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Abstract

Venous thromboembolism (VTE), which includes deep venous thrombosis and pulmonary embolism, is a major public health problem associated with increased morbidity and mortality. Despite the high recurrence risk associated with unprovoked VTE, extended anticoagulation remains controversial. Oral antithrombotic agents for extended VTE treatment comprise the vitamin K antagonists, aspirin, and the direct oral anticoagulants (also known as target-specific oral anticoagulants and formerly known as the new or novel oral anticoagulants) including rivaroxaban, dabigatran, apixaban, and edoxaban. The efficacy of these anticoagulants in reducing the risk of VTE recurrence (>80%-90% relative risk reduction) is offset by the risk of major bleeding that approaches 3% per year. Stratifying risks of recurrence and bleeding to identify patients at low, intermediate, or high risk and carefully considering the pharmacologic profile of the antithrombotic agents will help clinicians in choosing the optimal anticoagulant and duration and/or surveillance strategy. This review will discuss the current guidelines for extended VTE treatment, review the clinical trials involving the direct oral anticoagulants, and present the clinical considerations and concerns involving extended therapy.

Keywords

venous thromboembolism antithrombotic therapy

Introduction

Venous thromboembolism (VTE) is a major preventable public health problem associated with increased morbidity and mortality. It includes deep venous thrombosis (DVT), pulmonary embolism (PE), or both. Although the true incidence is unclear, the overall age- and sex-adjusted annual incidence of VTE was 1.2 per 1000 (0.5 per 1000 for DVT and 0.7 per 1000 for PE) based on the results of a 25-year population-based study.¹ Among patients who develop VTE, one-fifth dies immediately from PE and almost one-third dies within 30 days after initial presentation.² In addition to the high mortality associated with an initial acute VTE episode, patients are at a high risk for recurrence and morbidity thereafter. Of those patients who survive VTE, one-third develop recurrent VTE over a 8- to 10-year period, whereas another third develop the postthrombotic syndrome even up to 20 years after their event.^2,3 Approximately 4% of patients develop symptomatic chronic thromboembolic pulmonary hypertension (CTEPH) within 2 years after initial PE episode.⁴

Venous thromboembolism is categorized as either provoked or unprovoked. Provoked events are associated with identifiable risk factors that are usually transient but may be persistent. Transient risk factors include trauma, fracture, or surgery within 3 months, medical illness, extended travel, prolonged immobility, recent hospitalization, pregnancy, and estrogen therapy (hormone replacement therapy or contraceptive agents). Persistent “provoked” risk factors include active cancer and select thrombophilia including the antiphospholipid antibody syndrome. Venous thromboembolism that occurs in the absence of any identifiable risk factors is considered unprovoked.

The goals of VTE treatment are to prevent death from PE in the acute phase, prevent symptomatic recurrent VTE, and prevent or reduce morbidity from the postthrombotic and CTEPH syndromes. Treatment includes 3 phases: initial (0-7 days), long term (7 days to 3 months), and extended (3 months to an extended or indefinite period).⁵

Extended or long-term treatment of an unprovoked VTE after an initial event is a subject of debate and involves balancing the bleeding risk of ongoing anticoagulation versus the risk of VTE recurrence after stopping anticoagulation. The American College of Chest Physicians (ACCPs), the European Society of Cardiology (ESC) Guidelines, and the American Heart Association (AHA) scientific statement recommended 3 months of antithrombotic therapy for a first episode of a provoked proximal DVT or PE (with transient risk factors) but have issued varying recommendations for or against extended therapy for patients with unprovoked VTE based on their bleeding risk profile and the presence of persistent risk factors such as active cancer and history of recurrence (Table 1).^5
-7 None of these guidelines make specific recommendations regarding the optimal length of extended anticoagulation and generally leave it to the judgment of the individual physician presumably after a thorough risk–benefit assessment. Additionally, specific acquired or high-risk inherited thrombophilia patients including those with antiphospholipid antibody syndrome, antithrombin, protein C or S deficiencies, or homozygous or dual heterozygous carriers of factor V Leiden and/or prothrombin G20210A mutations are not discussed by the ACCP guidelines or AHA scientific statement. However, the ESC guidelines suggest individuals with a lupus anticoagulant, protein C or S deficiencies, and individuals homozygous for factor V Leiden or prothrombin G20210A may be candidates for indefinite anticoagulation.⁷ In clinical practice, many of these patients are treated with prolonged anticoagulation.

Table 1.

Antithrombotic Therapy and Prevention of Thrombosis: Summary of Guidelines and/or Scientific Statement From the American College of Chest Physicians, European Society of Cardiology, and the American Heart Association.^4
-6

VTE Risk Factor	VTE Location	VTE Episode	Bleeding Risk	Duration of Anticoagulation
Provoked by transient risk factor(s)	Proximal DVT or PE	–	–	3 months^a
Provoked by transient risk factor(s)	Isolated distal leg DVT	–	–	3 months^b
Unprovoked	Isolated distal leg DVT	First	Low	3 months^b
	Isolated distal leg DVT	First	Moderate to high	3 months^a
	Proximal DVT or PE	First	Low to moderate	Extended duration^b
	Proximal DVT or PE	First	High^c	3 months^a
	VTE	Second	Low	Extended duration^a
			Moderate	Extended duration^b
			High^c	3 months^b
Active cancer	VTE		Low to moderate	Extended duration^a
Active cancer	VTE		High	Extended duration^b

Abbreviations: DVT, deep venous thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

^aRecommended.

