgical or nonsurgical transient would consist of at least 5 days of parenteral risk factor. New to the most recent guidelines, anticoagulation (UFH or LMWH) along with a however, is the recommendation that patients VKA until a therapeutic anticoagulation win- with a ﬁrst VTE that is an unprovoked proximal dow was achieved. This treatment strategy is DVT or PE with a low or moderate bleeding risk limited by its dependence on initial parenteral receive extended or indeﬁnite anticoagulation anticoagulation administration, delayed onset, as opposed to 3 months of therapy. The guide- and numerous medication and dietary interac- lines further advise that extended or long-term tions. Furthermore, warfarin requires frequent therapy beyond 3 months continue with the coagulation monitoring and dose adjustments initial therapy of choice . to ensure the international normalized ratio Guidelines from the European Society of (INR) is in therapeutic range . Cardiology (ESC)  that were published in The optimal duration of anticoagulant ther- 2014 also included recommendations for the apy after the ﬁrst episode of unprovoked VTE extended treatment of VTE. These guidelines remains unclear. In patients with identiﬁable, identiﬁed patients with cancer and those who major, transient risk factors (i.e., recent sur- have experienced an unprovoked proximal DVT gery), anticoagulation therapy is usually dis- or PE who are at low risk of bleeding as candi- continued after 3 months, whereas continued dates for indeﬁnite treatment. The guidelines therapy without a scheduled stop date (ex- also comment on the use of NOACs with a tended anticoagulation) is recommended in recommendation (Class IIa, Level of Evidence B) patients with cancer-associated thrombosis . to consider dabigatran, rivaroxaban, or apixa- ban over VKA in patients who require extended anticoagulation therapy. GUIDELINES The most recent guidelines on the management ROLE OF NOACS of VTE from the American College of Chest IN THE TREATMENT OF ACUTE VTE Physicians (ACCP)  were released in 2016 and they differ notably from the earlier recom- The four NOACs (dabigatran, rivaroxaban, mendations released in 2012. The earlier apixaban, and edoxaban) were compared with guidelines  recommended the use of VKA conventional therapy (parenteral anticoagula- over LMWH in patients without cancer and tion followed by VKA) for the treatment of 4 Cardiol Ther (2018) 7:1–13 acute VTE in six clinical trials. These four drugs Food and Drug Administration for VTE pro- are synthetic, selective, and reversible inhibitors phylaxis in acutely ill medical patients. The of either factor Xa (rivaroxaban, apixaban, and APEX trial  compared the use of extended- edoxaban) or thrombin (dabigatran). The duration betrixaban (for 35–42 days) to a stan- NOACs, administered orally in ﬁxed doses, dard subcutaneous enoxaparin regimen (for produce predictable anticoagulant responses 10 ± 4 days) in 7513 patients hospitalized for that do not require routine monitoring. acute medical illnesses. The study population The study populations were similar across was stratiﬁed into different cohorts based on D- the trials evaluating all four drugs. All trials were dimer level and age, but in the overall study designed to demonstrate noninferiority of the population, betrixaban was associated with sig- NOAC compared to conventional treatment niﬁcantly fewer asymptomatic proximal DVT with LMWH followed by VKA. In all six trials, and symptomatic VTE [165 vs. 223; RR 0.76; the primary efﬁcacy outcome was recurrent VTE 95% CI (0.63–0.92); P = 0.006] with no differ- or VTE-related mortality. The primary safety ence in major bleeding [25 vs. 21; RR 1.19; 95% outcome was major bleeding deﬁned by the CI (0.67–2.12); P = 0.55]. International society of Thrombosis and