The use of oral anticoagulants for the treatment of venous thromboembolic events in an ED

American Journal of Emergency Medicine 32 (2014) 1526–1533

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American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem

Review

The use of oral anticoagulants for the treatment of venous thromboembolic events in an ED Charles V. Pollack Jr., MD ⁎ Department of Emergency Medicine, Pennsylvania Hospital, University of Pennsylvania

a r t i c l e

i n f o

Article history: Received 2 May 2014 Received in revised form 26 August 2014 Accepted 28 August 2014

a b s t r a c t Venous thromboembolism (VTE) is a disease spectrum that ranges from deep vein thrombosis (DVT) to pulmonary embolism (PE). Rapid diagnosis and treatment of VTE by emergency care providers are critical for decreasing patient mortality, morbidity, and the incidence of recurrent events. Recent American College of Chest Physicians guidelines recommend initial treatment with unfractionated heparin, low–molecular weight heparin, or fondaparinux overlapped with warfarin for a minimum of 5 days for the treatment of VTE in most cases. Warfarin monotherapy is thereafter continued for 3, 6, or 12 months. These guidelines were published before the approval of target-specific oral anticoagulants (TSOACs), and they have yet to be updated to reflect these new treatment options. For some patients, TSOACs, which act by directly inhibiting factor IIa or factor Xa, may provide safer, more convenient alternatives to warfarin. Their advantages include ease of use, reduced monitoring requirements, and lower bleeding risk than traditional therapy. Additionally, clinical trials have established noninferiority of TSOACs to warfarin for the prevention of recurrent VTE. These trials have demonstrated that TSOACs exhibit similar or lower bleeding rates, particularly intracranial bleeding rates compared with warfarin. Anticoagulation therapy with TSOACs may allow early discharge or outpatient management options for low-risk patients with DVT and PE. This review addresses the importance of early diagnosis and treatment of VTE, outcomes of VTE risk assessment, key efficacy and safety data from phase 3 clinical trials for the various TSOACs for the treatment of DVT and PE, and the corresponding considerations for clinical practice. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Venous thromboembolism (VTE) is a disease spectrum that spans deep vein thrombosis (DVT) to pulmonary embolism (PE). It is associated with high rates of morbidity and mortality, and can ultimately result in long-term complications, such as chronic thromboembolic pulmonary hypertension (CTEPH) [1] and postthrombotic syndrome (PTS) [2]. Venous thromboembolism occurs at a rate of 300,000 to 600,000 cases per year in the United States [3–6]. Acute VTE is frequently diagnosed by health care providers in the emergency department (ED). In the United States, an annual average of 201,000 ED visits resulted in a primary diagnosis of VTE, according to National Hospital Ambulatory Medical Care Surveys conducted between 1998 and 2006 [6]. Furthermore, the frequency of such ED visits is on the rise [4,6,7]. Rapid treatment of VTE by emergency physicians has been shown to decrease both mortality and the likelihood of long-term complications [8,9]. In most cases, current guidelines recommend administration of unfractionated heparin (UFH), low–molecular weight heparin (LMWH), or fondaparinux as a bridge to warfarin therapy for the treatment of VTE [10,11]. This regimen has disadvantages that include a 2-drug ⁎ Department of Emergency Medicine, Pennsylvania Hospital, University of Pennsylvania, 800 Spruce Street, Philadelphia, PA 19107. http://dx.doi.org/10.1016/j.ajem.2014.08.075 0735-6757/© 2014 Elsevier Inc. All rights reserved.

treatment strategy, use of injectable agents, numerous drug-drug interactions, food-drug interactions, and somewhat unpredictable levels of anticoagulation. Safety and efficacy assessments have been completed for the target-specific oral anticoagulants (TSOACs, previously referred to as novel oral anticoagulants), direct factor IIa or Xa inhibitors, which overcome some of these disadvantages. Target-specific oral anticoagulants provide treatment alternatives for patients with VTE presenting to the ED. This review discusses the importance of early diagnosis and treatment of VTE, as well as key efficacy and safety data from the phase 3 clinical trials for the various TSOACs for the treatment of DVT and PE, and considerations for clinical practice. Additionally, outcomes of VTE risk assessment are addressed. 2. Benefits of rapid VTE treatment Untreated PE is associated with a mortality rate of 18% to 35% [12], with the majority of deaths occurring in the first hour [13]. Notably, a study by Smith et al [8] in 2010 demonstrated that patients who achieved a therapeutic activated partial thromboplastin time (aPTT) within 24 hours experienced decreased mortality 30 days postevent and had lower in-hospital mortality. Conversely, patients who died in the hospital or within 30 days of an event took a longer time to reach a therapeutic aPTT level [8]. Emergency department intervention positively affected outcomes, and patients who received heparin in the ED

