Most patients who are found to have a pulmonary embolism are started on a medication to prevent future clots. For years, the drug of choice has been warfarin, a vitamin K antagonist that decreases the level of clotting factors. This medication works well but is notoriously complicated to use, requiring frequent monitoring with blood draws and subsequent dosing adjustments.
A newer medication, rivaroxaban, offers a more convenient alternative. Rivaroxaban works by directly inhibiting the clotting factor Xa and can be taken as a fixed-dose pill. And, according to new study results published this week in NEJM, rivaroxaban may be just as effective and safe as traditional therapy.
The EINSTEIN-PE randomized open-label trial enrolled more than 4,800 patients who had suffered an acute symptomatic pulmonary embolism, with or without symptomatic deep venous thrombosis. Patients were randomly assigned to receive either rivaroxaban (15 mg twice a day for three weeks, then 20 mg daily) or the standard therapy regimen of low molecular weight heparin overlapped and followed by a vitamin K antagonist. The study lasted approximately 9 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The primary safety outcome was clinically relevant bleeding, while secondary safety outcomes included major bleeding (defined as bleeding that resulted in a drop in hemoglobin of 2g/dl or more, required transfusion of 2 or more units of red cells, or involved a critical part of the body such as the brain).
No significant difference in efficacy was detected between the two study groups. Fifty out of 2419 patients (2.1%) in the intervention arm had a recurrent venous thromboembolism, as compared with 44 out of 2413 patients (1.8%) in the control arm (P<0.003 for non-inferiority, P=0.57 for superiority).
Similarly, no significant difference in safety was detected between the two groups for the primary outcome of clinically relevant bleeding. The first episode of clinically relevant bleeding during treatment occurred in 249 (10.3%) of patients in the intervention arm, as compared with 274 (11.4%) of patients in the control arm (P=0.23). For the secondary outcome of major bleeding, rivaroxiban actually seemed to offer an advantage over standard therapy: 26 patients (1.1%) in the intervention arm experienced major bleeding, as compared with 52 patients (2.2%) in the control arm (P=0.003).
Due to concern that giving the same dose of rivaroxaban to all patients might not be appropriate, various subgroups analyses were also performed. Rates of recurrent venous thromboembolism and bleeding were found to be similar in the two groups regardless of patient age, gender, kidney function, presence of obesity, or extent of pulmonary embolism.
In the intervention arm, adherence to the rivaroxaban treatment regimen was above 80% in 94.2% of patients. In the control group, the international normalized ratio (INR) – a reflection of the degree of anti-coagulation – was in the therapeutic range (2.0 to 3.0) only 63% of the time. The INR was too low 15% of the time, suggesting an increased risk of clotting, and too high 22% of the time, suggesting an increased risk of bleeding.
These findings may change how physicians approach the prevention of recurrent venous thromboembolism. If rivaroxiban is indeed just as safe and effective as vitamin K antagonists, it may be an alternative to consider for patients who have had a pulmonary embolism and require long-term anti-coagulant therapy but desire a convenient option.
Future studies will be useful for identifying specific patient profiles that may be particularly suited for treatment with rivaroxaban over standard therapy. For example, the results of the EINSTEIN-PE trial seem to suggest that rivaroxaban is associated with significantly lower rates of major bleeding, including intracranial bleeding, as compared with standard therapy. A better understanding of this perceived difference may help to inform treatment algorithms for patients with different risk factors and integrate the results of the EINSTEIN-PE trial into clinical practice.
How do you currently use rivaroxaban in your practice? For what types of patients would you consider switching from traditional anti-coagulant therapy to rivaroxaban?