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Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism

New England Journal of Medicine, Ahead of Print. <br/>
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Original Article

Jeffrey I. Weitz, M.D., Anthonie W.A. Lensing, M.D., Ph.D., Martin H. Prins, M.D., Ph.D., Rupert Bauersachs, M.D., Jan Beyer-Westendorf, M.D., Henri Bounameaux, M.D., Timothy A. Brighton, M.D., Alexander T. Cohen, M.D., Bruce L. Davidson, M.D., M.P.H., Hervé Decousus, M.D., Maria C.S. Freitas, M.D., Ph.D., Gerlind Holberg, V.D., Ph.D., Ajay K. Kakkar, M.B., B.S., Ph.D., Lloyd Haskell, M.D., Bonno van Bellen, M.D., Akos F. Pap, M.Sc., Scott D. Berkowitz, M.D., Peter Verhamme, M.D., Philip S. Wells, M.D., and Paolo Prandoni, M.D., Ph.D., for the EINSTEIN CHOICE Investigators

March 18, 2017DOI: 10.1056/NEJMoa1700518

Abstract

Background

Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin.

Methods

In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding.

Results

A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups.

Conclusions

Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439.)

Article

Venous thromboembolism, which includes deep-vein thrombosis and pulmonary embolism, is the third most common cause of vascular death after myocardial infarction and stroke.1-3 The mainstay of treatment is anticoagulation,4 and in patients without active cancer, guidelines suggest the use of direct oral anticoagulant agents such as rivaroxaban over vitamin K antagonists such as warfarin.4 Anticoagulation therapy is administered for 3 months or longer, depending on the balance between the risk of recurrent venous thromboembolism and the risk of bleeding.4 In patients without reversible risk factors, the risk of recurrent venous thromboembolism is as much as 10% in the first year if anticoagulation therapy is stopped.5-9 Patients in whom thrombosis was triggered by nonsurgical risk factors or who have persistent risk factors are at higher risk for recurrence than are those with postoperative thrombosis.10 In addition, because of overlapping risk factors, patients with venous thromboembolism are at increased risk for arterial thrombotic events, including myocardial infarction, stroke, and vascular death.11-13 Although extended anticoagulation therapy is effective for the prevention of recurrent venous thromboembolism,5-9 concern about bleeding often leads to a reluctance to continue anticoagulant treatment beyond 6 to 12 months. Attempts to reduce the risk of bleeding when treatment is extended include the use of lower-dose anticoagulant therapy and the use of aspirin in place of an anticoagulant agent.6,12-14

At a dose of 20 mg once daily, rivaroxaban is effective for stroke prevention in patients with atrial fibrillation15 and for the treatment of venous thromboembolism after an initial 21-day course of higher-dose therapy.7,16,17 At a dose of 10 mg once daily, rivaroxaban provides effective thromboprophylaxis after elective hip or knee arthroplasty.18-21 In the Reduced-dosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic Venous Thromboembolism (EINSTEIN CHOICE) trial,22 we compared the efficacy and safety of these two doses of rivaroxaban with those of aspirin in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was equipoise regarding the need for continued anticoagulation. Secondary aims of the study were to determine whether the lower dose of rivaroxaban was as effective as the higher dose and whether it was associated with less bleeding.

Methods

Study Design and Oversight

We conducted a randomized, double-blind, phase 3 study comparing the efficacy and safety of two doses of rivaroxaban with those of aspirin for the extended treatment of venous thromboembolism for up to 1 year after the initial 6 to 12 months of therapy.22 The trial was sponsored by Bayer Pharmaceuticals. The steering committee, which included both academic authors and those employed by the sponsor, had final responsibility for the design of the study, the development of the protocol, the oversight of the study, the verification of the data, and the analyses. The sponsor collected, maintained, and analyzed the data; the academic authors had access to the data at all times through the sponsor. The protocol (available with the full text of this article at NEJM.org) was approved by the institutional review board at each participating center. Written informed consent was obtained from all the patients.

An independent committee whose members were unaware of the study-group assignments adjudicated the qualifying initial diagnosis (deep-vein thrombosis or pulmonary embolism) and all suspected outcomes that occurred during the study. An independent data and safety monitoring committee periodically reviewed the study outcomes. All the members of the steering committee contributed to the interpretation of the results. The first three authors wrote the first draft of the manuscript, and all the steering committee members contributed to subsequent versions, made the decision to submit the manuscript for publication, and vouch for the accuracy and completeness of the data and for the fidelity of the study to the protocol.