Hae- Edoxaban became the ﬁrst NOAC evaluated mostasis criteria in the apixaban and dabigatran for use in cancer-associated VTE in the Hokusai trials, but a composite of major or clinically VTE Cancer study . This open-label, non- relevant non-major (CRNM) bleeding in the inferiority study compared 6–12 months of rivaroxaban and edoxaban trials. The rivaroxa- edoxaban to subcutaneous dalteparin (a ban trials had separate DVT and PE studies, both LMWH) in patients with active cancer who were powered for each population, whereas the other found to have acute symptomatic or incidental NOAC studies grouped all VTE patients together VTE. Although the rate of recurrent VTE was with varying numbers of patients with each nonsigniﬁcantly reduced with edoxaban com- condition. All the trials except for the rivarox- pared to LMWH [41 vs. 59; HR 0.71; 95% CI aban ones were double-blinded. Additionally, (0.48–1.06); P = 0.09], signiﬁcantly more major patients with severe renal dysfunction were bleeding events were associated with edoxaban excluded from all the studies. Of note, in the [36 vs. 21; HR 1.77; 95% CI (1.03–3.04); dabigatran and edoxaban trials, patients in both P = 0.04]. Although none of the NOACs are yet the NOAC and conventional therapy arm indicated or approved for use in cancer-associ- received 5 days of parenteral anticoagulation. ated VTE, these results are promising for this This differs from the rivaroxaban and apixaban population of patients (Table 2). trials, where patients were started immediately on either agent. All four NOACs were found to EXTENDED TREATMENT OF VTE be non-inferior to conventional treatment with regards to the primary efﬁcacy outcomes in the Evidence for VKA referenced phase III clinical trials. In terms of safety, apixaban was associated with signiﬁ- cantly fewer major bleeding events [0.6 vs. Much of the evidence and rationale for the long-term treatment of VTE stems from earlier 1.8%; HR 0.31; 95% CI (0.17–0.55); P\0.001] and edoxaban was associated with signiﬁcantly experience with VKA. The incidence of recur- rent VTE was evaluated following long-term fewer major or CRNM bleeding events [8.5 vs. 10.3%; HR 0.81; 95% CI (0.71–0.94); P = 0.004 versus extended duration therapy of idiopathic DVT by the Warfarin Optimal Duration Italian for superiority]. Table 1 highlights the primary efﬁcacy and safety outcomes from these phase Trial Investigators . In this trial, following isolated DVT, patients were randomized to III clinical trials. extended warfarin treatment for 12 months A ﬁfth NOAC, betrixaban, an oral, direct factor Xa inhibitor has not yet been studied in versus standard 3 months. Nearly two-thirds of the recurrences of thromboembolic events acute VTE or in prevention of VTE recurrence, but has gained approval from the United States occurred in the ﬁrst year after discontinuation Cardiol Ther (2018) 7:1–13 5 Table 1 Efﬁcacy and safety of NOACs for the acute treatment of VTE: results from clinical trials Trial Dabigatran Rivaroxaban Apixaban Edoxaban RE-COVER RE-COVER EINSTEIN- EINSTEIN- AMPLIFY Hokusai-VTE   II  DVT  PE   Year 2009 2014 2010 2012 2013 2013 Design Double-blind Double-blind Open-label Open-label Double-blind Double-blind # of patients 2539 2589 3449 4832 5395 8292 LMHW/ Yes Yes No No No Yes heparin bridge Treatment Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Edoxaban 60 mg daily; protocol 150 mg 150 mg 15 mg BID 15 mg BID 10 mg BID or 30 mg daily for BID BID for 3 weeks; for 3 weeks; for 7 days; patients w/CrCl then 20 mg then 20 mg then 5 mg 30–50 ml/min, daily daily BID weight B 60 kg, or receiving P-glycoprotein inhibitors Duration of 6 6 3, 6, or 12 3, 6, or 12 6 B 12 therapy (months) Primary Recurrent Recurrent Recurrent Recurrent Recurrent Recurrent VTE and efﬁcacy VTE and VTE and VTE