C.V. Pollack Jr. / American Journal of Emergency Medicine 32 (2014) 1526–1533

were more likely to achieve a therapeutic aPTT within 24 hours [8] and had reduced mortality rates both in-hospital and 30 days postevent [8]. The time from arrival in the ED to a computed tomography–based diagnosis of PE can be relatively short (2.4 hours); however, delays occur for 25% of patients [14]. Patients with delayed diagnoses of PE typically have more complicated clinical presentations and are more likely to experience an adverse outcome in-hospital [15]. These patients tend to have similar severity of PE and central-dominant clot distribution as patients diagnosed in the ED, but also tend to be older, with altered mental status, syncope, first time seizure at presentation, and prior cardiopulmonary diseases, that is, with concomitant clinical features that may diffuse focus away from a diagnosis of acute PE [15]. Anticoagulation is recommended for patients at a high risk of PE before confirmatory diagnostic testing; however, adherence to this guideline is somewhat limited [11,15,16]. Roughly 21% of patients who receive heparin anticoagulation are diagnosed with PE; regardless of the presence or absence of PE, these patients are significantly more likely to be admitted to an intensive care unit and demonstrate higher in-hospital mortality due to underlying illness [17]. The incidence of in-hospital hemorrhagic complications is low in patients receiving empiric systemic anticoagulation with heparin, regardless of the presence or absence of PE [17]. Patients with a high risk of PE should be treated with anticoagulation if the time to diagnosis is greater than 2.3 hours [14]. A dose of LMWH is superior to no treatment for diagnostic delays greater than 12.6 hours or 4.5 hours in low- or intermediate-risk patients, respectively [14]. Patients with a low pretest probability of DVT or PE can be discharged without anticoagulant therapy, with a confirmatory test for DVT or PE scheduled within 72 hours [18]. Aggressive treatment of DVT by emergency physicians reduces the risk of subsequent development of PTS [19], a cluster of symptoms and signs that are the most common complication of VTE. Postthrombotic syndrome occurs in 9.7% of DVT patients after anticoagulation treatment [20]. It is believed to occur when anticoagulant treatment prevents thrombus extension and embolization, but the acute thrombus is not completely cleared by the body’s own fibrinolytic mechanisms [21]. As a result, patients experience pain, heaviness, swelling, itching, skin changes, and ulceration of the affected extremity [2]. The greatest risk factors for the development of PTS (which can occur years after the initial DVT) are suboptimal inpatient management and malignancy [20]. Another complication of long-term, recurrent PE is CTEPH, pulmonary hypertension resulting from recurrent pulmonary thromboemboli. Chronic thromboembolic pulmonary hypertension is a condition that occurs in 3.8% of patients 2 years following survival of an episode of PE [1] and is associated with significant morbidity and mortality [22]. Recurrent VTE is the most important risk factor for CTEPH [22]. 3. Risk assessment and VTE Many individuals with DVT or PE are likely to experience recurrent events [23]. The risk of recurrence of PE depends on the characteristics of the thrombus; presence of risk factors; size of the PE; and presence of cardiac, metabolic, or hematologic comorbidity [12,24]. Risk factors for VTE are both inherited and acquired (Table 1). Transient or reversible triggers such as surgery, trauma, immobilization, or pregnancy are less likely to result in recurrent VTE, although nonsurgical causes of VTE carry a higher risk of recurrence than surgical causes (4.2% for nonsurgical causes vs 0.7% for surgical causes) [25]. Patients with symptomatic PE are more likely to have a recurrent event than patients with no symptoms of PE. Therefore, initial diagnosis of VTE and initiation of extended treatment are critical, as there is an elevated risk for recurrent thromboembolic events in patients who have experienced a first VTE [26]. A number of clinical scoring systems have been developed for the diagnosis of acute DVT and PE (Table 2) [27,28]. These tools have been extensively validated and are commonly applied. The Wells rule and the Geneva score each consist of weighted variables that are assessed to determine the probability of DVT or PE. These clinical prediction

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Table 1 Risk factors for VTE [10,11,98] Major risk factors for VTE

Inherited risk factors for VTE

Major abdominal surgery Hip/knee replacement Postoperative intensive care Late pregnancy Caesarian section Puerperium Fracture Varicose veins Abdominal/pelvic malignancy Advanced/metastatic cancer Hospitalization Institutional care Previous VTE

Antithrombin III deficiency Protein C deficiency Protein S deficiency Factor V Leiden mutation

Minor risk factors for VTE

Acquired risk factors for VTE

Congenital heart disease Congestive cardiac failure Hypertension Superior venous thrombosis Indwelling central vein catheter Oral contraceptive Hormone replacement therapy COPD Neurological disability Occult malignancy Thromboembolic disorders Long-distance sedentary travel Obesity Inflammatory bowel disorder Nephrotic syndrome Chronic dialysis Myeloproliferative disorders Paroxysmal nocturnal haemoglobinuria Behçet’s disease