^bSuggested.

^cBased on the 2012 American College of Chest Physicians Guidelines.

Selection of Patient, Drug, and Treatment Duration

Although recurrent VTE can occur any time after the initial episode, the highest incidence rates (10%-13%) occur during the first 6 to 12 months after stopping anticoagulation.⁸ Studies have shown a very high cumulative recurrence rate of about 10% to 13% at 1 year, 25% at 5 years, and 30% at 10 years for both provoked and unprovoked VTE events.^3,8 Despite the high efficacy of oral anticoagulation therapy in reducing the risk of VTE recurrence (> 80%-90% relative risk [RR] reduction), the preventive effect is not maintained after discontinuation of anticoagulation with most agents, while extended oral anticoagulation is associated with a risk of major bleeding of 0.9% to 3.0% per patient-year.^9

-16 Notably, the case fatality rate for recurrent VTE is between 5% and 13%, whereas a major bleeding episode has a case fatality rate of 13%.^17
-19 Given that rates of fatal VTE are similar to those of fatal bleeding on oral anticoagulation, stratifying recurrence and bleeding risks to identify patients at risk for new events will help clinicians in determining whether to continue long-term anticoagulation.

Recurrence Risk

Patients with VTE can be classified into 3 groups based on their VTE recurrence risk: low (those with major temporary risk factors such as trauma, fracture, or surgery), intermediate (those with minor transient risk factors, such as long travel and immobilization), and high (those with active cancer, high-risk inherited thrombophilia, antiphospholipid antibody syndrome, history of recurrent VTE, and previous unprovoked events).²⁰ Patients at high risk of VTE recurrence need to be considered for extended anticoagulation, whereas those at low risk usually only need anticoagulation for 3 months based on the ACCP and ESC guidelines and the AHA scientific statement.^5
-7 The length of anticoagulation in patients belonging to the intermediate-risk group must be individually tailored after reviewing all available information regarding their VTE recurrence risk, such as the presence of continuing risk factors, thrombus burden, thrombophilia, other comorbidities, and their potential bleeding risk.

Unprovoked VTE confers more than a 2-fold risk of recurrence, the cumulative incidence rates being 15.0% at 1 year, 40.8% after 5 years, and 52.6% after 10 years, compared with 6.6% at 1 year, 16.1% after 5 years, and 22.5% after 10 years in patients with provoked VTE.²¹ There is a 2-fold to 4-fold increased risk of recurrence in patients with active cancer, particularly those receiving chemotherapy and those with metastases.^3,8,22,23 Antiphospholipid antibody syndrome has a particularly high recurrence risk of VTE after a primary event, with risk ratios of 2.3 to 8.5 reported.^11,24

-28 Given that patients with antiphospholipid antibody syndrome are heterogeneous, those with multiple episodes of thrombosis, recurrent fetal loss, and thrombocytopenia are expected to have the highest VTE recurrence risk among this patient population. Considering the high recurrence risk, patients with antiphospholipid antibody syndrome are usually treated with indefinite anticoagulation, whereas patients with cancer are maintained on anticoagulation as long as their malignancy remains active.^11,25,26

Anatomic location of the VTE has predictive value for recurrence risk as well. Data comparing the recurrence risk of isolated (calf) DVT to isolated PE (no identifiable DVT) are conflicting, with some studies suggesting similar recurrence rates, whereas isolated PE was associated with higher recurrences in other studies.^8,29

-33 Patients with lower extremity DVT are at a higher risk for recurrence than those with upper extremity DVT, a less common anatomic location for DVT.^34,35 Recurrence is at least twice more common in patients with proximal DVT than distal DVT.^{13,22,33,36,37} Venous thromboembolism occurring at unusual anatomic locations such as visceral or cerebral veins has much lower recurrence rates, although evidence is limited, whereas the atypical location of VTE should raise the suspicion for an underlying malignancy or thrombophilia.³⁸

Additional patient characteristics associated with high risk for VTE recurrence include male sex, older age, high body mass index (BMI), tobacco use, high lipoprotein (a) and low high-density lipoprotein-cholesterol levels, presence of an inferior vena cava filter, continued estrogen use, elevated d-dimer after stopping anticoagulation, and neurological disease with leg paresis.^{2,8,21,30,39

-42} Venous thromboembolism recurrence risk in patients with inheritable thrombophilia depends on the type (natural anticoagulant deficiency vs genetic polymorphisms) and the number of defects. In patients with thrombophilia due to genetic polymorphisms, homozygous or dual heterozygous carriers of factor V Leiden and/or prothrombin G20210A mutations are at a higher risk for recurrent VTE than single heterozygous mutants. Even though deficiencies of inherited natural anticoagulants including antithrombin, protein C, and protein S are rare, these conditions increase the thrombosis recurrence rate 4-fold to 5-fold and necessitate consideration for indefinite anticoagulation.^43,44