VTE VTE and related death outcome related related related death death death Event rate 2.4% vs. 2.1% 2.3% vs. 2.2% 2.1% vs. 3.0% 2.1% vs. 1.8% 2.3% vs. 2.7% 3.2% vs. 3.5% of primary efﬁcacy outcome: NOAC vs. VKA Hazard 1.10 1.08 0.68 1.12 0.84 0.89 (0.70–1.13) ratio (HR), (0.65–1.84) (0.64–1.80) (0.44–1.04) (0.75–1.68) (0.60–1.18) P\0.001 95% P\0.001 P\0.001 P\0.001 P = 0.003 P\0.001 conﬁdence interval (CI) Primary Major bleed Major bleed Major or Major or Major bleed Major or CRNM bleed safety CRNM CRNM outcome bleed bleed 6 Cardiol Ther (2018) 7:1–13 Table 1 continued Trial Dabigatran Rivaroxaban Apixaban Edoxaban RE-COVER RE-COVER EINSTEIN- EINSTEIN- AMPLIFY Hokusai-VTE   II  DVT  PE   Event rate 1.6% vs. 1.9% 1.2% vs. 1.7% 8.1% vs. 8.1% 10.3% vs. 0.6% vs. 1.8% 8.5% vs. 10.3% of primary 11.4% safety outcome: NOAC vs. VKA HR, 95% 0.82 0.69 0.97 0.90 0.31 0.81 (0.71–0.94) CI (0.45–1.48) (0.36–1.32) (0.76–1.22) (0.76–1.07) (0.17–0.55) P = 0.004 P = 0.77 P = 0.23 P\0.001 BID twice daily dosing, CrCl creatinine clearance, CRNM clinically relevant nonmajor, DVT deep vein thrombosis, LMWH low molecular weight heparin, NOAC non vitamin K oral anticoagulant, PE pulmonary embolism, VKA vitamin K antagonist, VTE venous thromboembolism of anticoagulation in both treatment groups idiopathic VTE. Although the study was and at 3 years of follow-up, there was no sig- designed for subjects to receive an additional niﬁcant difference in incidence of recurrence 24 months of anticoagulation, pre-speciﬁed between the two treatment groups; thereby interim analysis led to the early termination of suggesting that extended anticoagulation the study after patients had been followed for treatment only delayed recurrence rather than an average of 10 months. Signiﬁcantly more reducing the risk of recurrence. Additionally, recurrent VTE were observed in the placebo the rates of major bleeding were 3.0 vs. 1.5% in group [27.4 vs. 1.3%/patient-year; HR 0.05; 95% the extended treatment group compared to the CI (0.01–0.37); P\0.001]. This was followed by placebo group. a 2003 study  that compared low-intensity The PADIS-PE study  similarly investi- warfarin therapy (INR goal 1.5–1.9) to conven- gated the role of extended VKA use but in tional intensity (INR goal 2.0–3.0) in the long- patients with PE as opposed to DVT. After term prevention of recurrent VTE in patients 6 months of warfarin therapy, patients with PE who had completed 3 months of conventional were randomized to 18 months (12 additional warfarin therapy. Low-intensity warfarin ther- months) extended therapy versus placebo. Once apy was associated with more episodes of again, extended warfarin therapy signiﬁcantly recurrent VTE compared to conventional dosing reduced the outcome of recurrent VTE (rate [16 vs. 6; HR 2.8; 95% CI (1.1–7.0); P = 0.03]. 3.3%) during the 18-month study period, but Furthermore, the low-intensity group experi- the beneﬁt was not maintained after discon- enced more bleeding episodes than the con- tinuation, as evidenced by a recurrence rate of ventional intensity [39 vs. 31 events; HR 1.3; 13.5% in the placebo group [hazard ratio (HR), 95% CI (0.8–2.1); P = 0.26]. 0.22; 95% conﬁdence interval (CI), 0.09–0.55; P = 0.001]. Rates of recurrent VTE did not differ EVIDENCE FOR NOACS at the end of the 42-month trial. A 1999 study published in the NEJM by There is a growing body of literature regarding Kearon et al.  compared warfarin to placebo the extended use of NOACs in the treatment of in patients who had already completed VTE. Currently, dabigatran, apixaban, and 3 months of therapy for a ﬁrst episode of Cardiol Ther (2018) 7:1–13 7 Table 2 Efﬁcacy and safety of NOACs for the extended treatment of VTE: results from clinical trials Trial Dabigatran Rivaroxaban Apixaban Edoxaban RE-MEDY