Patients

Patients were eligible for inclusion in the study if they were 18 years of age or older; had objectively confirmed, symptomatic proximal deep-vein thrombosis or pulmonary embolism; had been treated for 6 to 12 months with an anticoagulant agent, including a vitamin K antagonist or a direct oral anticoagulant agent such as dabigatran, rivaroxaban, apixaban, or edoxaban; and had not interrupted therapy for more than 7 days before randomization.

Patients were ineligible if they had a contraindication to continued anticoagulant therapy or if they required extended anticoagulant therapy at therapeutic doses or antiplatelet therapy. Additional ineligibility criteria included a calculated creatinine clearance of less than 30 ml per minute23,24 or hepatic disease associated with a coagulopathy. A full list of inclusion and exclusion criteria is provided in the Supplementary Appendix, available at NEJM.org.

Randomization

Randomization with a block size of six was performed with the use of an interactive voice-response system and was stratified according to the index diagnosis (deep-vein thrombosis or pulmonary embolism) and country. Patients were enrolled at least 24 hours after they had received the last dose of a direct oral anticoagulant agent or, if they were receiving a vitamin K antagonist, when the international normalized ratio was 2.5 or lower. Patients were assigned, in a 1:1:1 ratio, to receive 20 mg of rivaroxaban, 10 mg of rivaroxaban, or 100 mg of aspirin, all given once daily with food. Rivaroxaban (20 mg and 10 mg) and matching placebo were provided as identical-appearing, immediate-release film-coated tablets, whereas aspirin and matching placebo were provided as enteric-coated tablets. The intended duration of administration of the study drug was 12 months, but patients who underwent randomization after the requisite number of primary efficacy outcomes had been reached were treated for at least 6 months.

Outcome Measures

The primary efficacy outcome was a composite of symptomatic, recurrent fatal or nonfatal venous thromboembolism and unexplained death for which pulmonary embolism could not be ruled out. Recurrent venous thromboembolism included fatal and nonfatal pulmonary embolism and deep-vein thrombosis. Other efficacy outcomes were myocardial infarction, ischemic stroke, systemic embolism, venous thrombosis in locations other than the deep veins of the lower limbs, and death from any cause. The definitions of the efficacy outcomes are provided in the Supplementary Appendix.

The principal safety outcome was major bleeding.25 Other safety outcomes were clinically relevant nonmajor bleeding, a composite of major or clinically relevant nonmajor bleeding, and nonmajor bleeding that led to study-drug interruption for more than 14 days.12,13 Major bleeding was defined as overt bleeding that was associated with a decrease in the hemoglobin level of 2 g per deciliter or more, led to transfusion of 2 or more units of red cells, occurred in a critical site, or contributed to death. Clinically relevant nonmajor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, unscheduled contact with a physician, interruption or discontinuation of the study drug, or discomfort or impairment of activities of daily living.26 (Further details regarding the criteria are provided in the Supplementary Appendix.)

Surveillance and Follow-up

Patients underwent assessment, either in the clinic or by telephone, at days 30, 90, 180, 270, and 360 and at 30 days after stopping the study medication. All the patients who stopped a study treatment earlier than scheduled were followed until the end of the intended treatment period. Patients were instructed to report to the study center if they had symptoms suggestive of recurrent venous thromboembolism or bleeding. Prespecified objective testing was required for patients in whom an outcome event was suspected.22 Continuation of anticoagulant or antiplatelet therapy after study completion was at the discretion of the treating physician.

Statistical Analysis

The study was designed to test the hypothesis that each dose of rivaroxaban would be superior to aspirin with respect to the primary efficacy outcome. We determined that the occurrence of 80 primary efficacy outcome events would provide a power of 90% to show the superiority of each dose of rivaroxaban over aspirin (each at a two-sided alpha level of 0.05), assuming a relative risk reduction of 70% with 20 mg of rivaroxaban and of 60% with 10 mg of rivaroxaban.7 On the basis of an expected frequency of the primary efficacy outcome of 5.0% at 12 months with aspirin,12,13 we calculated that we would need to enroll 2850 patients. However, this number was increased to 3300 when review of blinded data revealed a lower-than-expected overall incidence of the primary efficacy outcome.

The efficacy and safety analyses included all the patients who had undergone randomization with valid informed consent and who had received at least one dose of a study medication (intention-to-treat population). The per-protocol population excluded patients who had a rate of adherence to the study-drug regimen of less than 80% or who had other major protocol violations. Efficacy outcomes were considered during the individual intended treatment period, whereas safety outcomes were considered during the time from administration of the first dose of a study drug to 48 hours after the administration of the last dose. Efficacy and safety outcomes were analyzed with the use of a Cox proportional-hazards model, stratified according to the index diagnosis (deep-vein thrombosis or pulmonary embolism). Kaplan–Meier curves were constructed to display the distribution of events over time.