Thrombophilia testing includes polymerase chain reactions for factor V Leiden and prothrombin G20210A gene mutation; levels of factor VIII, fasting plasma homocysteine, antithrombin (III), protein C and S; anticardiolipin antibodies (immunoglobulin [Ig] G and IgM), anti-β 2 glycoprotein I antibodies (IgG and IgM), and a lupus anticoagulant. Screening for thrombophilia after an initial VTE episode is a matter of debate, particularly with regard to the timing of the testing and who should be tested. It is generally recommended that testing be performed at least 3 weeks after the discontinuation of oral anticoagulation for a meaningful interpretation of many of the test results, although studies for factor V Leiden, prothrombin gene mutation, and anticardiolipin antibodies can be done at any time. General guidelines suggest that testing should be considered if it will predict recurrence or affect the length of anticoagulation. In our practice, patients who develop VTE at younger age, those who present with recurrence, and those who have a strong family history of thrombotic events are considered for testing to exclude thrombophilia. Obtaining such tests in the first-degree relatives of patients with inherited thrombophilia is more controversial and should be limited to those who have a strong history of VTE or special circumstances such as asymptomatic women at fertile age in whom a decision regarding peripartum thromboprophylaxis or use of oral contraceptives needs to be made.

Several investigators have proposed d-dimer concentrations and residual venous thrombosis (also referred to as residual vein obstruction) as methods for predicting VTE recurrence and guiding length of optimal anticoagulation after an initial unprovoked VTE episode. A 2008 systematic review of 1888 patients with a first-time unprovoked VTE who had completed at least 3 months of anticoagulation found that the annual VTE recurrence rates were 8.9% in patients with elevated d-dimer levels compared to 3.5% in those with negative d-dimer levels after 2 years of follow-up.⁴⁵ Prandoni et al found that patients with residual venous thrombus burden as assessed by duplex ultrasound is a powerful and independent risk factor for recurrent VTE and have reported a higher recurrence rate in contrast to those with early vein recanalization (hazard ratio—HR [95% confidence interval—CI), 2.4 [1.3-4.4]).^46
-48 However, the role of residual venous thrombosis for the prediction of VTE recurrence risk needs further validation.

Although there are few prediction models for risk assessment of VTE recurrence in patients after an unprovoked VTE, a validated prediction tool that incorporates all relevant recurrence risk factors is still lacking (Table 2). Some of the clinical prediction scores available include HERDOO2, DASH, and the Vienna prediction models (2010 and the 2014 updated version).^49
-51 The HERDOO2 version is a multivariable model for identifying women at low risk for VTE recurrence in whom anticoagulation might be safely discontinued after they complete 5 to 7 months of oral anticoagulation for an unprovoked VTE.⁴⁹ Four clinical variables in this model include postthrombotic signs (hyperpigmentation or edema or redness in either leg), d-dimer level ≥250 μg/L, obesity (BMI ≥ 30 kg/m²), and older age (age ≥65 years). Women were classified as high risk for recurrent VTE if they had 2 or more of these features and as low risk if they had 0 or 1 feature. However, this model is not applicable to men (as men were considered to always require long-term anticoagulation) and nonwhites. The Vienna prediction model has developed a nomogram utilizing patient’s sex, location of initial VTE (distal, proximal, or PE), and d-dimer levels to calculate one’s risk score and expected 1 and 5 years of cumulative recurrence rates for those with unprovoked VTE.⁵⁰ In 2014, this model was updated by integrating serial d-dimer measurements to the previous nomogram for predicting the recurrence risk from multiple time points after discontinuing anticoagulation.⁵¹ In this new model, separate points are assigned to sex, location of VTE, and the most recent d-dimer levels. The total number of points is calculated by adding these items. By mapping the total points on the nomogram to the cumulative recurrence rate (%), the recurrence risk within 12 and 60 months from the assessment of d-dimer levels is estimated. Patients were considered at low risk of recurrence if their total points score was <180. The DASH score comprises 4 predictors of recurrence: d-dimer after stopping anticoagulation, age <50 years, sex, and hormonal therapy-related VTE.⁵² The annual VTE recurrence rate ranges from a low of 3.1% for DASH scores <1.0 to as high as 12.3% for a score of >3. Although these prediction models may enable identification of patients with unprovoked VTE and a low-enough recurrence risk to consider a limited duration of anticoagulation, they require prospective, external validation before widespread clinical use.

Table 2.

Models for Predicting VTE Recurrence Risk.

	Predictive Variables	Recurrence Risk
HERDOO2 model	For white women only	Low risk: 0 or 1 feature
	Post thrombotic signs (hyperpigmentation or edema or redness in either leg)	High risk: 2 or more features
		Score ≤1: 1.6% recurrence rate
	d-Dimer level ≥250 μg/L
	Obesity (body mass index ≥30 kg/m²)
	Older age (age ≥65 years)
Vienna prediction models (2010 version)	Sex	Nomogram-based cumulative recurrence rates at 12 and 60 months
	Location of initial VTE
	d-Dimer levels
Vienna prediction models (2014 updated version)	Sex	Nomogram based on cumulative recurrence rates at 12 and 60 months from multiple time points after stopping anticoagulation
	Location of initial VTE
	Serial d-dimer levels
		By mapping the total points (sum of separate points assigned to sex, location of venous thromboembolism, and the most recent d-dimer levels) on the nomogram to the cumulative recurrence rate (%), the recurrence risk within 12 and 60 months from assessment of d-dimer levels are estimated
		Total points <180, 4.4% recurrence rate per nomogram
DASH score	d-Dimer abnormal after stopping anticoagulation (2 points)	Low risk: score ≤1, annual recurrence risk 3.1%
	Age ≤50 years (1 point)
	Sex (1 point for male sex)
	Hormonal therapy (−2 points)

Abbreviation: VTE, venous thromboembolism.