RE-SONATE EINSTEIN-EXT EINSTEIN- AMPLIFY-EXT Hokusai-VTE    CHOICE    Year 2013 2013 2010 2017 2013 2013 Design Double-bind Double-blind Double-blind Double-blind Double-blind Double-blind # of patients 2856 1343 1196 3396 2486 8292 Comparison arm Warfarin Placebo Placebo ASA 100 mg daily Placebo Warfarin Treatment protocol Dabigatran Dabigatran Rivaroxaban 20 mg Rivaroxaban 20 mg or Apixaban 5 mg Edoxaban 60 mg daily; 150 mg BID 150 mg BID daily 10 mg daily vs. ASA BID or apixaban or 30 mg daily for 100 mg daily 2.5 mg BID patients w/CrCl 30–50 ml/min, weight B 60 kg, or receiving P-glycoprotein inhibitors Duration of therapy 6–36 months; 6 months; after 6–12 months; after Up to 12 months; 12 months; after 3–12 months (months) after completing completing completing initial after completing completing initial 3 months initial 6–12 months initial 6–12 months initial 3 months 6–12 months Primary efﬁcacy outcome Recurrent or fatal Recurrent or fatal Recurrent VTE Recurrent fatal and Recurrent VTE or Recurrent VTE or death VTE VTE or nonfatal VTE and death from any from any cause unexplained unexplained death cause death Event rate of efﬁcacy Dabigatran Dabigatran Rivaroxaban 20 mg: Rivaroxaban 20 mg: Apixaban 5 mg: Edoxaban: 3.2% outcome: NOAC vs. 150 mg BID: 150 mg BID: 1.3% 1.5% 4.2% Warfarin: 3.5% comparison 1.8% 0.4% Placebo: 7.1% Rivaroxaban 10 mg: 2.5 mg: 3.8% Warfarin: 1.3% Placebo: 5.6% 1.2% Placebo: 11.6% ASA 100 mg: 4.4% 8 Cardiol Ther (2018) 7:1–13 Table 2 continued Trial Dabigatran Rivaroxaban Apixaban Edoxaban RE-MEDY RE-SONATE EINSTEIN-EXT EINSTEIN- AMPLIFY-EXT Hokusai-VTE    CHOICE    Hazard ratio (HR), 1.44 (0.78–2.64) 0.08 (0.02–0.25) 0.18 (0.09–0.39) 20 mg vs. ASA: 0.34 2.5 mg vs. placebo: 0.89 (0.70–1.13) 95% conﬁdence (0.20–0.59) 0.33 (0.22–0.48) P = 0.01 P\0.001 P\0.001 P\0.001 interval (CI) P\0.001 5 mg vs. placebo: 10 mg vs. ASA: 0.26 0.36 (0.25–0.53) (0.14–0.47) P\0.001 20 mg vs. 10 mg 1.34 (0.65–2.75) P = 0.42 Primary safety outcome Major bleed Major bleed Major or CRNM Major bleed Major bleed Major or CRNM bleed bleed Event rate of primary Dabigatran Dabigatran Rivaroxaban 20 mg: Rivaroxaban 20 mg: Apixaban 5 mg: Edoxaban: 8.5% safety outcome: 150 mg 150 mg 6% 0.5% 0.1% Warfarin: 10.3% NOAC vs. BID: 0.9% BID: 0.3% Placebo: 1.2% Rivaroxaban 10 mg: 2.5 mg: 0.2% comparison Warfarin: 1.8% Placebo: 0% 0.4% Placebo: 0.5% ASA 100 mg: 0.3% HR, 95% CI, P value 0.52 (0.27–1.02) Not estimable, 5.19 (2.3–11.7) 20 mg vs. ASA: 2.01 2.5 mg vs. placebo 0.81 (0.71–0.94) P = 0.06 P = 1.0 P\0.001 (0.50–8.04) P = 0.49 (0.09–2.64) P = 0.004 0.32 5 mg vs. placebo 10 mg vs. ASA: 1.64 0.25 (0.03–2.24) (0.39–6.84) P = 0.50 2.5 mg vs. 5 mg 20 mg vs. 10 mg:1.23 1.93 (0.37–4.03) (0.18–21.25) P = 0.74 ASA aspirin, BID twice daily dosing, CRNM clinically relevant non-major, NOAC non vitamin K oral anticoagulant, VTE venous thromboembolism Cardiol Ther (2018) 7:1–13 9 rivaroxaban have been studied in this setting whom there was equipoise with regards to (RE-MEDY/RE-SONATE, EINSTEIN, AMPLIFY- continuing anticoagulation. Rivaroxaban was EXT). These studies examined the continued associated with signiﬁcantly fewer recurrent and extended treatment of patients who had VTE than placebo [1.3 vs. 7.1%, HR 0.18; 95% already been started on anticoagulation treat- CI (0.09–0.39); P\0.001]. Additionally, there ment for VTE. was a signiﬁcant increase in the rate of major The extended treatment with dabigatran was (0.7 vs. 0%) and major or CRNM bleeding studied in the RE-SONATE and RE-MEDY trials. complications in the treatment group vs. pla- In the RE-SONATE  placebo control study, cebo [6.0 vs. 1.2%; HR 5.19; 95% CI (2.3–11.7); investigators compared 12 months of extended P\0.001]. use of dabigatran (150 mg twice daily) to pla- More recently, rivaroxaban was compared to