Prior history of VTE Malignancy (esp. tumors of lung, brain, ovaries, pancreas) Surgery (esp. neurosurgical or orthopedic) Major trauma Central venous access devices Pregnancy Immobilization (bed rest, surgery, travel) Congestive heart failure Myocardial infarction Stroke Advanced age Smoking Obesity Hormones for contraception or replacement therapy

COPD, chronic obstructive pulmonary disease.

tools may be best used for estimating the likelihood of PE prior to diagnostic confirmation [29,30]. Of note, the populations used for the development and validation of these clinical predictive scoring tools did not include pregnant women [26]. A simplified version of the revised Geneva score, in which each variable is assigned 1 point, has also been validated and shown to maintain diagnostic accuracy [28]. Many providers still rely on the “gestalt” approach, the simple clinical judgment about a most likely diagnosis. In fact, Wells’ score allows for that “gestalt” and awards it 3 points, which put the patient at least at moderate risk. Risk stratification can also be based on hemodynamic instability and right ventricular (RV) function [31]. Patients with RV dysfunction are classified as high-risk PE and account for approximately 5% of all patients with PE. The mortality rate in this group is 15% [5]. Right ventricular overload or asymptomatic dysfunction with hemodynamic stability is associated with intermediate-risk PE, and normal RV function is associated with low-risk PE [31]. Evaluation can be performed using bedside transthoracic echocardiography in the ED; a transesophageal study is not necessary. The Pulmonary Embolism Severity Index (PESI) was developed to estimate 30-day mortality in patients with acute PE [32] and may be used to identify patients who are potential candidates for outpatient care. In its original format, the PESI score was calculated based on 11 different variables, each with a different weighting system [32,33]; a simplified version, which may be easier to apply in the ED, has also been evaluated [34,35] (Table 2). The PESI score stratifies fewer patients into the lower-risk score than other studies but has a higher discriminatory power for predicting 30-day mortality than the Geneva score [33]. Additionally, Hestia and European Society of Cardiology criteria have both been shown to have good discriminative power for selecting patients at a low risk for adverse events who are candidates for outpatient treatment [36,37].

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C.V. Pollack Jr. / American Journal of Emergency Medicine 32 (2014) 1526–1533

Table 2 Risk calculators for VTE Wells Rule [27]

Simplified Geneva Score [28]

Variable

Weight

Variable

Weight

Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins) An alternative diagnosis is less likely than PE Heart rate N100 bpm

3

Age N 65 y

1

Immobilization or surgery in previous 4 wk

1.5

Previous DVT/PE Hemoptysis Malignancy (on treatment, treated in the last 6 mo, or palliative)

1.5 1

1

Clinical probability Low Intermediate High

b2 2-6 N6

4. Treatment guidelines 3

Previous DVT or PE

1

1.5

Surgery (under general anesthesia) or fracture (of the lower limbs) within past 1 mo Active malignant condition (solid or hematologic, currently active or considered cured b1 y) Unilateral lower-limb pain Hemoptysis Heart rate 75-94 bpm ≥95 bpm Pain on lower-limb deep venous palpation and unilateral edema Clinical probability Low Intermediate High

1

Simplified PESI[34]

1

1 1 1 1 1

0-1 2-4 ≥5

Hestia exclusion criteria for outpatient treatment[36]

Variable

Weight

Age N 80 y

1

History of cancer

1

Chronic cardiopulmonary disease

1

Pulse ≥110 bpm

1

Systolic blood pressure b100 mm Hg Arterial oxyhemoglobin saturation level b90%

1

Low High

of stroke, chronic kidney disease, history of gastrointestinal (GI) bleeding, and a serious comorbid condition [39]. Risk factors for VTE, low platelet count, anemia, and abnormal prothrombin time have also been associated with increased bleeding risk [40].

1

0 ≥1

Is patient hemodynamically Yes/No unstable? If thrombolysis or Yes/No embolectomy necessary? Active bleeding or high risk Yes/No of bleeding? Yes/No More than 24 h of oxygen supply to maintain oxygen saturation N90% Is PE diagnosed during Yes/No anticoagulant treatment? Yes/No Severe pain needing IV pain medication for more than 24 h? Yes/No Is there a medical or social reason for treatment in hospital for N24 h? Yes/No Does the patient have a creatinine clearance of b30 mL/min Does the patient have severe Yes/No liver impairment? Is the patient pregnant? Yes/No Yes/No Does the patient have a documented history of heparin-induced thrombocytopenia? If the answer to any question is yes, patient cannot be treated at home.

bpm, beats per minute.