The optimal length of extended antithrombotic therapy after an unprovoked VTE in patients without high recurrence risk features also needs to be further elucidated. REVERSE II is an ongoing clinical trial that is investigating the impact of cessation of anticoagulation after 5 to 12 months in low-risk patients after an index initial unprovoked VTE in comparison to continuation of oral anticoagulation in high-risk patients.⁵³

Choice of Extended Anticoagulation Regimens

It has clearly been established that recurrent VTE rates are minimal during extended anticoagulant therapy and that indefinite extension of oral anticoagulants prevents recurrence after unprovoked VTE. However, such benefits must be weighed against the safety profile of the anticoagulant and the convenience of anticoagulation management.

The choice of anticoagulation regimens for extended therapy in patients after unprovoked VTE depends on the patient’s renal and liver function, bleeding risk, thrombosis recurrence risk, history of coronary artery disease, need for laboratory monitoring, and geographic accessibility for follow-up and treatment costs. Various evidence-based anticoagulation regimens for extended VTE treatment include the vitamin K antagonists (VKAs), adjusted full-dose subcutaneous (SC) or intravenous unfractionated heparin (UFH), SC low-molecular-weight heparin (LMWH), SC fondaparinux, aspirin, the direct oral anticoagulants (DOACs) including the direct thrombin inhibitor (DTI), dabigatran, and the factor Xa inhibitors, rivaroxaban, edoxaban, and apixaban. Although adjusted full-dose SC UFH, LMWH, and fondaparinux are effective alternate options for extended anticoagulation, the parenteral route of administration makes their use less favorable. Risk for osteoporosis, a well-known complication of UFH limiting its long-term use, however, is felt to be substantially lower with the LMWH preparations and even lower with fondaparinux.^54,55 In this review, we will focus on the oral antithrombotic drugs with an indication for extended prophylaxis after unprovoked VTE (Table 3).

Table 3.

Choice of Extended Oral Anticoagulation Regimen After Unprovoked VTE.

Category	Drug
Vitamin K antagonist	Warfarin
Irreversible inhibitor of cyclooxygenase 1 enzyme	Aspirin
Direct thrombin inhibitor	Dabigatran
Factor Xa inhibitor	Edoxaban^a
	Rivaroxaban
	Apixaban

Abbreviations: FDA, Food and Drug Administration; VTE, venous thromboembolism.

^aNo FDA approval for extended VTE prophylaxis.

Vitamin K Antagonist

The VKA, warfarin has a slow onset of action and a long half-life. Several factors including age, sex, race, body surface area, weight, drugs, plasma vitamin K levels, decompensated heart failure, active cancer, and genetic polymorphisms affect its dosing. The effect of warfarin is reversed with vitamin K, fresh frozen plasma, or prothrombin complex concentrates (PCCs). In addition to the bleeding risk, the need for laboratory monitoring, dose adjustments, potentials for drug and diet interactions are significant barriers to long-term VKA therapy.

Vitamin K antagonists have long been the standard of therapy for extended VTE treatment. Results of 4 trials found extended VKA therapy maintaining a target international normalized ratio (INR) of 2.5 reduced recurrent VTE by about 90% (RR [95% CI], 0.12 [0.05-0.25]) in patients at high risk for recurrence at the cost of about a 2.6-fold increase in major bleeding events compared with discontinuation of VKA therapy.^5,11,56
-58 The major bleeding risk with extended conventional intensity VKA therapy ranges from 0.9% to 3.0% per patient-year.^9

-15

Many physicians have used a lower-intensity INR target of 1.75 (1.5-1.9) as demonstrated in the PREVENT trial.¹⁴ However, this approach has been shown to be less effective when compared to conventional intensity INR target of 2.0 to 3.0, as reported in the ELATE trial.¹⁵ Despite lower recurrence rates during extended anticoagulant treatment, VKA therapy does not confer additional clinical advantage after its discontinuation.

Direct Oral Anticoagulants

The DOACs have emerged as potential alternatives to the VKAs for both primary and secondary VTE prophylaxis. Their rapid onset of action, predictable pharmacodynamics, and pharmacokinetics with oral fixed-dose regimens, lack of need for routine monitoring, short half-life, limited drug and food interactions, and improved benefit to risk ratio make them an attractive alternative to VKAs for extended VTE treatment. However, several practical concerns regarding their use exist. These include a lack of a readily available antidote for reversal in active bleeding for all of the DOACs except dabigatran, the possibility of toxicity in patients with renal impairment and lack of an easily available assay to determine their therapeutic effect in those suspected of noncompliance or treatment failure.⁵⁹ In addition, documented guidelines for directing clinicians on how to manage patients on extended treatment using the DOACs are particularly sparse.⁶⁰

