February 20th, 2013

New Studies Examine Prolonged Anticoagulation for VTE Recurrence

Three studies published in the New England Journal of Medicine provide important new information about the risks and benefits of extended prophylaxis using two of the new oral anticoagulants in patients who have had venous thromboembolism (VTE).

In the RE-MEDY and the RE-SONATE trials, the role of dabigatran was examined in patients who had completed at least 3 months of initial VTE therapy. In RE-MEDY, the active-control study, 2,866 patients felt to be at increased risk for recurrent VTE were randomized to warfarin or dabigatran. In RE-SONATE, the placebo-control study, 1,353 patients were randomized to either dabigatran or placebo. In both studies, dabigatran was effective at preventing recurrent VTE. Compared with warfarin, dabigatran treatment resulted in fewer major or clinically relevant bleeding episodes. Compared with placebo, dabigatran resulted in more bleeding episodes.

Recurrent VTE:

  • 1.8% for dabigatran versus 1.3% for warfarin, HR 1.44 (0.78-2.64)
  • 0.4% for dabigatran versus 5.6% for placebo, HR 0.08 (0.02-0.25)

Major or clinically relevant bleeding:

  • 5.6% for dabigatran versus 10.2% for warfarin, HR 0.54 (0.41-0.71)
  • 5.3% for dabigatran versus 1.8% for placebo, HR 2.92 (1.52-5.60)

In AMPLIFY-EXT (previously published online), 2,486 VTE patients were randomized to either placebo or apixaban (2.5 or 5 mg twice daily) for an additional 12 months after completing an initial standard anticoagulation regimen for 6-12 months. At both doses, apixaban treatment was associated with a large reduction in clinical events and no increase in major bleeding events.

Recurrent VTE:

  • 1.7% for low-dose apixaban versus 1.7% for high-dose apixaban versus 8.8% for placebo, RR 0.19 (0.11-0.33) for low-dose apixaban and 0.20 (0.11-0.34) for high-dose apixaban

Major or clinically relevant bleeding:

  • 3.2% for low-dose apixaban versus 4.3% for high-dose apixaban versus 2.7% for placebo, RR 1. 20 (0.69-2.10) for low-dose placebo and 1.62 (0.96-2.73) for high-dose apixaban

In an accompanying editorial, Jean Connors writes that “deciding how to balance the risks and benefits of extended anticoagulation is difficult” in patients with unprovoked VTE, since the risk of recurrent VTE may reach 40% at 5 years. Patients at low-to-moderate risk of recurrence may benefit from aspirin, which “may be safer than the newer agents,” though “it appears to have less efficacy in reducing recurrent events.” For patients at higher risk, “the new targeted anticoagulants are attractive alternatives to warfarin. The finding that a low prophylactic dose of apixaban has the same efficacy as the full therapeutic dose, with no increased risk of major bleeding, may tip the risk-to-benefit ratio in favor of extended treatment for this patient population. The wide therapeutic window of this agent enables use of a lower dose that retains great efficacy with no or only a minimal increase in bleeding.”

2 Responses to “New Studies Examine Prolonged Anticoagulation for VTE Recurrence”

  1. Donald Hislop, MS MD says:

    How do I decide “patients felt to be at increased risk for recurrent
    risk of VTE”?

  2. Judith Andersen, AB, MD says:

    Data continuing to emerge from the Ottawa Research Institute suggest that men of any age with “unprovoked” VTE (no trauma, surgery, cancer,etc) have a significant risk of recurrence — whereas women with a similar lack of provocation have risk related to evidence of venous insuffiency/post-thrombotic syndrome (Men Continue and HER-DOO2). Given the morbidity of recurrent disease and the convenience, unmonitored safety and non-interference with cardioprotective dietary strategies of the new oral agents, most prominently rivaroxaban and apixaban, long-term anticoagulation for men with “idiopathic” VTE seems like a no-brainer.

    Evaluation and adjudication for women is more complex — and the role of hormone replacement therapy must be evaluated carefully. Transdermal estrogen replacement appears safer from both recurrent VTE and cardiovascular morbidity perspectives than oral replacement, suggesting that the “first (hepatic) pass” issue with oral supplementation may be operative in VTE provocation (the real downside of the WHI and its findings is the ridiculous “one size fits all” replacement strategy that was employed. The subgroup data suggesting that women who received only estrogen, i.e. those with no uterus, had better cardiac outcomes than those who received both estrogen and progesterone are very interesting — and the benefits in terms of bone density and cardiovascular health seem evident from small substudies.

    I think the Canadian data are robust. Are American men similar to Canadian men in terms of diet, BMI, smoking, lack of exercise? I don’t know, but I think it likely that US males are not more fit than their Canadian counterparts and that the bottom line is, if you cannot find a compelling reason to interrupt therapy for a man with unprovoked VTE, continuing one of the new agents might be a reasonable choice. For a woman with an unprovoked VTE, the data are less clear, but the outcomes of rethrombosis +/- embolism can be catastrophic. As always, clinical judgment must come to the fore — and clinicians who make these decisions must be conversant with the potential consequences of a decision to continue or desist.