The majority of patients with acute but not life-threatening PE, that is, PE without hemodynamic instability, are primarily classified as low-risk (1% short-term mortality) patients with nonmassive PE [5]. A smaller fraction of patients classified with PE without hemodynamic instability are high-risk patients, with atypical presentation of PE, who are candidates for admission [5]. Several prediction rules have been developed for estimation of risk for major bleeding during anticoagulant therapy; however, none of these studies had c-statistic values that indicated that major bleeding was predicted at better-than-chance levels [38]. Factors proposed to increase the risk of bleeding include age more than 65 years, a history

Recent American College of Chest Physicians (ACCP) guidelines for the treatment of VTE were published before the approval of any TSOACs, and they have yet to be updated to reflect these new treatment options. As such, the current guideline-based standard of care for the treatment of acute VTE is the administration of LMWH or fondaparinux (UFH under certain conditions) [10,11], followed by overlapping treatment with a vitamin K antagonist (VKA) such as warfarin. Because of warfarin’s slow onset of action, treatment administration should overlap that of heparin for at least 5 days until an international normalized ratio (INR) of 2.0 or greater is achieved for at least 24 hours. The parenteral agent can be discontinued once the INR has stabilized between 2.0 and 3.0. Although Food and Drug Administration (FDA) approval for the treatment of acute VTE had not yet been attained, the ACCP guidelines did also recommend that, based on clinical data, the TSOAC rivaroxaban could be given at an initial dose of 15 mg twice daily for 3 weeks and then reduced to 20 mg once daily for the remainder of treatment. Based on clinical data, dabigatran is an additional option for long-term therapy. Treatment guidelines recommend that long-term anticoagulation with LMWH, UFH, fondaparinux, rivaroxaban, or dabigatran be continued for at least 3 months, 6 to 12 months, or longer depending on whether the underlying cause of VTE was provoked or unprovoked, the persistence of risk factors, and the risk of bleeding complications [11]. Subsequent to the publication of these guidelines, both rivaroxaban and dabigatran have been approved for treatment of VTE [41,42]. Patients with a high likelihood of PE should receive anticoagulation without waiting for diagnostic confirmation [10,11]. The risk of death from VTE is significantly reduced with anticoagulant therapy; intravenous (IV) heparin improves the overall survival of patients with PE [8]. The use of UFH must be monitored with aPTT. In the event of severe or lifethreatening PE with shock or hypotension, patients should be given IV UFH and thrombolytic therapy as appropriate. Low–molecular weight heparin should not be used in patients with severe renal impairment (creatinine clearance of b30 mL/min) [11]. Unless considering thrombolysis, LMWH is preferred over UFH, as it has better bioavailability, has lower risk of heparin-induced thrombocytopenia, and results in lower rates of bleeding and decreased risk of osteoporosis when used for long-term therapy [43]. Patients with acute DVT of the leg are recommended for treatment at home with LMWH over hospitalization provided home circumstances are adequate [11]. Low-risk patients with acute PE may be discharged early [11]. 5. Changing landscape of treatment options As mentioned, per ACCP guidelines, initial treatment options for VTE (published before the FDA approval of any TSOACs for that indication) are UFH, LMWH, and fondaparinux. Unfractionated heparin acts through binding antithrombin and inactivates serine proteases. Low–molecular weight heparin has a longer half-life, is more specific for antithrombin, produces a more predictable level of anticoagulation, and has fewer adverse effects than UFH. For the treatment of VTE, LMWH overlapped with warfarin for a minimum of 5 days and followed by 12 weeks of VKA therapy has been shown to be as effective as UFH + VKA with no difference in major bleeding or mortality [44]. The indirect factor Xa inhibitor fondaparinux is more specific than LMWH and has a longer half-life [45]. It requires less monitoring than UFH; and like LMWH, it is not associated with heparin-induced thrombocytopenia. However, both LMWH and fondaparinux have multiple drug interactions [46–48].

