Elsevier

The Lancet Haematology

Volume 1, Issue 1, October 2014, Pages e37-e46
The Lancet Haematology

Articles
Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials

https://doi.org/10.1016/S2352-3026(14)70018-3Get rights and content

Summary

Background

Patients with venous thromboembolism and cancer have a substantial risk of recurrent venous thromboembolism and bleeding during anticoagulant therapy. Although monotherapy with low-molecular-weight heparin is recommended in these patients, in clinical practice many patients with venous thromboembolism and cancer do not receive this treatment. We aimed to assess the efficacy and safety of a single-drug regimen with oral rivaroxaban compared with enoxaparin followed by vitamin K antagonists, in the subgroup of patients with cancer enrolled in the EINSTEIN-DVT and EINSTEIN-PE randomised controlled trials.

Methods

We did a subgroup analysis of patients with active cancer (either at baseline or diagnosed during the study), a history of cancer, or no cancer who were enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Eligible patients with deep-vein thrombosis (EINSTEIN-DVT) or pulmonary embolism (EINSTEIN-PE) were randomly assigned in a 1:1 ratio to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy (enoxaparin 1·0 mg/kg twice daily and warfarin or acenocoumarol; international normalised ratio 2·0–3·0). Randomisation with a computerised voice-response system was stratified according to country and intended treatment duration (3, 6, or 12 months). The prespecified primary efficacy and safety outcomes of both the trials and this subanalysis were symptomatic recurrent venous thromboembolism and clinically relevant bleeding, respectively. We did efficacy and mortality analyses in the intention-to-treat population, and bleeding analyses for time spent receiving treatment plus 2 days in the safety population (all patients who received at least one dose of study drug). The EINSTEIN-DVT and EINSTEIN-PE studies are registered at ClinicalTrials.gov, numbers NCT00440193 and NCT00439777.

Findings

In patients with active cancer (diagnosed at baseline or during treatment), recurrent venous thromboembolism occurred in 16 (5%) of 354 patients allocated to rivaroxaban and 20 (7%) of 301 patients allocated to enoxaparin and vitamin K antagonist (hazard ratio [HR] 0·67, 95% CI 0·35 to 1·30). Clinically relevant bleeding occurred in 48 (14%) of 353 patients receiving rivaroxaban and in 49 (16%) of 298 patients receiving standard therapy (HR 0·80, 95% CI 0·54 to 1·20). Major bleeding occurred in eight (2%) of 353 patients receiving rivaroxaban and in 15 (5%) of 298 patients receiving standard therapy (HR 0·42, 95% CI 0·18 to 0·99). The overall frequency of recurrent venous thromboembolism in patients with only a history of cancer (five [2%] of 233 patients in the rivaroxaban group vs five [2%] of 236 in the standard therapy group; HR 0·98, 95% CI 0·28–3·43) was similar to that of patients without cancer (65 [2%] of 3563 vs 70 [2%] of 3594, respectively; HR 0·93, 95% CI 0·66–1·30), but the frequency was increased in patients with active cancer at baseline (six [2%] of 258 vs eight [4%] of 204, respectively; HR 0·62, 95% CI 0·21–1·79) and most markedly increased in patients whose diagnosis of cancer was made during the study (ten [10%] of 96 vs 12 [12%] of 97, respectively; HR 0·80, 95% CI 0·34–1·88). The overall frequency of major bleeding in patients with only a history of cancer (one [<1%] patient in the rivaroxaban group vs four [2%] patients in the standard therapy group; HR 0·23, 95% CI 0·03–2·06) was similar to that of patients without cancer (31 [1%] vs 53 [1%], respectively; HR 0·58, 95% CI 0·37–0·91), but was increased in patients with active cancer at baseline (five [2%] vs eight [4%], respectively; HR 0·47, 95% CI 0·15–1·45) and was highest in those with cancer diagnosed during the study (three [3%] vs seven [7%], respectively; HR 0·33, 95% CI 0·08–1·31).

Interpretation

In patients with active cancer and venous thromboembolism, rivaroxaban had similar efficacy to prevent recurrence of venous thromboembolism and reduced the number major bleeding events compared with treatment with enoxaparin and a vitamin K antagonist, although there was no difference between groups for clinically relevant bleeding. Based on these results, a head-to-head comparison of rivaroxaban with long-term low-molecular-weight heparin in patients with cancer is warranted.

