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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 4  |  Page : 172-178

Newer oral anticoagulants in venous thromboembolism


1 Senior Consultant Cardiology, Indraprastha Apollo Hospital, New Delhi, India
2 Associate Consultant Cardiology, Indraprastha Apollo Hospital, New Delhi, India

Date of Submission11-Oct-2020
Date of Decision12-Nov-2020
Date of Acceptance26-Nov-2020
Date of Web Publication25-Oct-2021

Correspondence Address:
Dr. Ranjan Modi
Indraprastha Apollo Hospitals, New Delhi - 110 076
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jicc.jicc_73_20

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  Abstract 


Venous thromboembolism (VTE) is an important medical condition for morbidity and mortality. Adequate anticoagulant treatment is necessary to reduce short- and long-term VTE related conditions. In the past low molecular weight heparin (LMWH) and Vitamin K antagonists (VKAs) have been the mainstay of anticoagulation therapy for VTE patients. The patients require frequent monitoring with INR to keep balance between effectiveness and safety in clinical practice. NOACs have been the main stay of treatment in conditions requiring effective anticoagulation. They may prove to do the same in VTE. This article analyses, the present literature on use of NOACs in VTE.

Keywords: INR, non-Vitamin K antagonist oral anticoagulants, pulmonary embolism, venous thromboembolism


How to cite this article:
Modi S, Modi R. Newer oral anticoagulants in venous thromboembolism. J Indian coll cardiol 2021;11:172-8

How to cite this URL:
Modi S, Modi R. Newer oral anticoagulants in venous thromboembolism. J Indian coll cardiol [serial online] 2021 [cited 2021 Dec 5];11:172-8. Available from: https://www.joicc.org/text.asp?2021/11/4/172/329151




  Introduction Top


Venous thromboembolism (VTE) remains an important medical condition for morbidity and mortality, leading to health-related economic burden. Effective anticoagulant treatment is necessary to reduce short- and long-term VTE-related conditions.[1] For many years, low-molecular-weight heparin (LMWH) and Vitamin K antagonists (VKAs) have been the mainstay of anticoagulation therapy for VTE patients, but the use of these agents had clinically relevant drawbacks and limitations,[2],[3] which include slow onset and offset of action, drug–food and drug–drug interactions, and genetic polymorphism, leading to variable response. Due to such limitations, they require frequent monitoring with INR to keep balance between effectiveness and safety in clinical practice.[3] One Indian study had shown poor outpatient VKA anticoagulant control with high proportion of subtherapeutic Prothrombotic time (PT) values and high complication rates.[4]

Need for newer oral anticoagulants

Need for frequent laboratory monitoring is a challenge for outpatient management with VKAs. Therefore, an oral anticoagulant with a wide therapeutic window without routine laboratory monitoring would be a good alternative to VKAs in the treatment, as well as secondary prevention of deep vein thrombosis (DVT).

The most significant change in VTE therapy is the introduction of non-VKA oral anticoagulants (NOACs) that specifically inhibit either thrombin or factor Xa. These novel agents exhibit a rapid onset and offset of action, fewer food and drug interactions, predictable anticoagulant effect, and absence to need for routine coagulation monitoring, when compared to traditional agents.[5],[6]

Non-Vitamin K antagonist oral anticoagulants

Two classes of oral direct anticoagulant agents are presently used in clinical practice. The NOACs are broadly classified into two major categories: direct thrombin inhibitors and direct factor Xa inhibitors. Dabigatran is a direct thrombin inhibitor, while the other three, i.e., rivaroxaban, apixaban, and edoxaban, are direct factor Xa inhibitors.[3] The NOACs offer advantages of predictable pharmacokinetic profile and lesser food and drug interactions compared to VKAs. Moreover, they do not require routine monitoring.