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Following the initial treatment of VTE, warfarin is the most widely used anticoagulant in the United States. Warfarin has a narrow therapeutic window and a wide variability of response. Patients undergoing long-term warfarin therapy often have suboptimal maintenance of therapeutic INR, only remaining within the therapeutic range 54% of the time; must cope with many drug and food interactions, frequent monitoring, and dose adjustments; and have a higher risk of bleeding [46,49]. In the wider population, statistics are not much improved, with studies suggesting that although anticoagulation clinics increase time in therapeutic range, patients on warfarin remain within the INR therapeutic range less than 70% of the time [50,51]. Nonetheless, there are more than 30 million prescriptions for warfarin written annually in the United States [52]. Approximately 21,000 hospitalizations for warfarin-related hemorrhages occur each year, which account for 63% of all warfarin-related hospitalizations [53]. Of all hospitalizations involving warfarin, 95% are the result of unintentional overdoses [53]. For some patients, TSOACs, which act by directly and specifically targeting factor IIa (thrombin) or factor Xa (FXa), may provide safer, more convenient alternatives to warfarin. Advantages include ease of use; reduced monitoring requirements; and, compared with warfarin, reduced drug-drug and food-drug interactions and decreased bleeding risk. The use of TSOACs may improve patient adherence and decrease the significant costs associated with VTE [54]. Dabigatran targets factor IIa, the serine protease thrombin, which activates factors V, VII, and XI to generate more thrombin and stimulate platelet aggregation by catalyzing the conversion of fibrinogen to fibrin [55]. Apixaban, edoxaban, and rivaroxaban act on the serine protease FXa, the convergence point of the intrinsic and extrinsic coagulation pathways. FXa binds to FVa, forming a prothrombinase complex that is the primary site of amplification, allowing 1 molecule of FXa to catalyze approximately 1000 molecules of thrombin [56]. By inhibiting FXa, thrombin generation is inhibited; and thrombin-induced positive feedback via FVa (prothrombinase) and FVIIIa (tenase) is prevented [56]. Target-specific oral anticoagulants generally reach peak plasma concentrations within 4 hours and have half-lives that range between 5 and 15 hours (Table 3) [41,42,57–63]. Much of the clearance of TSOACs is dependent on kidney function; however, the degree of clearance varies widely among the agents. Approximately 80% of dabigatran is cleared through the kidneys, prolonging its half-life under conditions of impaired renal function [58]. Rivaroxaban is also cleared largely by the kidneys, although one-third is left unchanged, one-third remains as the inactive metabolite, and the final one-third is cleared by the liver [64]. Edoxaban is eliminated primarily in urine and feces, with roughly one-third of the elimination occurring through the kidneys [65]. Apixaban has the least renal dependence of the TSOACs [55], but it is also eliminated by oxidative metabolism through the kidney and feces [60]. A reduced dose of edoxaban 30 mg once daily (the standard dose is 60 mg) was studied in the Hokusai-VTE study for patients with moderate renal impairment, low body weight, and concomitant use with strong P-glycoprotein (P-gp) inhibitors, and was shown to maintain efficacy and result in less bleeding than warfarin [66]. Reduced doses of dabigatran, apixaban, and rivaroxaban have not been studied in VTE.

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6. TSOACs and VTE Clinical trials have established that the TSOACs are noninferior to standard therapy for the prevention of recurrent VTE and exhibit similar or lower bleeding rates (Table 4). Both the dabigatran [67,68] and edoxaban [66] clinical trials were designed with at least 5 days of initial parenteral anticoagulant therapy followed by the TSOAC; no initial parenteral anticoagulant was mandated in clinical trials for rivaroxaban [69,70] or apixaban [71]. Both rivaroxaban and apixaban were initially administered at higher doses, and then patients were administered lower doses for longer-term treatment. Rivaroxaban, as studied in the Oral Direct Factor Xa Inhbitor Rivaroxaban in Patients With Acute Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism (EINSTEIN-DVT and EINSTEIN-PE) trials, is initially given at 15 mg twice daily for 3 weeks and then decreased to 20 mg once daily [69,70]. Similarly, apixaban is initially administered at 10 mg twice daily for 7 days and then decreased to 5 mg twice daily as studied in the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial [71]. A significantly lower risk of intracranial bleeding, which accounts for almost 9% of major bleeding and significant mortality rates with warfarin therapy, occurred in 0.09% of the patients treated with TSOACs, compared with 0.25% of the patients treated with VKA (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.16-0.94) [72].

6.1. Dabigatran The majority of patients enrolled in the clinical trial Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism (RE-COVER I) had an initial diagnosis of DVT only (69.1% in the dabigatran group, 68.6% in the warfarin group), less than one-quarter (21.2% dabigatran and 21.4% warfarin) of the patients had PE only, and roughly 10% (9.5% dabigatran, 9.8% warfarin) had PE plus DVT. All patients received IV UFH or subcutaneous LMWH for at least 5 days prior to treatment. Enrolled patients were at least 18 years old, with objectively diagnosed acute, symptomatic DVT of the legs or with PE and for whom 6 months of anticoagulant therapy was considered appropriate therapy [67]. Dabigatran was noninferior to warfarin, with the primary outcome, 6-month incidence of recurrent, symptomatic, objectively confirmed VTE and related deaths, occurring in 2.4% of patients treated with dabigatran for VTE compared with 2.1% of the patients treated with warfarin (HR, 1.10; 95% CI, 0.65-1.84; P b .001) [67]. A second study, RE-COVER II, was conducted with the same design as RE-COVER I. Patient distributions were similar to RECOVER I, with the bulk of patients diagnosed with DVT only (68.5% dabigatran, 67.8% warfarin), less than one-quarter with PE only (23.3% dabigatran, 23.1% warfarin), and roughly 10% with both DVT and PE (8.1% dabigatran, 9.1% warfarin). The results of RECOVER I and II were combined, with a pooled HR for recurrent VTE of 1.09 (95% CI, 0.76-1.57) for dabigatran [68]. In the pooled analysis for dabigatran, there was a marginally significant reduction of major bleeding compared with warfarin [68].