Results

Study Patients

From March 2014 through March 2016, a total of 3396 patients from 244 sites in 31 countries were enrolled. After the exclusion of 31 patients (0.9%) because they did not receive any study drug, 3365 patients were included in the primary analyses. The characteristics of patients in the three study groups were similar at baseline, as was the median duration of study treatment (Table 1). Figure 1 shows the random assignment and follow-up of the patients.

Efficacy

A primary efficacy outcome event occurred in 17 of 1107 patients (1.5%) who were receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) who were receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) who were receiving aspirin. Fatal venous thromboembolism occurred in 2 patients (0.2%) who were receiving 20 mg of rivaroxaban, in no patients who were receiving 10 mg of rivaroxaban, and in 2 patients (0.2%) who were receiving aspirin (Table 2). Both rivaroxaban doses were superior to aspirin with respect to the primary efficacy outcome (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). The hazard ratio for the comparison between the 20-mg and 10-mg rivaroxaban regimens was 1.34 (95% CI, 0.65 to 2.75; P=0.42). Similar results were found for the other efficacy outcomes (Table 2, and Table S4 in the Supplementary Appendix).

With aspirin, the rate of recurrent venous thromboembolism was 3.6% among the patients in whom the index event was provoked (i.e., associated with a known event, such as surgery or hospital admission) and 5.6% among those in whom the index event was unprovoked (i.e., idiopathic) (Table 3). Rates of recurrence in patients whose index events were provoked or unprovoked were lower in both the 20-mg rivaroxaban group (1.4% and 1.8%, respectively) and the 10-mg rivaroxaban group (0.9% and 1.5%, respectively) than in the aspirin group. Figure 2A shows the time course of symptomatic fatal or nonfatal recurrent venous thromboembolism. Of the 31 patients who were excluded from the analyses because they did not take any study drug, 1 patient who was assigned to receive 20 mg of rivaroxaban had a nonfatal primary efficacy outcome event.

Safety

Major bleeding occurred in 6 patients (0.5%) in the 20-mg rivaroxaban group and in 5 patients (0.4%) in the 10-mg rivaroxaban group, as compared with 3 patients (0.3%) in the aspirin group (Table 4). Figure 2B shows the time course of major bleeding episodes.

Clinically relevant nonmajor bleeding occurred in 30 patients (2.7%) in the 20-mg rivaroxaban group and in 22 patients (2.0%) in the 10-mg rivaroxaban group, as compared with 20 patients (1.8%) in the aspirin group (Table 4). Similar results were found for the composite outcome of major or clinically relevant nonmajor bleeding. Nonmajor bleeding that was associated with a study-drug interruption for more than 14 days occurred in 17 patients (1.5%) in the 20-mg rivaroxaban group and in 12 patients (1.1%) in the 10-mg rivaroxaban group, as compared with 12 patients (1.1%) in the aspirin group.

Other Outcomes

Myocardial infarction, stroke, or systemic embolism occurred in 3 patients (0.3%) in the 20-mg rivaroxaban group, in 5 patients (0.4%) in the 10-mg rivaroxaban group, and in 7 patients (0.6%) in the aspirin group (Table 2). The rates of death from any cause were 0.7% and 0.2% in the 20-mg and 10-mg rivaroxaban groups, respectively, as compared with 0.6% in the aspirin group. Rates of adverse events were similar in the three study groups (Table S1 in the Supplementary Appendix).

In prespecified subgroup analyses of the primary efficacy outcome and the composite outcome of major and clinically relevant nonmajor bleeding, results were consistent with the overall treatment effects (Figs. S1 through S4 in the Supplementary Appendix). During the 30-day follow-up after the end of the active study period, symptomatic recurrent venous thromboembolism occurred in 2 patients (0.2%) in the 20-mg rivaroxaban group, in 4 patients (0.4%) in the 10-mg rivaroxaban group, and in 6 patients (0.6%) in the aspirin group.

