EINSTEIN CHOICE
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Clinical Question
In patients with VTE who have completed 6-12 months of anticoagulation, does long-term rivaroxaban treatment reduce the rate of recurrent VTE compared to aspirin?
Bottom Line
In patients with VTE who have completed 6-12 months of anticoagulation, rivaroxaban 10 mg/d reduces the risk of recurrent VTE without significantly increasing the risk of bleeding compared to aspirin.
Major Points
The majority of patients with provoked VTE can be treated with a limited course of anticoagulation therapy (e.g., 3-6 months) followed by therapy discontinuation. In patients without reversible risk factors for VTE, the risk of recurrent VTE remains elevated after 6-12 months of therapeutic anticoagulation, and extended-duration anticoagulation is often warranted. The bleeding risk associated with extended-duration anticoagulation have led investigators to evaluate intermediate- or low-dose antithrombotic agents in this setting. This includes the ASPIRE and WARFASA trials of aspirin and the AMPLIFY-EXT trial of apixaban.
Published in 2017, EINSTEIN-CHOICE enrolled patients who had completed 6-12 months of therapeutic anticoagulation for acute VTE, either provoked (~60%) or unprovoked (~40%). Patients were excluded if they had a contraindication to continued anticoagulation including liver failure, renal failure, or required concurrent antiplatelet therapy. Patients were randomized 1:1:1 to rivaroxaban 20 mg/d, rivaroxaban 10 mg/d, or aspirin 100 mg/d, and each group was provided with a matching placebo. Therapy was initiated at least 24 hours following the last dose of therapeutic anticoagulation and was intended to continue for 12 months. Patients were followed for the primary efficacy outcome, which was the composite of symptomatic, recurrent fatal or nonfatal VTE or unexplained death for which PE could not be ruled out, and major bleeding was the primary safety outcome.
After approximately 1 year of study-drug treatment, recurrent VTE occurred at a rate of 1.5% in patients receiving rivaroxaban 20 mg/d, at 1.2% in patients receiving rivaroxaban 10 mg/d, and at 4.4% in patients receiving aspirin. Major bleeding occurred at a rate of 0.5% in patients receiving rivaroxaban 20 mg/d, in 0.4% receiving 10 mg/d, and in 0.3% of patients receiving aspirin. Clinically relevant nonmajor bleeding was identified in 2.7% of patients receiving rivaroxaban 20 mg/d, in 2.0% of patients receiving 10 mg/d, and in 1.8% of patients receiving aspirin.
The main conclusion of this study is that up to 1 year of rivaroxaban at a dose of either 20 mg/d or 10 mg/d is efficacious in preventing recurrent VTE in patients who have completed 6-12 months of primary anticoagulant therapy, and this approach is not associated with increased bleeding compared to aspirin 100 mg/d. It is not known whether the efficacy of this strategy extends to patients who receive less than 6 months of primary anticoagulant therapy, or whether more than 1 year of extended prophylaxis with rivaroxaban would continue to yield a similar risk/benefit ratio. Specific groups were underrepresented in this study, including those with active malignancy (~2.5% of enrolled patients) and those with known thrombophilia (~6-7%), and thus it is unknown whether this study's results can be extrapolated in these populations.
Guidelines
ACCP Antithrombotic Therapy for VTE Disease (2016, adapted): [1]
- In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over vitamin K antagonist (VKA) therapy (all Grade 2B)
- In patients with DVT of the leg or PE and cancer (“cancer-associated thrombosis”), as long-term (first 3 months) anticoagulant therapy, LMWH is recommended over other agents (Grade 2C)
- In patients with DVT of the leg or PE who receive extended therapy, recommend no need to change the choice of anticoagulant after the first 3 months (Grade 2C)
- In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), recommend switching to treatment with LMWH at least temporarily (Grade 2C).
- In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer, time-limited period (eg, 6, 12, or 24 months) (Grade 1B).
- In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B).
- In patients with a second unprovoked VTE and who have a (i) low bleeding risk (see text), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (Grade 1B); (ii) moderate bleeding risk (see text), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B); or (iii) high bleeding risk (see text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 2B).
- In patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), and (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B).
- In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B).
ESC Guidelines on the diagnosis and management of acute pulmonary embolism (2014, adapted):[2]
- For patients with PE secondary to a transient (reversible) risk factor, oral anticoagulation is recommended for 3 months (class I, level B).
- For patients with unprovoked PE, oral anticoagulation is recommended for at least 3 months (class I, level A).
- Extended oral anticoagulation should be considered for patients with a first episode of unprovoked PE and low bleeding risk (class IIa, level B).
- Anticoagulation treatment of indefinite duration is recommended for patients with a second episode of unprovoked PE (class I, level B).
