Sometimes three months just isn’t enough. Sure, you’ve given that clot time to resorb, but maybe you have an unprovoked event that needs lifelong anticoagulation, or maybe it was provoked, but the provocation is still around. Either way, you’ve decided you need long-term anticoagulation. Usually, that means more of the same. Continue the rivaroxaban, continue the dabigatran, continue the warfarin if you’re not a candidate for target specific oral anticoagulants. But some folks who thought EINSTEIN CHOICE was a reasonable name for a trial had another idea.
Patients, Intervention, Comparator, and Outcomes
This multinational trial took 3396 patients who had already undergone between 6 and 12 months of anticoagulation for VTE (including PE) and randomized them to one of three arms: ASA 81mg daily, rivaroxaban 20mg daily (therapeutic dose) or rivaroxaban 10mg daily (prophylactic dose). There was no placebo arm. The primary outcome was a composite of recurrent VTE or unexplained death possibly caused by PE, with major bleeding as the principal safety outcome.
A Bit of Context
Let’s pause on inclusion criteria for a second, because it’s not immediately clear who these patients are. When treating VTE, there is broad consensus that three months is your minimum duration of therapy. After that, there is no longer broad consensus. If there is a clear provoking factor (the patient had a knee replacement, say, and is now walking), it’s probably reasonable to stop at three months. If the patient has cancer, clearly they need lifelong therapeutic anticoagulation. However, what about the broad swath of people in the middle? The people with unprovoked events, or those whose events are provoked but still have some of those same provoking factors? Currently, there’s no great data to guide continuing anticoagulation versus stopping and hoping, but we do know that they have a recurrence rate of VTE significantly higher than the general population, and we know that continuing anticoagulation (unsurprisingly) does significantly mitigate this risk.
There have been attempts recently to paint aspirin as kind of a “middle way” for these patients, with the 2012 WARFASA trial and some subsequent metanalyses demonstrating a significant relative risk reduction with low-dose aspirin versus placebo in these patients. This is probably a good place to note that the EINSTEIN CHOICE trial was funded by Bayer, whose branded aspirin is actually one of their top 10 sellers despite the drug having been generic since 1920.
And what does Bayer get for their money? No surprises, but no great joy either. The primary outcome occurred in 1.5% of participants on 20mg rivaroxaban, 1.2% of those on 10mg rivaroxaban, and a hard-to-watch 4.4% of those on 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). Meanwhile, the rates of major bleeding were 0.5%, 0.4%, and 0.3%, with the rates of “clinically relevant non-major bleeding” 2.7%, 2.0%, and 1.8% for the three groups respectively. The number needed to treat with rivaroxaban 10mg instead of aspirin to prevent one episode of recurrence is 33.
So the takeaway is, rivaroxaban significantly outperforms aspirin in prevention of VTE recurrence without a significant increase in major bleeding, and looks especially nice at the prophylactic 10mg dose. This is the first direct comparison of these three therapies, but each of the has beaten placebo before (EINSTEIN-Extension for rivaroxaban 20mg, the WARFASA trial for aspirin), and the results seen here are pretty similar. This is the first data for the 10mg dose status post VTE, and things look good. If Bayer was hoping for a significant reduction in major bleeding risk with ASA to accompany the inferior prevention of VTE recurrence, no such luck. Still, ASA did once again result in lower VTE recurrence than that previously seen in placebo groups.
If you have a patient who has completed three months of therapeutic anticoagulation status post VTE and does not have another indication for anticoagulation, rivaroxaban 10mg might be worth a look. This significantly reduced rates of recurrence compared to ASA 81mg, and was comparable to the effect size of the 20mg dose (which has previously beaten placebo) without a significant increase in bleeding over ASA.
Read the primary source here.