In clinical trials, the DOACs demonstrated noninferior efficacy for extended treatment of VTE, whereas their safety profiles were similar or even slightly improved when compared to conventional therapy with LMWH and a VKA. Specifically, extended anticoagulation with the DOACs resulted in at least an 80% to 90% reduction in VTE recurrence.^16,61
-63 As has been observed with the VKAs, VTE recurrence risk reduction was not maintained after discontinuing the DOACs, with the exception of dabigatran where benefit of extended treatment was maintained during the 12 months of extended follow-up after its discontinuation.¹⁶ In previous extended treatment studies, bleeding (defined as the combination of major bleeding and clinically relevant nonmajor bleeding) events were less frequent with edoxaban and dabigatran compared to warfarin (HR [95% CI], 0.8 [0.7-0.9], and 0.5 [0.4-0.7], respectively).^16,63 Bleeding rates of apixaban 2.5 mg twice a day and placebo were similar, whereas the risk of clinically relevant bleeding with rivaroxaban as compared with placebo was considered acceptable (HR [95% CI], 5.2 [2.3-11.7]).^61,62 Notably, all bleeding rates were lower than the VKAs when used for extended VTE treatment. In a meta-analysis of 24,455 patients with acute VTE, the DOACs reduced major and fatal bleeding by 40% and 64%, respectively.⁶⁴ There was no significant difference between individual DOACs, and the number needed to treat in place of a VKA was 149 to prevent 1 major bleeding event.⁶⁴

Dabigatran

The US Food and Drug Administration (FDA) approved dabigatran for acute and extended treatment of VTE. Dabigatran, a DTI, does not require laboratory monitoring. The recommended dose is 150 mg twice a day administered orally. Acute treatment requires a minimal 5-day treatment with a parenteral anticoagulant prior to initiating dabigatran based on the original trial.⁶⁵

Extended anticoagulation with dabigatran effectively prevents VTE recurrence. The RE-MEDY and RE-SONATE trials demonstrated that dabigatran was superior to placebo and noninferior to warfarin for long-term VTE prophylaxis (6-36 months) with a bleeding risk that was lower than warfarin but higher when compared to placebo (Supplementary Table 1).¹⁶ Patients with a creatinine clearance (CrCl) <30 mL/min, those who were receiving hemodialysis, women of childbearing potential without proper contraceptive measures, pregnant women or those who were breast feeding, and those with liver dysfunction at baseline were excluded from these trials. It has also been recommended that dabigatran should be used with caution in the elderly patients and patients with cancer and coronary artery disease. Notably, there was a higher incidence of acute coronary events in the dabigatran arm when compared to the warfarin arm for extended therapy (0.9% vs 0.2%); however, such a difference was not observed in the placebo-controlled study. Dabigatran was also associated with a higher risk for acute coronary events than the control agent in a meta-analysis of 30 514 patients from 7 noninferiority trials as well.⁶⁶ Although the additive antithrombotic effect of warfarin by inhibition of both intrinsic and extrinsic pathways of coagulation cascade and possibly low cardiovascular risk among patients in the warfarin arm could be potential explanations, further studies assessing whether dabigatran increases the risk for acute coronary events are required. Of note, 2 recent trials suggested that myocardial infarction was not an adverse event associated with dabigatran.^67,68

Apixaban

Apixaban is an oral direct factor Xa inhibitor with fixed dose administration approved by the FDA for acute and extended VTE treatment. It does not require laboratory monitoring. The recommended dose for extended VTE prophylaxis is 2.5 mg given orally twice a day.

The AMPLIFY-EXT investigators proved the efficacy and safety of apixaban at 2 doses (5 and 2.5 mg each twice a day) for extended treatment (12 months) in 2486 patients who had acute VTE and had clinical equipoise regarding the cessation of anticoagulation therapy at the end of 6 to 12 months of the treatment (Supplementary Table 1).⁶¹ Both doses of apixaban were clinically equivalent in their efficacy and safety outcomes. However, clinically relevant nonmajor bleeding events occurred more frequently in the 5.0-mg arm compared to the 2.5-mg and placebo arms (4.2% vs 3.0% and 2.3%), respectively. Overall, these results favor the 2.5-mg dose as the preferred dose for extended VTE prophylaxis. Although the VTE recurrence rate of 8.8% in the placebo group indicates that study participants had reasonable VTE recurrence risk, this study did not include patients at high recurrence risk in whom there was no clinical equipoise regarding extending anticoagulation, such as those with the antiphospholipid antibody syndrome. Based on this study results, 14 patients need to be treated for preventing 1 episode of recurrent VTE in contrast to 200 patients who need to be treated for causing 1 clinically relevant bleeding event. Apixaban should be used with caution in patients older than 75 years of age, body weight less than 60 kg, or moderate to severe renal impairment.⁶¹ The safety and efficacy of apixaban for long-term anticoagulation of unprovoked VTE after 18 to 24 months is still not established.

Rivaroxaban

Rivaroxaban has been approved by the FDA for acute and extended VTE treatment. It is a direct factor Xa inhibitor that is orally administered, has minimal drug or food interactions, and does not require laboratory monitoring. For the acute treatment of VTE, rivaroxaban is given twice daily at 15 mg for 3 weeks followed by a simple, fixed dose of 20 mg once a day for the duration of treatment. The dose is also 20 mg per day for extended VTE treatment.

