Oral rivaroxaban gives similar outcomes to enoxaparin followed by a vitamin K antagonist in the treatment of patients with deep vein thrombosis (DVT), according to a controlled trial; a continuation study found that further treatment with rivaroxaban reduced DVT events compared to placebo at the expense of an increased risk of major bleeding.

Venous thromboembolism (VTE) is common and can be treated effectively using an oral vitamin K antagonist (warfarin etc.) with initial low-molecular-weight heparin injections until a therapeutic INR is reached. Prolonged treatment reduces the risk of recurrence, however good management of such therapy is not easy and the risk to benefit balance is debated. This randomised open-label non-inferiority trial compared standard treatment of DVT using enoxaparin and a vitamin K antagonist with oral rivaroxaban, a direct Factor Xa inhibitor that has been shown to be effective in prophylaxis of VTE.

Patients for the acute treatment study were of legal age for consent and had acute, symptomatic, objectively confirmed proximal DVT, without symptomatic pulmonary embolism. They were randomised to treatment with oral rivaroxaban (15mg bd for 3 weeks, then 20mg daily) or standard treatment with warfarin or acenocoumarol plus initial enoxaparin to cover until a therapeutic INR was reached. Treatment duration was 3, 6, or 12 months, decided by treating physician. Patients for the continuation study had confirmed VTE and had been treated for 6 or 12 months with warfarin/acenocoumarol or rivaroxaban; they were randomised double-blind to rivaroxaban or placebo for a further 6 or 12 months. Primary efficacy outcome for both arms of the study was recurrent VTE; primary safety outcomes were major or clinically-significant non-major bleeding for the acute study and major bleeding for the continuation study.

There were 3,449 patients randomised to the acute study (rivaroxaban 1,731, standard therapy 1,718) and included in the intention-to-treat analysis: 13 in each group did not receive their intended treatment - 6 patients assigned to rivaroxaban received standard treatment and were included in the safety analysis for that treatment. The primary efficacy outcome was suspected in 230 patients in the rivaroxaban group and in 215 patients in the standard-therapy group and was confirmed in 36 and 51, respectively. Thus the primary efficacy outcome occurred in 2.1% of patients in the rivaroxaban group and in 3.0% of patients in the standard-therapy group (hazard ratio [HR], 0.68; 95% CI, 0.44 to 1.04; P<0.001 for non-inferiority with a one-sided test, and P=0.08 for superiority with a two-sided test). The primary safety outcome occurred in the same proportion of patients in both groups (8.1%; HR with rivaroxaban, 0.97; 95% CI, 0.76 to 1.22; P=0.77).

The continuation study enrolled 1,197 patients, 560 (47.5%) of whom were referred from outside the acute trial; 602 received rivaroxaban, and 595 placebo (1 excluded due to invalid informed consent). The primary efficacy outcome occurred in 8 patients (1.3%) in the rivaroxaban group vs. 42 (7.1%) in the placebo group (HR, 0.18; 95% CI, 0.09 to 0.39; P<0.001, relative risk reduction, 82%). Patients in the rivaroxaban group had a higher risk of the main safety outcome (major bleeding), which occurred in 4 patients (0.7%) vs. none of the patients in the placebo group (P=0.11). There were no fatal bleeding episodes. The secondary safety outcome of clinically relevant non-major bleeding was increased from 1.2% in the placebo group to 5.4% with rivaroxaban. The combined adverse outcome of recurrent VTE plus major bleeding occurred in 12 vs. 42 patients respectively (HR 0.28; 95% CI, 0.15 to 0.53; P<0.001).

The authors conclude that rivaroxaban has similar efficacy to standard therapy for the acute treatment of DVT with similar safety. They note potential limitations with the open label design introducing diagnostic bias, but comment that the actual outcomes reported suggest that there was no major bias in reporting outcomes. They also conclude that continued therapy reduces the risk of recurrence with an acceptable safety profile, and that this may alter the risk-benefit balance when considering whether to continue treatment.

[Editor's note: at the time of posting, rivaroxaban is licensed in the EU only for prevention, not for treatment of VTE.]