Dabigatran

Dabigatran etexilate, an oral prodrug, is rapidly converted by esterases to dabigatran, which competitively inhibits both free and fibrin-bound thrombin.[3]

Dabigatran can be given as a simple, fixed-dose regimen without need for routine laboratory monitoring. The RE-COVER studies compared dabigatran versus warfarin in patients with acute VTE who initially received parenteral anticoagulation therapy.[7],[8] Dabigatran was found to be noninferior to warfarin for the primary outcome of recurrent VTE and related deaths, and major bleeding rates were found to be Jess with dabigatran compared to warfarin in individual studies.[7],[8]

The pooled analysis of RE-COVER and RE-COVER-II studies also showed noninferiority of dabigatran for the primary efficacy outcome of recurrent symptomatic VTE and related deaths and significantly lower bleeding rates compared to warfarin in the treatment of acute VTE.[8]

At present, dabigatran has approval for the treatment and secondary prevention of DVT and PE in patients who have been treated with a parenteral anticoagulant (unfractionated heparin or LMWH/fondaparinux) for 5–10 days.

Rivaroxaban

Rivaroxaban is a selective and reversible direct oral factor Xa inhibitor.[3] In 2011, the US Food and Drug Administration (FDA) approved rivaroxaban to reduce the risk of DVTs and PEs from occurring after knee or hip replacement surgery. In 2012, the US FDA approved it for the treatment of acute DVT or PE, reducing the risk of recurrent DVT and PE following initial treatment.[9],[10] Rivaroxaban can be given as a simple, fixed dose regimen without the need for routine laboratory monitoring.[11] The efficacy of rivaroxaban was evaluated in the EINSTEIN studies (EINSTEIN-DVT and EINSTEIN-PE) for the treatment of acute DVT/PE, respectively.[11],[12]

These studies showed that compared with LMWH/VKA treatment, rivaroxaban was noninferior for recurrent VTE and had similar or fewer major hemorrhages.[11],[12]

Apixaban

Apixaban is also a selective and reversible direct oral factor Xa inhibitor.[3] The AMPLIFY study compared apixaban with subcutaneous enoxaparin, followed by warfarin in the treatment of acute VTE.[13] For primary efficacy outcome of recurrent symptomatic VTE or VTE-related death, apixaban was noninferior to the conventional therapy; however, for major bleeding and the composite outcome of major bleeding and clinically relevant nonmajor bleeding, apixaban was superior compared to conventional therapy.[13]

Edoxaban

Edoxaban is an oral, selective factor Xa inhibitor.[3] Edoxaban is administered once daily and has a rapid onset of action.[14] Edoxaban is approved by the US FDA for the treatment of DVT and PE following 5–10 days of initial parenteral anticoagulation therapy.[15] In the Hokusai-VTE study, edoxaban therapy for 3–12 months was compared with warfarin in patients with acute VTE, who had initially received heparin therapy for 5–10 days.[14] In this study, it was found to be noninferior to warfarin for primary efficacy outcome of recurrent symptomatic VTE.[14] The principal safety outcome of major or clinically relevant nonmajor bleeding was significantly less with edoxaban compared to warfarin.[14]

Rivaroxaban and edoxaban offer the possibility of once-daily administration.[4],[16],[17] Care should be taken when using all NOACs in patients with impaired renal function.[3] Reduced doses of NOACs were not tested in patients with VTE, with the exception of edoxaban, which was given at a reduced dose of 30 mg in the Hokusai trial.[18] No data are currently available on the use of NOACs in pregnancy, breastfeeding women, and children.


  Non-Vitamin K Antagonist Oral Anticoagulants for the Initial and Long-term Treatment of Venous Thromboembolism Top


Overall, in the initial and long-term treatment of patients with VTE, six randomized trials have been performed [Table 1]: 2 studies with dabigatran, 2 studies with rivaroxaban, and 1 study each with apixaban and edoxaban.[18] All the trials were designed to demonstrate noninferior efficacy of NOACs compared with conventional anticoagulant treatment.
Table 1: Trials of non-Vitamin K antagonist in venous thromboembolism

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In all the studies, noninferiority was considered to be a significant achievement, as the main advantage of these agents over conventional treatment is oral administration in fixed doses without laboratory monitoring. Different criteria for definitions of noninferiority were used across the studies. These criteria contributed to different sample size estimations.