Rivaroxaban should be avoided if the CrCl is <30 mL/min and is contraindicated in patients with moderate to severe hepatic insufficiency or any liver disease coagulopathy. It should also be avoided in patients less than 18 years of age or during pregnancy and breast-feeding. Obesity does not appear to affect the concentration of the drug, whereas levels increase in patients whose body weight is less than 50 kg.

Rivaroxaban was proven effective in continued treatment of 1196 patients with VTE with an acceptable bleeding risk, as compared with placebo in the EINSTEIN-extension study. Patients with VTE who had completed 6 to 12 months of therapy were randomized to placebo or rivaroxaban. Rivaroxaban reduced the VTE recurrence risk by 82% (Supplementary Table 1).⁶² The major bleeding event rate was 0.7%, without any fatal bleeding events. At the cost of 4 major bleeding and 25 clinically relevant nonmajor bleeding events (predominantly mucosal bleeding), rivaroxaban prevented 34 recurrent VTE events. Of note, patients with older age, cancer, renal impairment, and morbid obesity were scarcely represented in this trial. The lower rates of bleeding in the rivaroxaban study compared to VKA in the observational studies, though promising, could be potentially attributed to the selection bias involved in this study. More data are required on the safety of rivaroxaban in these special populations.

Edoxaban

Edoxaban, an oral factor Xa inhibitor, is approved by the FDA for the acute treatment of VTE following 5 to 10 days of initial parenteral anticoagulant therapy. It does not have approval for extended treatment. The recommended dose is 60 mg once daily. In patients with a CrCl of 15 to 50 mL/min or a body weight of 60 kg or less, or those on potent P glycoprotein inhibitors, the dose is reduced to 30 mg once daily.

The Hokusai-VTE study evaluated the efficacy and safety of edoxaban in 8240 patients with VTE, including those with severe PE (up to one-third of the study population).⁶³ In contrast to the EINSTEIN and AMPLIFY studies utilizing a single-drug strategy, this study is notable for the use of the traditional sequence of a minimum of 5-day heparin lead-in followed by oral anticoagulation. Approximately 65% and 9% of the patients included in this trial had unprovoked VTE and cancer, respectively. Patients with a CrCl of less than 30 mL/min were excluded from this trial. Edoxaban, as compared with warfarin, was noninferior with respect to preventing symptomatic recurrent VTE (HR [95% CI], 0.89 [0.7-1.13]) and superior with respect to bleeding (HR [95% CI], 0.81 [0.71-0.94]) for a treatment period of at least 3 months and a maximum of 12 months. The reduced edoxaban dose of 30 mg once daily also maintained the efficacy and significantly lowered the bleeding risk compared to warfarin in patients with renal impairment or low body weight, which constituted approximately one-fifth of the study population.

Direct Oral Anticoagulant Concerns

The DOACs have varying degrees of dependence on renal clearance for elimination, with the percentage renal clearance ranging from 80%, 50%, 33%, and 27%, respectively, for dabigatran, edoxaban, rivaroxaban, and apixaban. As a result, periodic monitoring of renal function is advised in patients on DOACs. Dabigatran and rivaroxaban should be avoided in patients with VTE with a CrCl less than 30 mL/min, whereas edoxaban should be dose adjusted for patients of low body weight or renal insufficiency and avoided in patients with CrCl less than 15 mL/min. No dose adjustments are recommended for apixaban 2.5 mg twice daily in patients with renal impairment. Dabigatran, rivaroxaban, and edoxaban are contraindicated in dialysis-dependent patients; however, the package insert states that apixaban can be used in patients on hemodialysis.⁶⁹

There are several drug interactions with the DOACs worth mentioning. Direct oral anticoagulants depend on P-glycoprotein transporter for their oral bioavailability and renal clearance. Hepatic clearance of rivaroxaban and apixaban is dependent on CYP3A4 type cytochrome P450. Strong inducers or inhibitors of the CYP 3A4 and P-glycoprotein systems can affect DOAC plasma concentrations and effect. The lack of a readily available assay to determine the DOACs’ anticoagulant effect makes their concomitant use with the drugs that interact with these systems and their quantitative assessment in the face of emergency situations challenging, and they should be avoided (Table 4).⁶⁰ The prothrombin time (using neoplastin as a reagent) may provide modest qualitative assessment of rivaroxaban. Anti-factor Xa chromogenic assays have been used for measuring the factor Xa inhibitors. Although these assays are commercially available for assessing plasma factor Xa inhibitor levels, their clinical significance is not yet established. An activated partial thromboplastin time (aPTT), thrombin time (TT), diluted thrombin time (dTT), and ecarin clotting time (ECT) provide assessment of dabigatran effect, the aPTT and TT qualitatively and ECT and dTT quantitatively. Although a normal dabigatran-specific dTT or TT indicates no clinically relevant dabigatran anticoagulant effect, both ECT and dTT are not commercially readily available in the United States.

Table 4.

Laboratory Assessment of Direct Oral Anticoagulant Effect.