Table 3 Pharmacokinetics and pharmacodynamics of TSOACs

Time to Cmax (h) Half-life (h) Renal elimination (%) Transporters Cytochrome P450 metabolism (%) Potential drug interactions

Dabigatran [42,58]

Rivaroxaban [41,57,64,99]

Apixaban [59–61,100]

Edoxaban [62,63,65]

1-2 12-17 80 P-gp None Quinidine, amiodarone, potent P-gp inhibitors

2-4 5-13 66 P-gp/BCRP 66 Potent inhibitors of CYP3A4 and P-gp

3-4 12 25 P-gp 15 Potent inhibitors of CYP3A4 and P-gp

1-2 10-14 35 P-gp b4 Potent inhibitors of P-gp

BCRP, breast cancer resistance protein; Cmax, maximum observed plasma concentration; CYP3A4, cytochrome P450 3A4.

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C.V. Pollack Jr. / American Journal of Emergency Medicine 32 (2014) 1526–1533

Table 4 Summary of TSOAC clinical trials [66–71] Trial

RECOVER I (N = 2539) VTE or related death Major bleeding RECOVER II (N = 2589) VTE or related death Major bleeding

n (%)

n (%)

Dabigatran 150 mg BID for 6 mo

Warfarin

30 (2.4)

27 (2.1)

20 (1.6)

24 (1.9)

30 (2.3)

28 (2.2)

15 (1.2)

22 (1.7)

Rivaroxaban 15 mg BID for 3 wk, then 20 mg QD for 3, 6, or 12 mo EINSTEIN-DVT (N = 4382) Recurrent 36 (2.1) symptomatic VTE Major or CRNM 139 (8.1) bleeding EINSTEIN-PE (N = 4382) Recurrent 50 (2.1) symptomatic VTE Major or CRNM 249 (10.3) bleeding Apixaban 10 mg BID for 7 d, then 5 mg BID for 6 mo AMPLIFY (N = 5395) Symptomatic recurrent VTE or related death Major bleeding

Hokusai-VTE (N = 8292) Symptomatic recurrent VTEb Major or CRNM bleedingb

HR (95% CI) P value for noninferiority

1.10 (0.65-1.84) P b .001 0.82 (0.45-1.48) 1.08 (0.64-1.80) P b .001 0.69 (0.36-1.32)

Enoxaparin to VKA

51 (3.0) 138 (8.1)

44 (1.8) 274 (11.4)

0.68 (0.44-1.04) P b .001 0.97 (0.76-1.22) P = .77 1.12 (0.75-1.68) P = .003 0.90 (0.76-1.07) P = .23

Enoxaparin to VKA

59 (2.3)

71 (2.7)

15 (0.6)

49 (1.8)

Edoxaban 60 mg QD for 3 to 12 mo

Warfarin

130 (3.2)

146 (3.5)

349 (8.5)

423 (10.3)

0.84 (0.60-1.18) P b .001 0.31(0.17-0.55) P b .001a

0.89 (0.70-1.13) P b .001 0.81 (0.71-0.94) P = .004a

P values for the primary outcome are for noninferiority with the exception of major bleeding for apixaban. BID, twice daily; QD, once daily. a Denotes superiority. b Patients with moderate renal impairment, low body weight, and concomitant use with strong P-gp inhibitors received a reduced dose of 30 mg.

Rivaroxaban and enoxaparin/VKA treatment produced similar rates of major and clinically relevant nonmajor (CRNM) bleeding, the primary safety end point (Table 4). Major bleeding occurred in 0.8% of patients treated with rivaroxaban and 1.2% of enoxaparin/VKA-treated patients. Patients receiving rivaroxaban had an increase in CRNM bleeding, which was mostly mucosal. Both the total rates of mortality and cardiovascular events were low in both groups. No differences in efficacy were found based upon the location or extent of the DVT [69]. In the EINSTEIN-PE trial, rivaroxaban as a single-drug approach was given for anticoagulant therapy for acute PE, with or without DVT, replacing both heparin or enoxaparin and VKA [70]. Patients were diagnosed with acute symptomatic PE, with or without DVT. Although rivaroxaban therapy is designed to be a single-drug approach, a total of 92.5% of patients treated with rivaroxaban and 92.1% of patients treated with enoxaparin-VKA therapy were pretreated with LMWH, heparin, or fondaparinux for less than 48 hours before randomization. Furthermore, there were few enrolled who were hemodynamically unstable and might have been candidates for fibrinolytic therapy. No significant differences in efficacy were present based on the severity of PE, the presence of DVT with PE, or prior occurrence of DVT or PE. Rivaroxaban did not differ from warfarin for the primary safety end point of a first major or CRNM bleeding episode (Table 4) and was associated with significantly less major bleeding. 6.3. Apixaban The AMPLIFY trial [71] enrolled patients with proximal DVT or PE and did not include patients with active cancer for whom long-term treatment with LMWH was planned. A total of 86.5% of patients treated with apixaban and 85.7% of patients receiving conventional therapy were treated with LMWH, heparin, or fondaparinux for less than 48 hours prior to randomization. Following a 1-week loading dose, treatment duration was 6 months. Apixaban was noninferior to conventional therapy for the primary efficacy outcome of recurrent symptomatic VTE or death related to VTE. Reductions in the composite of major bleeding and CRNM bleeding were significantly larger for apixaban compared with warfarin. No differences were seen for patients with DVT receiving apixaban vs conventional therapy (2.3% vs 2.7%, respectively) in the AMPLIFY trial [71]. No differences in efficacy or safety were present based upon the anatomical extent of the index DVT. No differences were seen for patients with PE receiving apixaban vs conventional therapy (2.3% vs 2.6%, respectively), and the extent of the index PE did not appear to impact the efficacy of apixaban. No differences in safety were present based upon the anatomical extent of the index PE. 6.4. Edoxaban