All the studies used recurrence and VTE-related death as the primary efficacy outcome. In the apixaban trial, the primary safety outcome was major bleeding, whereas, in the remaining trials, it was a composite of major and clinically relevant nonmajor [Figure 1] and [Figure 2].
Figure 1: Efficacy outcomes of bledding in non-Vitamin K antagonist oral anticoagulants in venous thromboembolism

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Figure 2: Efficacy outcomes of symptomatic recurrent VTE in non-Vitamin K antagonist oral anticoagulants in venous thromboembolism

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“Single-drug approach” was used for the evaluation of rivaroxaban and apixaban, which means that the initial heparin treatment is used for no longer than 48 h.[17],[19],[20] Thus, increased doses of rivaroxaban (50% of the maintenance dose for 3 weeks) and apixaban (100% of the maintenance dose for 1 week) were used. This increase in the doses was observed in previous trials evaluating NOACs without initial heparin treatment.[21],[22],[23] However, initial heparin pretreatment (5–9 days) was used with dabigatran and edoxaban.[4],[16],[18]

Concerning the primary efficacy outcomes, dabigatran,[6] rivaroxaban,[24] apixaban,[17] and edoxaban[18] were all noninferior to conventional treatment. Apixaban, edoxaban, and dabigatran all showed significant reduction in major bleeding compared to conventional treatment;[16],[17],[18] similar rates of clinically relevant bleeding compared with conventional treatment were observed with rivaroxaban.[24] A statistically nonsignificant decrease in the incidence of intracranial hemorrhage was reported with all NOACs; however, due to the small size of the studies, it was not considered a definite safety effect. In the Hokusai study of edoxaban versus warfarin, fatal bleeding was significantly reduced (2 vs. 10 events).[18]

For evaluating the incidence of gastrointestinal or mucosal bleeding with NOACs in patients with VTE, data were unsatisfactory. Twice-daily apixaban could be preferred for its safety profile, as shown by the 69% reduction in major bleeding.[17]

There are no direct head-to-head comparisons available for NOACs in VTE treatment. Dabigatran or edoxaban could be the preferred choice of anticoagulation in patients requiring heparin treatment in the acute phase. The regimen consisting of NOACs and heparin different from those evaluated in the clinical trials could expose the patients to undertreat and overtreat.

It can be appreciated from the trials that if pre-NOAC administration of LMWH lasted <7 days, the initial increased doses of apixaban and rivaroxaban should be given for 7 or 21 days, respectively. If LMWH treatment lasted >7 days, it may be reasonable to start apixaban with the maintenance dose (5 mg twice daily) or to continue LMWH up to 3 weeks and then start with the maintenance dose of rivaroxaban (20 mg once daily).

Recommendation for the use of NOACs in VTE treatment is summarized in [Table 2].
Table 2: Present Recommendation for non-Vitamin K antagonist oral anticoagulants in the treatment of venous thromboembolism

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Edoxaban is the only NOAC, for which dose reduction has been tested in patients with creatinine clearance between 30 and 50 ml/min, weighing <60 kg, or receiving concomitant treatment with P glycoprotein inhibitors.