Discussion

Clinical strategies for extended anticoagulation in patients with venous thromboembolism are uncertain. Previous studies have shown that as compared with placebo, aspirin reduced the relative risk of recurrent venous thromboembolism by 32% (2.4 percentage points),12,13 whereas a 20-mg dose of rivaroxaban reduced the relative risk by 82% (6.8 percentage points).7 Consistent with those findings, our study shows that as compared with aspirin, both the 20-mg and 10-mg doses of rivaroxaban reduced the relative risk of recurrent venous thromboembolism by about 70% (approximately 3 percentage points). These benefits were observed with rates of major and clinically relevant nonmajor bleeding that were low and similar to those with aspirin. Therefore, we found that rivaroxaban was more effective than aspirin for the prevention of recurrent venous thromboembolism and was associated with a similar risk of bleeding.

What are the clinical implications of these findings? This study included patients with both provoked and unprovoked venous thromboembolism for whom there was equipoise regarding the need for continued anticoagulation. Patients with unprovoked venous thromboembolism are known to be at high risk for recurrence, but the risk of recurrence among those in whom venous thromboembolism was provoked by minor transient or persistent risk factors is less certain. We found that patients with venous thromboembolism with ongoing risk factors have an appreciable risk of recurrence because even with aspirin, the rate of recurrent venous thromboembolism in such patients was 3.6%, as compared with a rate of recurrence of 5.6% in those with unprovoked venous thromboembolism. Rivaroxaban reduced the relative risk of recurrence by about 70% in patients with both unprovoked and provoked venous thromboembolism. Consequently, the number of patients who would need to be treated for up to 12 months with rivaroxaban instead of aspirin to prevent one episode of fatal or nonfatal recurrent venous thromboembolism without increasing the risk of bleeding was 33 with the 20-mg dose and 30 with the 10-mg dose. Prevention of recurrent pulmonary embolism is particularly important, because the case-fatality rate at 30 days is at least twice as high with pulmonary embolism as with deep-vein thrombosis.27

Our study has several potential limitations. First, patients who required extended treatment with therapeutic doses of anticoagulant agents were excluded. Therefore, it remains unknown whether the 10-mg dose of rivaroxaban would be sufficient to prevent recurrence in such patients. Second, in this study and in the previous trial comparing rivaroxaban with placebo for extended treatment of venous thromboembolism, therapy was given for up to 12 months. Consequently, additional studies are needed to determine the utility of continuing treatment for longer periods. Third, our study was not powered to show the noninferiority of the 10-mg dose of rivaroxaban to the established treatment regimen of 20 mg, so any conclusions with respect to this issue are speculative.

In conclusion, we found that rivaroxaban, at both a treatment dose (20 mg) and a thromboprophylactic dose (10 mg), was more effective than aspirin for the prevention of recurrent venous thromboembolism among patients who were in equipoise for continued anticoagulation. The lower risk of a recurrent event among the patients who received rivaroxaban was associated with a rate of bleeding similar to that with aspirin.

Supported by Bayer Pharmaceuticals.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on March 18, 2017, at NEJM.org.

Source Information

From the Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton, ON (J.I.W.), and the Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa (P.S.W.) — both in Canada; Bayer Pharmaceuticals, Leverkusen (A.W.A.L., M.C.S.F., G.H., A.F.P., S.D.B.), Vascular Medicine, Klinikum Darmstadt, Darmstadt (R.B.), the Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz (R.B.), and the Department of Hematology, Medical Clinic I, University Hospital Carl Gustav Carus, Dresden (J.B.-W.) — all in Germany; the Department of Epidemiology and Technology Assessment, University of Maastricht, Maastricht, the Netherlands (M.H.P.); the Division of Angiology and Hemostasis and the Faculty of Medicine, University of Geneva, Geneva (H.B.); the Department of Haematology, Prince of Wales Hospital, Sydney (T.A.B.); the Department of Haematology and Oncology, King’s College London (J.B.-W.), the Department of Haematological Medicine, Guy’s and St. Thomas’ Hospitals, King’s College Hospital (A.T.C.), and Thrombosis Research Institute and University College London (A.K.K.) — all in London; the University of Washington School of Medicine, Seattle (B.L.D.); Centre d’Investigation Clinique 1408, Sainbiose U1059, Investigation Network on Venous Thromboembolism, Service de Médecine Vasculaire et Thérapeutique, Centre Hospitalo-Universitaire, Hôpital Nord, Saint Etienne, France (H.D.); Janssen Research and Development, Raritan, NJ (L.H.); Hospital Beneficência Portuguesa, São Paulo (B.B.); Vascular Medicine and Hemostasis, University of Leuven, Leuven, Belgium (P.V.); and the Department of Cardiothoracic and Vascular Sciences, Vascular Medicine Unit, University of Padua, Padua, Italy (P.P.).

Address reprint requests to Dr. Weitz at the Thrombosis and Atherosclerosis Research Institute, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada, or at .

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