This prespecified pooled analysis of two large, randomized studies evaluated the efficacy and safety of a single-drug approach with oral, fixed-dose rivaroxaban versus the combination of subcutaneous enoxaparin and INR-titrated VKA therapy in patients with acute symptomatic VTE. We found that rivaroxaban had similar efficacy as standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups. Overall, the rates of recurrent VTE and major bleeding were low in the standard-therapy group and were similar to those in contemporary clinical studies[5, 10, 16, 17].
Some limitations of our study should be noted. Firstly, we used an open-label design that could have biased assessment of outcomes. Nevertheless, efforts were made to limit investigator bias, including the requirement to use objective and validated tests to confirm suspected recurrent VTE and the use of an independent committee, whose members were blinded to treatment assignment, to adjudicate outcome events. Secondly, in the standard-therapy arm the choice of VKA was limited to acenocoumarol and warfarin, which might not have been the VKA of choice for some participating centers. However, INR monitoring was intensive and required assessment at least once a month. The time patients spent in the target therapeutic range (INR, 2.0–3.0) was in line with that achieved in contemporary studies. Therefore, we believe the results obtained in this large, global study, with limited exclusion criteria, are valid and can be generalized to typical patients with DVT and/or PE.
Pooling the results of EINSTEIN-DVT and EINSTEIN-PE enabled us to derive clinically relevant results for important subgroups of patients. Large clots and a history of (multiple episodes of) VTE are conditions that are of special concern to clinicians. Here, the efficacy of rivaroxaban was similar in patients presenting with small, intermediate, or extensive DVT or PE and was similar to standard-therapy. Likewise, the efficacy of rivaroxaban was similar both in patients presenting with a first episode of VTE and in those with a history of one or more episodes of VTE.
Bleeding is the most common complication of anticoagulant treatment; in this analysis, it occurred as often in patients receiving rivaroxaban as in patients receiving standard-therapy. However, major bleeding, the most worrying complication, was statistically significantly less frequent in patients treated with rivaroxaban. This reduction was seen mainly in fatal and nonfatal critical-site bleeding, such as intracranial and retroperitoneal bleeding. It is well known that VKA therapy is a challenge in patients who are elderly, have impaired renal function, are frail, or have cancer. Particularly in these patients, rivaroxaban yielded favorable clinical results. In fragile patients, the incidence of major bleeding was reduced from 4.5% with standard-therapy to 1.3% with rivaroxaban. This translates into averting one major bleeding event for every 31 fragile patients treated with rivaroxaban rather than standard-therapy, and the risk of recurrent VTE remained similar. In patients with cancer, the incidence of both bleeding and recurrent VTE tended to be lower, resulting in a favorable benefit–risk profile. However, selective inclusion of patients with cancer might have occurred: patients with a life expectancy of <3 months were excluded, and, according to guidelines, long-term subcutaneous low-molecular-weight heparin is the treatment of choice for patients with VTE and cancer. In addition, patients diagnosed with cancer after randomization were retrospectively reclassified to the cancer group. However, unless rivaroxaban or standard-therapy could have differential effects on a new diagnosis of cancer during the trial, the principle of randomization was maintained using an intention-to-treat approach to the analysis. Therefore, we believe that in patients with cancer who develop VTE, rivaroxaban may be considered as an alternative in those cases in which the attending physician would have given standard-therapy rather than long-term low-molecular-weight heparin. Based on the observed results in patients with cancer, a head-to-head comparison of rivaroxaban with long-term low-molecular-weight heparin seems warranted.