In RE-COVER I, dabigatran was noninferior to warfarin for patients with initial symptomatic PE who experienced the primary outcomes of recurrent symptomatic, objectively confirmed VTE, or a VTE-related death [67]. In the pooled analysis of RE-COVER I and II, no significant differences in safety or efficacy were present for the subgroup of patients with a pretreatment diagnosis of PE [68].

6.2. Rivaroxaban The EINSTEIN clinical trials for rivaroxaban separated patients based on diagnosis of DVT vs PE. Patients were eligible for the EINSTEIN-DVT trial if they exhibited acute symptomatic proximal DVT without PE. A total of 73.0% of patients treated with rivaroxaban and 71.0% of patients treated with enoxaparin-VKA therapy were pretreated with LMWH, heparin, or fondaparinux for less than or equal to 48 hours before randomization [69]. Treatment duration, determined by a physician before randomization, was for a total of 3, 6, or 12 months.

The Hokusai-VTE trial, the largest single study of TSOAC-treated VTE to date [66], enrolled 8292 patients in a randomized, double-blind fashion to investigate edoxaban, which is currently under consideration for approval by the FDA, vs traditional therapy for the treatment of VTE. All patients received initial treatment with open-label enoxaparin or UFH for at least 5 days prior to treatment. Enrolled patients were at least 18 years old, with objectively diagnosed acute, symptomatic DVT of the popliteal, femoral, or iliac veins or with acute, symptomatic PE (with or without DVT) [66]. Edoxaban was noninferior to heparin/VKA for the primary efficacy outcome of adjudicated symptomatic recurrent VTE. Edoxaban was noninferior to heparin/VKA, with a first recurrent VTE or VTE-related death experienced by 3.2% of the patients in the edoxaban-treated group vs 3.5% of the patients in the warfarin-treated group. Edoxaban had superior safety to standard therapy for the primary safety end point (Table 4). Major bleeding occurred in 1.4% of the edoxaban group and in 1.6% of the heparin/VKA group (HR, 0.84; 95% CI, 0.591.21) [66]. In particular, fewer nonfatal intracranial bleeding events

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occurred in the edoxaban-treated patients (0.1% vs 0.3%) [66]. Patients who qualified for a dose reduction of edoxaban (n = 733 for edoxaban, n = 719 for warfarin) had fewer instances of recurrent VTE (3.0% vs 4.2%; HR, 0.73; 95% CI, 0.42-1.26) and less clinically relevant bleeding (7.9% vs 12.8%; HR, 0.62; 95% CI, 0.44-0.86) compared with patients who received warfarin [66]. No between-group differences were present for the DVT only group, with 3.4% of patients treated with edoxaban and 3.3% of patients treated with warfarin experiencing the primary outcome of recurrent symptomatic VTE (HR, 1.02; 95% CI, 0.75-1.38) [66]. In the Hokusai-VTE trial, patients with PE were assessed for levels of N-terminal pro-brain natriuretic peptide, a marker of RV dysfunction. In patients with PE and an N-terminal pro-brain natriuretic peptide level of at least 500 pg/mL, recurrent VTE occurred in 3.3% of edoxabantreated patients and in 6.2% of the warfarin-treated group (HR, 0.52; 95% CI, 0.28-0.98). A subset of the patients with PE assessed with RV dysfunction by computerized tomography showed similar results (HR, 0.42; 95% CI, 0.15-1.20) [66]. Thus, recurrences of VTE were reduced in this population. 7. Considerations for clinical practice Results from the multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry, a study of the characteristics, outcomes, and management of patients with acute PE in the ED, showed that systemic non-vitamin K–dependent anticoagulation is initiated in the ED in 84% of patients with VTE [16]. The most common ED treatment was UFH, followed closely by enoxaparin [16]. Only a minority of patients received fondaparinux or dalteparin [16]. Despite recommendations, heparin was administered before diagnostic imaging in only 9% of patients [16]. Although mortality rates for patients diagnosed with PE in the ED were found to be only 1.1% [16], much lower than the 10% to 15% mortality rate reported elsewhere [16], these results still suggest that current treatment guidelines have not been fully integrated into all ED practices. There are some treatment management concerns that should also be noted for the current anticoagulant options. These include differences in patient responses to VKA antagonists due to common genetic polymorphisms, a need for frequent monitoring of INR, and a risk of major and nonmajor bleeding events. Furthermore, LMWH and fondaparinux are administered by subcutaneous injection, which may limit their use as chronic agents. The advantages of TSOACs include ease of use, fixed dosing regimens, reduced monitoring requirements, equivalent or superior safety to warfarin, no risk of heparin adverse effects such as heparin-induced thrombocytopenia, fewer contraindications, and shorter half-lives than VKA. Their use may allow early discharge or outpatient management options for low-risk patients with DVT and PE. Their primary disadvantages are cost and lack of specific reversal agents. Although TSOACs have fewer drug-drug interactions than warfarin, they do carry some drug restrictions. Dabigatran is known to interact with P-gp inducers or inhibitors, apixaban and rivaroxaban are known to interact with P-gp and cytochrome P450 isoenzyme 3A4 inducers, and edoxaban is known to interact with P-gp inhibitors. Careful consideration of concomitant medication use is necessary when choosing a TSOAC. Table 5 provides a list of common P-gp inducers and inhibitors. As a group, the TSOACs are associated with reduced risk of intracranial hemorrhage; however, meta-analysis has shown an association of increased risk of GI bleeding with TSOAC treatment for treatment of venous thrombosis [73]. Because of limited numbers of GI bleeding events in the phase 3 VTE trials, more information regarding bleeding risks and the TSOACs is available from patients with atrial fibrillation (AF) receiving either dabigatran or rivaroxaban for stroke prevention. In these patients, dabigatran has been shown to produce higher rates of bleeding at 150 mg twice daily compared with warfarin, (HR, 1.50; 95% CI, 1.19-1.89; P b .001); but dabigatran 110 mg twice daily produces similar GI bleeding compared with warfarin [74]. An analysis of