The reduced doses of rivaroxaban or apixaban in patients with VTE and moderate renal failure have not been evaluated in clinical trials with respect to efficacy and safety. When NOACs are used in such patients, renal function should be checked at least twice a year.[3]

Various meta-analyses with NOACs for the treatment of VTE have concluded the safety of NOACs being better than conventional therapy, major bleeding (1.8% vs. 3.1% per patient-year), fatal bleeding (0.1% vs. 0.3% per patient-year), and case-related fatality rates (6% vs. 10%). This meta-analysis, which included 10 trials and 35,029 patients, also found that the rates of recurrent VTE (4.1% vs. 4.4% patient-years) and the related case-fatality rates (CFRs) (16% vs. 13%) were similar in NOACs or conventional therapy.[25] In a subsequent meta-analysis, NOACs were found to have reduction in all-cause mortality.[26]

A network meta-analysis, of indirect comparison of NOACs for the treatment of VTE, revealed a relative risk for major bleeding event of 0.42 for apixaban versus dabigatran; 0.57 for apixaban versus rivaroxaban; 0.37 for apixaban versus edoxaban; 0.74 for rivaroxaban versus dabigatran; 0.64 for rivaroxaban versus edoxaban; and 1.15 for edoxaban versus dabigatran.[8]

In all of the studies, following subgroup analyses were performed on the efficacy and safety of NOACs.

Elderly patients

An analysis of the dabigatran trials showed that the efficacy of dabigatran versus warfarin was slightly higher in elderly patients, with an equal efficacy at approximately 60 years of age,[16] though the difference in efficacy was not statistically significant at any age. Concerning clinically relevant bleeding, the risk reduction in dabigatran was influenced by age and was greater in younger patients.

No age effect in efficacy and safety was observed in subgroup analyses in the rivaroxaban, apixaban, and edoxaban studies.[17],[18],[24] This may be noted as only <5% of the patients included in Phase III studies of these trials were aged >80 years. In patients aged >75 years, meta-analysis revealed a significantly lower rate of recurrent VTE.[9] In these patients, a significant reduction in major bleeding was associated with NOACs.

Renal insufficiency

Subgroup analysis of the rivaroxaban studies showed increasing rates of recurrent VTE in patients with deteriorating renal function,[10] similar to that observed in the conventional treatment. However, rivaroxaban favored conventional treatment in regard to major bleeding. No such effect was observed in respect to efficacy and safety across renal function impairment categories in subgroup analyses in the dabigatran, apixaban, and edoxaban studies.[16],[17],[18]

Extreme body weight

The analysis performed to determine the association between body weight and clinical outcomes in patients treated with rivaroxaban compared with conventional therapy[11] found no association between body weight (<50 kg, >50 to <100 kg, and >100 kg) and risk of recurrent VTE. There was no change in major bleeding observed in reference to body weight in rivaroxaban, whereas with conventional treatment, major bleeding was common in patients with low bodyweight. No effects on efficacy and safety were observed in subgroup analyses for bodyweight categories in the dabigatran, apixaban, and edoxaban studies. However, due to the representation of patients with body weight <50 kg being marginal in these trials, these findings may be inconclusive.

For acute symptomatic VTE, the efficacy of NOACs in patients with a bodyweight >100 kg was consistent with that of the general population.[9]

Thus, the efficacy and safety of apixaban and dabigatran in the treatment of VTE were confirmed across various different classes of body mass index, but caution was recommended with the use in patients with body weight <50 and >150 kg.

Fragile patients

Among patients included in studies with rivaroxaban, majority were categorized as fragile in view of age >75 years, moderate or severe renal impairment (a creatinine clearance level <50 ml/min), or bodyweight <50 kg.[24] In these subgroup of patients, major bleeding was significantly lower with rivaroxaban, unlike in nonfragile patients. A favorable efficacy profile was shown with edoxaban compared with warfarin in the subgroup analysis in fragile patients, without any safety concern. Recurrent VTE was more common in fragile than in nonfragile patients, with no difference between treatment groups.

Nonsteroidal anti-inflammatory agents

An analysis performed in the rivaroxaban trials on the efficacy and safety of concomitant treatment with nonsteroidal anti-inflammatory drugs (NSAIDs)[12] showed that the incidence of clinically relevant bleeding (37.5% vs. 16.6% per patient-year) and major bleeding (6.5% vs. 2.0% per patient-year) was higher in patients concomitantly treated with NSAIDs and anticoagulant agents.