DOAC	Prothrombin Time^a	Activated Partial Thromboplastin Time^a	Thrombin Time^a	Diluted Thrombin Time^b	Antifactor Xa Chromogenic Assay^a	Ecarin Clotting Time/Ecarin Chromogenic Assay^b
Dabigatran	Not useful	Qualitative assessment	Qualitative assessment	Quantitative assessment	Not useful	Quantitative assessment
Rivaroxaban	Qualitative assessment^c	Not useful	Not useful	Not useful	Quantitative assessment; unclear clinical significance	Not useful
Apixaban	Not useful	Not useful	Not useful	Not useful	Quantitative assessment, unclear clinical significance	Not useful
Edoxaban	Not useful	Not useful	Not useful	Not useful	Quantitative assessment, unclear clinical significance	Not useful

^aReadily available.

^bNot commercially available.

^cUsing neoplastin as reagent.

Additional investigations are necessary to establish the safety and efficacy of DOACs for extended treatment of cancer-associated VTE, particularly in direct comparison with LMWH. The EINSTEIN-extension, AMPLIFY-EXT, RE-COVER, and Hokusai-VTE studies included small number of patients with cancer, and subgroup analyses in EINSTEIN-extension and RE-COVER were of the post priori nature, limiting current evidence on DOACs for cancer-related VTE therapy and prophylaxis. A recent meta-analysis compared the DOACs with traditional anticoagulation for patients with cancer having VTE. Recurrence of VTE was reported as 3.9% and 6.0% and major bleeding 3.2% and 4.2%, respectively, favoring the DOACs over standard anticoagulation.⁷⁰

Another major limitation of both the AMPLIFY-EXT and EINSTEIN-extension studies is that the controlled arm consisted of placebo treatment instead of alternate anticoagulation therapy.

Management of bleeding in patients on DOACs is challenging. Recently, an antidote for dabigatran (idarucizumab) received FDA approval; however, there are no specific antidotes currently available for reversal of the factor Xa inhibitors. Protamine and vitamin K are not effective, and in those with bleeding or suspected DOAC overdose, anticoagulation must be immediately discontinued. In addition to supportive care, nonspecific coagulants, such as desmopressin and ε-aminocaproic acid, may be considered though there is no supportive evidence.⁶⁰ In cases of severe or life-threatening bleeding, PCC (which is a concentrate of factors II, VII, IX, and X), activated PCC (PCC with activated factor VIIa, also called FEIBA), recombinant factor VIIa, and platelet concentrates in those with thrombocytopenia or receiving concomitant long-acting antiplatelet drugs should be considered, though supporting evidence is limited.⁷¹ Activated oral charcoal may be considered if ingestion is recent (within 2 hours). Dabigatran is dialyzable, with approximately 65% of the agent being removed over 4 hours.^60,72 Hemodialysis is not effective for rivaroxaban, edoxaban, or apixaban removal.

There are several antidotes in trials and/or under FDA review with one just recently approved. Idarucizumab (a product of Boehringer Ingelheim), a monoclonal antibody fragment that binds free and thrombin-bound dabigatran, demonstrated complete reversal of its anticoagulant effect within minutes in the REVERSE-AD trial.⁵⁹ Intravenous administration of idarucizumab (dose of 5 g) is approved by the FDA for reversing the anticoagulant effect of dabigatran for an emergent or urgent surgery/procedure or in cases of uncontrolled or life-threatening bleeding. Dabigatran may be considered for treating patients who prefer DOACs but are at increased bleeding risk. Others include agents that inactivate the factor Xa inhibitors. Andexanet alfa (PRT064445; Portola Pharmaceuticals, San Francisco, California, USA) binds to factor Xa inhibitors and antithrombin, yet has no procoagulant activity and aripazine (PER-977; Perosphere Inc, Danbury Connecticut, USA), a d-arginine compound that reverses DOACs and heparin.⁷³

Aspirin

Increased levels of platelet and endothelial activation markers in patients with VTE suggested the potential for using antiplatelet agents for VTE prophylaxis.^74

-78 A few randomized studies have demonstrated the role of aspirin as a possible alternative to extended oral anticoagulant therapy for secondary prophylaxis of VTE.

The WARFASA trial showed that aspirin resulted in about a 40% risk reduction for secondary prevention of a first, unprovoked VTE after 6 to 18 months of anticoagulation, as compared with placebo, without a significant increase in major bleeding risk.⁷⁹ Patients with cancer, inherited thrombophilia, and bleeding episodes during anticoagulation were excluded from this study. These efficacy results are similar to the 20% to 50% risk reduction associated with aspirin use for primary prophylaxis of VTE.^80
-82 However, the results of the ASPIRE trial did not find a significant reduction in recurrent VTE risk with aspirin versus placebo in patients after initial anticoagulation for a first unprovoked VTE, despite a 34% reduction in major vascular events and a significant net clinical benefit without increasing bleeding.⁸³

The data therefore suggest that aspirin has limited utility in the management of VTE, and its use should be restricted to patients with a low VTE recurrence risk who may also be at risk for atherosclerosis, particularly coronary artery disease. There is no role for aspirin in the secondary prevention of VTE in patients at high risk of recurrence.