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Table 5 P-gp inducers and inhibitors [101] P-gp inducers Rifampicin Cyclosporine Dexamethazone Tipranavir Carbamazepine Phenytoin Venlafaxine St. John’s wort P-gp inhibitors Tariquidar Valspodar Azithromycin Clarithromycin Erythromycin Itraconazole Ivermectin Ketoconazole Mefloquine Ofloxacin Rifampin Cyclosporine Tacrolimus Cimetidine Omeprazole Indiavir Lopinavir Nelfinavir Ritonavir

Saquinavir Amitriptyline Chlorpromazine Desiparmine Disulfiram Doxepin Haloperidol Imipramine Sertraline Varenicline Coinvaptan Elacridar Grapefruit juice Isoflavones Orange juice Progesterone Qurecetin Testosterone Troaglitazone

postmarketing reports did not show higher rates of bleeding for dabigatran compared with those associated with warfarin [75]. Rivaroxaban GI bleeding rates are increased in AF patients (3.2%) compared with warfarin (2.2%, P b .001) [76]. No increases in apixaban GI bleeding rates have been shown compared with warfarin (HR, 0.89; 95% CI, 0.70-1.15; P = .37) in AF patients [77]. More frequent GI bleeds occur with edoxaban 60 mg than warfarin (1.51%; HR, 1.23; 95% CI, 1.02-1.50; P = .03); however, edoxaban 30 mg produced fewer GI bleeds relative to warfarin (0.82%; HR, 0.67; 95% CI, 0.53-0.83; P b .001) in patients with AF [78]. Bleeding risk is a concern for all patients receiving anticoagulation therapies. Current recommendations call for delay of procedures for 6 to 24 hours, if possible, for patients receiving warfarin; otherwise, vitamin K can be used for reversal [79]. Fresh frozen plasma or coagulation factors may be administered concomitantly to speed up reversal, as vitamin K reversal has a slow onset of at least 24 hours [80]. Currently, there are no specific reversal agents for the novel oral anticoagulants. Infusion of prothrombin complex concentrates has been shown to be effective in reversing changes in prothrombin time and endogenous thrombin potential induced by rivaroxaban [81,82]. Activated prothrombin complex concentrate, factor VIII inhibitor bypassing activity, and an active recombinant form of factor VII [82,83], hemostatic agents used for bleeding and bleeding deficiencies, have also been tested for feasibility as reversal agents [84,85]. Additionally, PER977, a synthetic small molecule [86,87], and PRT064445, a catalytically inactive human recombinant FXa [88], are under investigation. Dabigatran, which is 35% protein bound, may be removed by dialysis, as recommended by package insert; but this procedure may not be feasible in unstable patients [42,89]. Although edoxaban is 40% to 59% protein bound, dialysis has not been shown to be effective for its removal [90,91]. Rivaroxaban and apixaban are 95% and 87% protein bound, respectively, and cannot be removed by dialysis [13,60,92]. Given all the evidence, TSOACs should be considered as part of the treatment armamentarium for VTE in the ED setting, especially for those patients for whom other standard treatment options may not be ideal [93–97].

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