cebo following initial treatment. The rates of aspirin for the extended treatment of VTE in recurrent VTE or death (primary endpoint) were EINSTEIN-CHOICE . This randomized, signiﬁcantly lower in the treatment group [0.4 double-blind, phase 3 study assigned patients vs. 5.6%; HR 0.08; 95% CI (0.02–0.25); with VTE who had already completed 6– P\0.001]. There were signiﬁcantly higher rates 12 months of therapy, and in whom there was of major or CRNM bleeding in the dabigatran equipoise with regards to continuing anticoag- group compared to warfarin [5.3 vs. 1.8%; HR ulation, to receive one of two different doses of 2.92; 95% CI (1.52–5.60); P = 0.001]. rivaroxaban (20 or 10 mg once daily) or aspirin The RE-MEDY  trial is the only trial to (100 mg once daily) for up to 1 year. Patients date that has compared the extended use of a with clear indication for therapeutic dose anti- NOAC directly to warfarin for recurrent VTE coagulation were excluded from this study. prevention. This active control study random- Furthermore, of the patients randomized to ized patients to either dabigatran (150 mg twice rivaroxaban 20 and 10 mg and aspirin groups, daily) or warfarin for 6–36 months, following at 39.8, 42.6, and 41.4%, respectively, had histo- least 3 months of initial anticoagulation ther- ries of unprovoked VTE while the rest were apy. Recurrent or fatal VTE occurred in 1.8 and provoked. Recurrent VTE occurred with signiﬁ- 1.3% of patients on dabigatran and warfarin, cantly less frequency in both rivaroxaban respectively [HR 1.44; 95% CI (0.78–2.64); groups than the aspirin group [20 mg: 1.5 vs. P = 0.01 for noninferiority]. Although the 4.4%, HR 0.34, 95% CI (0.20–0.59); 10 mg: 1.2 number of major bleeding events between the vs. 4.4% HR 0.26, 95% CI (0.14–0.47), P\0.001 two groups did not signiﬁcantly differ, the for both). There was no signiﬁcant difference in number of major or CRNM bleeding events did, rates of major bleeding in the two rivaroxaban with signiﬁcantly fewer in the dabigatran group groups vs. aspirin [20 mg: 0.5 vs. 0.3%; HR 2.01; [5.6 vs. 10.2%, HR 0.58; 95% CI (0.41–0.71); 95% CI (0.50–8.04); P = 0.32; 10 mg: 0.4 vs. P\0.001]. As seen in prior studies comparing 0.3%; HR 1.64; 95% CI (0.39–6.84); P = 0.50]. dabigatran to warfarin, the number of ACS This study introduced the concept of a low-dose events was higher in the dabigatran group (0.9 of rivaroxaban (10 mg once daily), to be used vs. 0.2%, P = 0.02) . after completing long-term therapy, that was The extended use of rivaroxaban was ﬁrst more effective than aspirin in the prevention of evaluated in EINSTEIN-EXT , a study con- recurrent VTE with a similar bleeding risk ducted in parallel to the original EINSTEIN-DVT proﬁle. study, which found rivaroxaban to be non-in- Apixaban is the third NOAC that has been ferior to LMWH/VKA for the treatment of acute, studied for the extended treatment of VTE. symptomatic DVT. The extended study was a AMPLIFY-EXT  was a randomized, double- double-blind, randomized, event-driven superi- blind study that compared two doses of apixa- ority study that compared rivaroxaban (20 mg ban (5 and 2.5 mg twice daily) to placebo for once daily) to placebo for an additional 6–- 12 months of extended therapy in patients who 12 months in patients who had already com- had already completed 6–12 months of apixa- pleted 6–12 months of treatment for VTE and in ban for treatment of VTE. Over 90% of patients 10 Cardiol Ther (2018) 7:1–13 enrolled in this trial had a history of unpro- moderate bleeding risk. These new recommen- voked VTE. Both doses of apixaban were asso- dations thereby created a signiﬁcant population ciated with signiﬁcantly reduced recurrent VTE of candidates for indeﬁnite anticoagulation. or death from any cause compared to placebo Providers