December 12th, 2012


The current guidelines from the American College of Chest Physicians (Kearon et al Chest 2012) and the Scientific Statement from AHA (Jaff et al Circulation 2011) favor 3-6 months of anticoagulation with no further treatment thereafter in unprovoked deep vein thrombosis/pulmonary embolism (DVT/PE), largely due to the risk of bleeding in the setting of prolonged warfarin therapy. Two studies have been published this year in NEJM that challenge this practice.

In the AMPLIFY-EXT study, Agnelli et al report that the use of apixaban, the oral factor Xa inhibitor, in patients with a history of DVT or PE for 12 months after 6-12 months of therapy with oral anticoagulants decreased the risk of recurrent DVT or PE or death compared to placebo. Two doses of apixaban were studied, both of which reduced the risk of DVT/PE/death from 11.6% with placebo to ~4%, depending on the dose of apixaban used (4.2% with 5 mg of apixaban or 3.8% with 2.5 mg of apixaban).

These results are similar to those observed in the WARFASA study published earlier this year and featured in an “Expert Is In” post here at CardioExchange. In that study, ASA 100mg was administered for 2 years after the discontinuation of anticoagulant therapy (and compared to placebo). DVT/PE recurred in 11.2% in those who received placebo over the 2-year period vs. 6.6% of the patients treated with ASA.

Taken together these articles reinforce the need for prolonged treatment in patients with unprovoked DVT/PE. More than 90% of the patients in the AMPLIFY-EXT study had unprovoked DVT/PE, and in the placebo group nearly 9% had a recurrent venous thromboembolism (VTE) or VTE-related death in the 12 months follow-up. With a 10% recurrence rate over the course of a year, DVT/PE should be managed as a lifelong condition, just the same way we manage ischemic heart disease.

  • Are you planning to use apixaban or aspirin as extended treatment for your patients with DVT/PE??
  • How long are you treating your patients with unprovoked DVT/PE?


7 Responses to “AMPLIFYING Treatment for DVT/PE”

  1. Dan Hackam, MD PhD says:

    There was a trial about 9 years ago called PREVENT which showed that low dose warfarin, to an INR of about 1.5, prevented 64% of recurrent DVTs and PE’s following the initial 6 month period of therapeutic anticoagulation (the PI was Dr Paul Ridker). The on-treatment analysis showed a >80% risk reduction (this included only patients who continued on the drug). This would be an extremely inexpensive way to do it.

  2. William DeMedio, MD says:

    For those who want a low cost, low risk, and multiple benefit approach who cantolerate it I side with ASA. It can be taken daily for a long time. The other options also have their niche. I also agree with Dr Hackam above.

  3. David Powell , MD, FACC says:

    Sounds like we need a aspirin vs. novel anticoagulant trial for extended DVT treatment. I will postulate that the novel agent has an edge on aspirin. A low D-dimer one month after cessation of anticoagulation predicts no recurrence. Depending on the result, either aspirin or the novel agent would be chosen.

    I have used the PREVENT regimen.

    As far as duration of therapy: indefinite. I believe the use of anticoagulation only postpones the recurrence risk (at least for extended prophylaxis).

    The interplay with thrombophilia evaluation is also interesting. Does heterozygosity for Factor 5 Leiden effect the decision? I have heard different opinions.

  4. Dan Hackam, MD PhD says:

    In provoked DVT/PE there is no recommendation to screen for that. In unprovoked, spontaneous, idiopathic DVT/PE, get the full thrombophilia panel (if you can). I would use warfarin and titrate to an INR between 1.5 and 2.0, as per the PREVENT trial regimen. This led to a 64% reduction in recurrent DVT/PE after an initial median 6.5 month full dose treatment (intention-to-treat analysis; the OT analysis showed even steeper risk reductions). This seems to be more effective than the data for ASA, but I agree a comparative trial would be useful.

  5. Dutch researchers Vink et al developed a formula to determine optimum length of anticoagulation therapy in the setting of DVT and PE. The formula requires some assumptions regarding bleeding risk and recurrence risk, but provides a useful concept (Vink R, Kraaijenhagen RA, Levi M, Buller HR. Individualized duration of oral anticoagulant therapy for deep vein thrombosis based on a decision model. J Thromb Haemost. 2003; 1: 2523–2530.) Another practice is to examine for residual venous thrombosis on ultrasound (similar to Dr Powells D-dimer suggestion). Thanks for the great comments so far and highlighting important studies.

  6. Esteban Gandara, MD says:

    Some comments,

    1- A therapeutic strategy using an INR between 1.5 and 2 carries the same bleeding risk as 2-3, and reduced efficacy (ELATE study)
    2-ASA appears to reduce the risk by a 30% . Patients with unprovoked VTE who are at high risk for recurrent VTE are more likely to benefit from anticoagulation.
    3-Patients should be managed using well design clinical prediction tools such as the one from the REVERSE cohort (Rodger CMAJ 2008). Single predictors such as d-dimer or RVO do not discriminate very low risk patients who can be managed without anticoagulation.
    4-Residual vein thrombosis does not appear to be a predictor of recurrent VTE in patients with unprovoked VTE (See Carrier et al. JTH 2011)
    5- In a recent systematic review a negative d-dimer is associated with an annualised risk for recurrent VTE is 3.7 per 100 patient years (95% CI 3.2 to 4.3), and 8.8 per 100 patient years (95% CI 6.2 to 11.3). Based on this results D-dimer should not be used as the only method to decide duration of anticoagulation or if it is safe to stop

  7. David Powell , MD, FACC says:

    The ELATE trial had an unusually low bleeding rate in the full dose warfarin group, not reproducible in other trials including one by the same griup.
    Apixaban looks excellent from the major bleeding standpoint, both in this trial, AVEROES and ARISTOTLE.