Obstacles of Extended Anticoagulation

An important adverse effect of anticoagulation is bleeding. The benefits of extended anticoagulation for prolonged VTE treatment must be carefully weighed against the bleeding risk in every patient. Identification of subgroups of patients at the highest risk for VTE recurrence and/or for bleeding is crucial in maximizing the net clinical benefit in this population.

Patients with pregnancy or drug allergy also complicate antithrombotic choice, while the benefits of anticoagulation may be trivial to none in patients with a limited life expectancy due to nonthrombotic causes.

Other barriers for extended anticoagulation include the potential for noncompliance and an inability to complete frequent laboratory monitoring (necessary with the VKAs) because of geographic inaccessibility. Although the DOACs have the ability to relieve anticoagulation clinics from the care of patients suitable for these agents, the economic impact of such a transition is yet to be established.

Patients on extended antithrombotic treatment need periodic reassessment of their medications and their adherence, as well as their risk–benefit profile of continuing anticoagulation and laboratory parameters including renal and liver function and a complete blood count. Baseline renal function, age, frailty, and presence of coagulopathy should be reviewed when considering monitoring schemes. Renal function should be monitored at least yearly if the CrCl is ≥ 60 mL/min, every 6 months if the CrCl is 30 to 60 mL/min, and every 3 months if the CrCl ≤ 30 mL/min and more often in the elderly, those with worsening renal function and the fragile patients with other comorbidities.⁸⁴

Bleeding Risk

Recent trauma or major surgery with a potential for bleeding or active bleeding, a familial bleeding diathesis, intracranial neoplasm, arteriovenous malformation, or aneurysm all pose a contraindication to anticoagulation. Additional factors that predispose patients for bleeding include older age, frail stature, elevated fall risk, hypertension, history of bleeding, prior stroke or transient ischemic attack, liver disease, renal impairment, baseline anemia, thrombocytopenia, and cancer and concurrent use of other antithrombotic agents. In addition, patients taking other antithrombotic drugs and P-glycoprotein and strong CYP3A4 inhibitors and inducers are also at increased risk.

There are no models currently available for predicting bleeding risk during extended anticoagulation. The Registro Informatizado de Enferemedad TromboEmbolica Registry investigators proposed a bleeding risk assessment score based on 6 admission characteristics to identify patients with VTE at low, intermediate, or high risk for major bleeding during the initial 3 months of anticoagulation.⁸⁵ The score assigns 2 points to recent bleeding, 1.5 points to serum creatinine levels >1.2 mg/dL or anemia, and 1 point to age >75 years, cancer, or PE at baseline. Based on these points, patients are stratified into low-risk group (0 points), intermediate-risk group (1-4 points), and high-risk group (>4 points), with the likelihood ratios for major bleeding being 0.14 in the low-risk group versus 2.96 in the high-risk group. This scoring model did not take into account the presence of concomitant drugs and comorbidities that could affect the bleeding risk and did not include patients without 3-month follow-up. This scoring system, though not developed for extended anticoagulation, may be utilized for guiding assessment of bleeding risk on extended anticoagulation until precise models for this purpose are developed.

Conclusion

Determining the best antithrombotic drug and the optimal length and intensity for extended VTE treatment is complex. This decision must be tailored after taking into account each individual’s VTE recurrence and bleeding risk, as well as the pharmacological profile of each antithrombotic agent, potential for drug and diet interactions, patient preferences, and cost considerations. Warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban are potent anticoagulants for extended VTE therapy reducing recurrent VTE risk by more than 80% to 90% compared to no treatment. Aspirin for secondary VTE prophylaxis results in a lower risk reduction of approximately 40% also compared to no treatment but may be acceptable for the patient with low VTE recurrence risk who is also at risk for atherosclerosis. The risk of clinically relevant bleeding with dabigatran, apixaban, edoxaban, and rivaroxaban is lower than warfarin when used for extended VTE prophylaxis. Future studies should evaluate protocols for VTE management with focus on patient risk stratification and selection of appropriate antithrombotic agents.

Footnotes

Acknowledgments

The authors acknowledge Boehringer Ingelheim Pharmaceuticals, Inc medical team for their accuracy review service.

Author Contributions

Dr Joseph and Dr Bartholomew have contributed to conception or design, contributed to acquisition, analysis and interpretation of studies, drafted the manuscript, and critically revised the manuscript. They gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Prof John R. Bartholomew receives fees of $5,000 or more per year as a paid consultant, speaker, or member of an advisory committee for Daiichi Sankyo, Inc. Prof Bartholomew has consulted for, received compensation for serving as a fiduciary from, or received royalties from Boehringer Ingelheim, but instructed them to donate all compensation to not-for-profit causes or to the Cleveland Clinic to support research and education.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Supplemental Material

The online supplemental tables are available at .

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Managing Extended Oral Anticoagulation After Unprovoked Venous Thromboembolism

Abstract

Keywords

Introduction

Selection of Patient, Drug, and Treatment Duration

Recurrence Risk

Choice of Extended Anticoagulation Regimens

Vitamin K Antagonist

Direct Oral Anticoagulants

Dabigatran

Apixaban

Rivaroxaban

Edoxaban

Direct Oral Anticoagulant Concerns

Aspirin

Obstacles of Extended Anticoagulation

Bleeding Risk

Conclusion

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

Supplemental Material

References