Clinically relevant bleeding was more common in aspirin users than in nonusers. Major bleeding occurred in 4.8% per patient-year in aspirin users compared with 2.2% per patient-year in nonusers. Increases in risk for clinically relevant and major bleeding were similar for rivaroxaban and conventional treatment.

A similar analysis on the efficacy and safety of concomitant treatment with NSAIDs and dabigatran had 10% of patients receiving aspirin and 20% of patients receiving NSAIDs.[13] It revealed no apparent difference in recurrent VTE in the groups of aspirin and NSAIDs versus without. The incidence of bleeding was similar or nonstatistically lower for dabigatran versus warfarin in the analysis.

Hence, treatment with concomitant NSAIDs/low-dose aspirin with NOAC resulted in no statistically significant interactions in view of efficacy or safety.


  Non-Vitamin K antagonist Oral Anticoagulants for Extended Treatment of Venous Thromboembolism Top


Dabigatran, rivaroxaban, and apixaban have been compared with placebo in patients to assess the clinical benefit of continued anticoagulation,[19],[27],[28] which have all been superiority trials. However, the trail of dabigatran compared with warfarin for extended treatment of VTE[27] has been an noninferiority trial. The primary outcome of all the studies was recurrent VTE and VTE-related death, except the survey with apixaban, which added overall mortality to VTE-related deaths as the primary outcome.

The primary safety outcome in all of the studies was major bleeding. Treatment duration varied from 12 months in the dabigatran and apixaban studies versus placebo to 6 or 12 months in the rivaroxaban study. In the study of dabigatran versus warfarin, treatment was extended till 36 months.

Dabigatran,[29] rivaroxaban,[19] and apixaban[28] have been assessed to be more effective than placebo for the extended treatment of VTE with a rate of major bleeding being low. Dabigatran, rivaroxaban, and the higher dose of apixaban were associated with an increased rate of clinically relevant bleeding, but lower dose of apixaban did not show the same. It was as effective and safe as compared to the higher dose for the extended treatment of VTE.[28] Dabigatran was found to be noninferior to warfarin for the extended treatment of VTE, with an improved safety profile.[27] In a meta-analysis of placebo-controlled studies on extended treatment, both all-cause mortality and recurrent VTE were lower with NOACs than with placebo (0.6% vs. 1.1% per year and 1.9% vs. 10.9% per year, respectively).[26] No significant difference between treatments was observed in CFRs of VTE recurrence. No fatal bleeding events were reported with NOACs during extended treatment though a nonsignificant increase in major bleeding was reported in patients receiving NOACs.

Non-Vitamin K antagonist oral anticoagulants in extended therapy for venous thromboembolism prevention

Long-term anticoagulant treatment is effective in the treatment of acute VTE. However, the risk of recurrence remains once the therapy is discontinued. The risk of recurrence can be 5%–10% during the 1st year.[11] Extended therapy with anticoagulants is an option to reduce the risk of recurrence. The extension studies have proved the efficacy and safety of NOACs in patients with VTE. All NOACs have been evaluated for extended therapy versus placebo.[30],[31],[32] They were found to be superior to placebo in reducing the risk of primary efficacy end point of symptomatic recurrent VTE or death from VTE. The incidence of major bleeding was low with all NOACs. However, as expected, all the NOACs significantly increased the risk of clinically relevant nonmajor bleeds and total bleeds in comparison to placebo. In addition, dabigatran (150 mg BD) was compared with dose-adjusted warfarin (INR 2–3) for extended therapy for VTE prevention in 2866 patients with the longest period of treatment up to 36 months. In this study, less major bleeding, significantly less major or clinically relevant bleeding, and significantly less any bleeding events were seen with dabigatran with noninferior rates of VTE and VTE-related deaths compared to dose-adjusted warfarin.[30] One systematic review and network meta-analysis of efficacy and safety of oral anticoagulants and antiplatelet for secondary prevention of VTE showed that oral anticoagulants are more efficacious and safe compared to aspirin or observation alone.[33]

The recently published MARINER Trial which evaluated rivaroxaban for thromboprophylaxis after hospitalization for medial illness reported that rivaroxaban 45 days after discharge was not associated with a significantly low risk of symptomatic VTE or death compared to placebo, with the incidence of bleeding in the NOAC group being low.