- Alternatives to a VKA for patients who need extended anticoagulation (class IIa, level B):
- Rivaroxaban 20 mg daily
- Dabigatran 150 mg BID (or 110 mg BID for patients ≥80 years of age or taking concomitant verapimil)
- Apixaban 2.5 mg BID
- In patients who receive extended anticoagulation, the risk-benefit ratio of continuing such treatment should be reassessed at regular intervals (class I, level C).
- In patients who refuse to take or are unable to tolerate any form of oral anticoagulants, aspirin may be considered for extended secondary VTE prophylaxis (class IIb, level B).
- For patients with PE and cancer, LMWH should be considered for the first 3-6 months (class IIa, level B).
- For patients with PE and cancer, extended anticoagulation should be considered for an indefinite period or until the cancer is cured (class IIa, level C).
Design
- Randomized, double-blinded, phase 3 study
- N=3,365 patients with acute VTE
- Rivaroxaban 20 mg/d (N=1,107)
- Rivaroxaban 10 mg/d (N=1,127)
- Aspirin 100 mg/d (N=1,131)
- Setting: 244 sites in 31 countries
- Enrollment: 2014-2016
- Mean follow-up: ~1 year
- Analysis: Intention-to-treat
- Primary endpoints:
- Recurrent VTE
- Major bleeding
Population
Inclusion Criteria
- Adult patients with proximal DVT or PE
- Completed 6-12 months of primary anticoagulant therapy with either vitamin K antagonist or novel anticoagulant (without interruption of anticoagulant therapy for more than 7 days)
Exclusion Criteria
- Indication for therapeutic anticoagulation
- Indication for antiplatelet therapy or NSAIDs
- Liver dysfunction (due to coagulopathy)
- Renal dysfunction (i.e., GFR ≤30)
- Contraindication to anticoagulation (e.g., active bleeding)
- Life expectancy <6 months
- Concomitant use of strong inhibitors of CYP3A4 and P-gp
Baseline Characteristics
From the rivaroxaban 20 mg/d group.
- Mean age: 58 years
- Female: 46%
- Weight:
- <70 kg: 24.9%
- 70 to ≤90 kg: 42.5%
- >90 kg: 32.5%
- BMI:
- <30: 64%
- ≥30: 35%
- CrCl:
- 30 to <50: 4%
- 50 to <80: 25%
- ≥80: 71%
- Index event:
- Isolated DVT: 51%
- Isolated PE: 34%
- Both DVT and PE: 14%
- Classification:
- Provoked: 60%
- Unprovoked 40%
- Hormonal therapy:
- Estrogen: 0.7%
- Progestin: 2.6%
- Known thrombophilia: 7.1%
- Prior VTE: 18%
- Active cancer: 2.3%
- Median duration of study drug administration: 349 days
Interventions
Enrollment:
- Enrolled >24 h after last dose of therapeutic anticoagulant
Stratified randomization into groups with 1:1:1 ratio:
- Rivaroxaban 20 mg/d
- Rivaroxaban 10 mg/d
- Aspirin 100 mg/d
Outcomes
Comparisons are rivaroxaban 20 mg/d vs. rivaroxaban 10 mg/d vs. aspirin 100 mg/d.
Primary Efficacy Outcomes
- Recurrent Venous Thromboembolism
- 1.5% vs. 1.2% vs. 4.4%
Primary Safety Outcomes
- Major Bleeding
- 0.5% vs. 0.4% vs. 0.3%
Secondary Outcomes
- Primary efficacy outcome or death from any cause
- 2.1% vs. 1.3% vs. 4.9%
- Major or clinically relevant non-major bleeding
- 3.3% vs. 2.4% vs. 2.0%
- Clinically relevant non-major bleeding
- 2.7% vs. 2.0% vs. 1.8%
- Non-major bleeding requiring drug interruption for >14 days
- 1.5% vs. 1.1% vs. 1.1%
Adverse Events
- Any adverse event
- 17.5% vs. 17.4% vs. 17.1%
Criticisms
- The study did not consider the financial toxicity associated with extended anticoagulant therapy; the cost of rivaroxaban might discourage prolonged courses of anti-coagulation with a novel anti-coagulant.
- Patients who required an extended duration of therapeutic anticoagulation were excluded from study enrollment, and therefore these interventions are not necessarily well established in this group.
- Mean age is lower than normal VTE age so hard to generalize to the older population.
- Funded by Bayer Pharmaceuticals
- Study lasted for 1 year, but did not look into whether continued treatment is necessary.
- Non-inferiority trial was not performed to show 10 mg/d is noninferior to the current treatment dose of 20 mg/d.
Funding
- Funding provided by Bayer Pharmaceuticals
- Conflict of Interest disclosed