considering whether extended [5 mg: 4.2 vs. 11.6%; relative risk (RR) 0.36; 95% anticoagulation is indicated for their patient CI (0.25–0.53); P\0.001; 2.5 mg: 3.8 vs. 11.6%, should therefore take four variables into con- RR 0.33; 95% CI (0.22–0.48); P\0.001]. Epi- sideration: the locations of the VTE, whether sodes of major bleeding did not differ signiﬁ- the patient has active cancer, whether the VTE cantly between groups but the 5-mg dose of the was provoked or unprovoked, and the patient’s study drug did have signiﬁcantly more episodes bleeding risk. The ACCP recommends extended of CRNM bleeding than placebo [4.2 vs. 2.3%; use anticoagulation in the treatment of a ﬁrst RR 1.82; 95% CI (1.05–3.18)] whereas the 2.5- time, unprovoked, proximal DVT or PE in a mg dose did not [3.0 vs. 2.3%; RR 1.29, 95% CI patient with a low or moderate bleeding risk or (0.72–2.33)]. a patient with a second time, unprovoked DVT Edoxaban has not yet been studied in a or PE in a patient with a low or moderate dedicated extension study. In the original ran- bleeding risk . domized, double-blind, noninferiority study, Currently, there are no head-to-head com- Hokusai-VTE , patients with acute VTE were parisons of NOACs in the extended treatment of randomly assigned to receive edoxaban or war- VTE. Furthermore, trying to draw comparisons farin for 3–12 months. Interestingly, efﬁcacy based on the individual studies mentioned was evaluated at 12 months of follow-up, above is limited by differences in study designs, regardless of the duration of treatment. Nota- inclusion and exclusion criteria, patient demo- bly, 87% of patients (7227) continued treat- graphics, and characteristics. That is why the ment beyond 3 months and 40% of patients guidelines do not recommend a speciﬁc NOAC, (3320) continued treatment for a full but instead advise that drug-speciﬁc adverse 12 months. Edoxaban was noninferior to war- events, individual cost and coverage, dosing farin in the primary efﬁcacy outcome, ﬁrst frequency, and patient preference be taken into recurrent VTE or VTE-related death [130 vs. 146; consideration when choosing a NOAC. Of the HR 0.89; 95% CI (0.70–1.13); P\0.001 for existing NOACs, only rivaroxaban and apixaban noninferiority]. Edoxaban was associated with have been examined at doses lower than estab- signiﬁcantly fewer episodes of major or CRNM lished regimens, although edoxaban was stud- bleeding [349 vs. 423; HR 0.81; 95% CI ied at reduced doses for patients with CrCl (0.71–0.94); P = 0.004 for superiority]. 30–50 ml/min, weight B 60 kg, or those receiv- ing P-glycoprotein inhibitors. The emergence of reduced-dose regimens DISCUSSION with the EINSTEIN-CHOICE and AMPLIFY-EXT studies are likely to further change the future The 2016 recommendations from the American management of extended therapy for secondary College of Chest Physicians will foreseeably VTE prevention. The authors of AMPLIFY-EXT change the way in which VTE is currently make a strong argument for extended therapy managed. The recent update recommends with apixaban with a number needed to treat to NOACs over VKA for the ﬁrst 3 months of prevent one episode of recurrent VTE (fatal or treatment in patients with DVT of the leg or PE nonfatal) of 14, and a number needed to harm without cancer . Additionally, for extended (major or CRNM bleeding) of 200 . The or long-term therapy beyond 3 months, it is EINSTEIN-CHOICE study noted a reduction in recommended to continue with the initial the relative risk of recurrent VTE by nearly 70% therapy of choice. Lastly, extended therapy with both the 20- and 10-mg doses of rivarox- (with no scheduled stop date) is recommended aban. The beneﬁts observed in the study came in patients with a ﬁrst or second unprovoked with rates of major and CRNM bleeding that proximal DVT