Funding

Bayer HealthCare Pharmaceuticals and Janssen Research & Development.

Introduction

The EINSTEIN-DVT1 and EINSTEIN-PE2 studies compared rivaroxaban (an oral direct inhibitor of factor Xa) with enoxaparin given with and followed by a vitamin K antagonist for the treatment of deep-vein thrombosis (EINSTEIN-DVT) or pulmonary embolism (EINSTEIN-PE).1, 2 Both studies used an identical design, treatment regimens, outcome definitions and adjudication processes, and a pooled analysis of the two trials showed similar efficacy and a lower incidence of major bleeding events in patients treated with rivaroxaban compared with those treated with enoxaparin and vitamin K antagonist.3, 4 The results of these studies formed the basis for regulatory approval of rivaroxaban for acute and extended treatment of deep-vein thrombosis and pulmonary embolism.

Roughly 10–20% of patients with acute deep-vein thrombosis or pulmonary embolism have either a history of cancer or active cancer.5, 6, 7 Additionally, a diagnosis of previously undetected malignant disease is often made in patients during the first months after acute presentation of unprovoked deep-vein thrombosis or pulmonary embolism.8, 9, 10

Patients with cancer have a treatment dilemma because anticoagulant treatment with vitamin K antagonists carries not only a residual high risk of recurrent venous thromboembolism but also a high risk of serious bleeding.11, 12 In a meta-analysis of studies comparing standard treatment (low-molecular-weight heparin and vitamin K antagonist) in patients with cancer and venous thromboembolism with long-term low-molecular-weight heparin treatment alone for 3–6 months, patients receiving long-term low-molecular-weight heparin had a relative risk reduction for recurrent venous thromboembolism of more than 50% compared with those receiving standard treatment; however, low-molecular-weight heparin therapy was associated with a statistically non-significant increase in risk of major bleeding.13 Therefore, patients with cancer and venous thromboembolism are recommended to receive monotherapy with long-term low-molecular-weight heparin.14, 15, 16, 17, 18 However, the level of this recommendation is qualified as 2b (ie, weak with underlying evidence of moderate quality). Consequently, on the basis of medical, economical, and quality-of-life considerations, many physicians still treat patients who have cancer and venous thromboembolism with vitamin K antagonists.

The EINSTEIN-DVT and EINSTEIN-PE studies assessed patients with deep-vein thrombosis or pulmonary embolism, and did not exclude patients with cancer. We aimed to analyse the efficacy and safety of rivaroxaban compared with enoxaparin given concurrently with a vitamin K antagonist, followed by vitamin K antagonist alone, in the subgroups of patients in these trials with a history of cancer, active cancer at baseline, and cancer that became symptomatic after randomisation. Additionally, we compared the frequency of events in these patients with those without any history of cancer.

Section snippets

Study design and participants

In a subgroup analysis, we included patients with cancer from the EINSTEIN-DVT and EINSTEIN-PE trials (two randomised, open-label, phase 3 studies). Patients were potentially eligible for the EINSTEIN-DVT and EINSTEIN-PE studies if they had symptomatic deep-vein thrombosis or pulmonary embolism. The main exclusion criteria were a therapeutic dose of low-molecular-weight heparin, fondaparinux, or unfractionated heparin for more than 48 h before randomisation; more than a single dose of a vitamin

Results

Between March 22, 2007, and March 12, 2011, 8281 patients (3449 in the EINSTEIN-DVT trial and 4832 in the EINSTEIN-PE trial) were enrolled at 314 sites in 38 countries; 4150 patients were randomly assigned to receive rivaroxaban and 4131 were randomly assigned to receive standard therapy. Of the 655 (8%) patients with any active cancer, 462 (6%) presented with the diagnosis at baseline, and 193 (2%) were diagnosed with cancer during the study. A further 469 (6%) patients had a history of cancer

Discussion

This subgroup analysis in patients with acute venous thromboembolism showed similar efficacy of a single-drug approach with oral, fixed-dose rivaroxaban to the combination of subcutaneous enoxaparin and INR-titrated therapy with vitamin K antagonist in patients with cancer, and consistent results across all important clinical subgroups. The increased risk of recurrent venous thromboembolism and major bleeding, and increased mortality in patients with active cancer compared with those without

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