Duration of therapy in deep vein thrombosis

The duration of extended anticoagulant therapy in DVT depends on the risk or recurrent VTE (fatal/nonfatal) and bleeding complications. The RIETE Registry Data of 41,826 patients with a mean duration of anticoagulation therapy for 7.8 months showed 16.1% CFR of recurrent VTE during the first 3 months compared to 2.0% beyond this period, while the CFR of major bleeding was 20.2% during the first 3 months, compared to 18.2% beyond this period. These findings suggest a reduction in CFR of recurrent VTE over time with no major change in bleeding risk with continued use of anticoagulant.[29] In one meta-analysis of seven randomized trials, 2925 patients with the first episode of VTE who received different durations of anticoagulation were followed up for 24 months after stopping the anticoagulation therapy.[30] This study showed a higher recurrence of VTE if anticoagulation was stopped at 1.0 or 1. 5 months compared with at 3 months or later, and similar recurrence of VTE if anticoagulation was stopped at 3 months compared with at 6 months or later.[31]

Current American College of Chest Physicians 10th guidelines recommend long-term (at least 3 months) anticoagulant therapy for patients with DVT (proximal or distal) or PE over no such therapy.[32] Decision to further extend anticoagulant therapy should be at physician's discretion based on the benefit versus the risk of its continuation considering the patients profile.


  Management of Isolated Distal Deep Vein Thrombosis Top


DVT is defined as distal when it is limited to below the popliteal vein.

In a recent trial of patients with distal DVT, they were randomized to receive the LMWH nadroparin or placebo for 42 days[33] which reported no significant advantage of anticoagulant treatment. It also found that distal DVT extends to the proximal veins or causes pulmonary embolism in a nonnegligible proportion of patients. It can be assumed that patients with calf DVT may not benefit from NOACs and thus should be denied the advantage of NOACs. The lack of evidence in this indication is undeniable.


  Conclusions Top


The lack of evidence of superiority can lead to some clinicians to refrain from using them in clinical practice. However, the advantages in terms of bleeding complications and practicality of NOACs confer their importance in treatment.

For the management of VTE, NOACs have been shown to be at least as effective as warfarin with less bleeding complication and more convenient to deliver. The results obtained with these agents allow effective and simplified treatment in a large proportion of patients with VTE.

The improved benefit-to-risk profile of NOACs relative to conventional therapy has the potential to change practice in extended treatment of unprovoked VTE or in those with persistent risk factors. Indeed, the benefit of extending treatment with low doses may increase the proportion of patients on NOACs. However, when one needs to decide regarding the extended treatment, the poor predictive value of bleeding risk scores in such patiemts, need to be taken into account.

The real-world safety profile of NOACs still remains to be defined; however, if their efficacy to safety profile is confirmed, as in various trials, then they can lead to significant reduction in medical costs for the patients.

The Prevention of Thromboembolic Events Registry showed that in clinical practice, NOACs were more frequently used for the treatment of VTE in younger patients (age <65 years). Their use was less frequent in those with lower weight, renal insufficiency, and diabetes and those at risk of bleeding (according to HAS-BLED score).

Although trials with >30,000 patients have shown positive results of NOACs in VTE, this subset of population may not be the real-world representative. There were discrepancies in the two mentioned subsets with respect to variables such as mean age and mortality rates. Thus, in compromised patients and complex clinical settings, caution should be observed with requirement of a significantly high level of clinical judgment to identify the patients to be treated and exclude the ones likely to have complications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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