of the leg or PE and a low or were similar to aspirin, at both doses of Cardiol Ther (2018) 7:1–13 11 rivaroxaban. The authors do caution, however, therapy for the prevention of recurrent VTE. that the EINSTEIN-CHOICE study was not The extension studies described above highlight powered to demonstrate the noninferiority of the efﬁcacy and conﬁrm the safety of the pro- the 10-mg dose of rivaroxaban to the estab- tracted use of apixaban, dabigatran, rivaroxa- lished treatment dose of 20 mg. ban, and edoxaban for the secondary The results of AMPLIFY-EXT are limited by prevention of recurrent VTE. Recent guidelines the patient characteristics of the study, princi- also recommend the extended use of these pally the fact that only 15% of the patients NOACs in this setting. The introduction of a studied were greater than 75 years of age and thromboprophylactic dose of anticoagulation, over 90% of patients had a creatinine clearance with comparable efﬁcacy and tolerable bleeding (CrCL) greater than 50 ml/min. The patient risk proﬁles, may further contribute to future population of EINSTEIN-CHOICE is similar with changes in the secondary prevention of recur- a CrCL greater than 50 ml/min in over 95% of rent VTE. We expect these recent studies, com- patients and an average age of 58 years . bined with the changes in guideline Additionally, only 2–3% of patients had a recommendations, to translate to a larger pop- known cancer and 6–7% a known throm- ulation of patients on extended duration ther- bophilia, thereby limiting the extrapolation of apy with a NOAC for the prevention of the data to these unique populations. Special recurrent VTE. Further research is needed in patient populations, such as patients with can- broader patient populations to complement the cer, the elderly, and those at the lowest and existing literature to determine the effectiveness highest weight indices were only lightly repre- and safety of extended NOAC use, in varying sented in the extension studies. Furthermore, doses, in patients with VTE. those with severe renal dysfunction were excluded. Therefore, the data drawn from the extension studies largely applies to a middle- ACKNOWLEDGEMENTS aged adult population, and must be carefully considered when applied to a more complex patient. Funding. No funding or sponsorship was Based on the results of the EINSTEIN- received for this study or publication of this CHOICE study, the FDA recently approved the article. No external funding has been used for use of the reduced dose (10 mg) of rivaroxaban its preparation. for risk reduction of recurrent VTE after com- pleting 6 months of initial anticoagulant ther- Authorship. All named authors meet the apy with conventional dosing. International Committee of Medical Journal In patients at high risk for recurrence with Editors (ICMJE) criteria for authorship for this low to moderate bleeding risk, the use of low- article, take responsibility for the integrity of dose regimens offers a proven option for risk the work as a whole, and have given their reduction with a favorable bleeding risk. The approval for this version to be published. lack of anticoagulation monitoring, coupled with simple dosing regimens with oral route of Reviewing Assistance. During the peer-re- administration, suggests that NOACs will con- view process, the manufacturer of the agent tinue to be more widely used as a ﬁrst-line agent under review was offered an opportunity to in patients with VTE. comment on the article. Changes resulting from comments received were made by the author based on their scientiﬁc and editorial merit. CONCLUSIONS Disclosures. 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Cardiology and Therapy – Springer Journals
Published: Mar 10, 2018
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