Direct oral anticoagulants to treat VTE in patients with cancer?

Four direct oral anticoagulants were approved by the FDA in the last few years and are all now indicated for the treatment of DVT and PE.  These include:

• Direct thrombin inhibitor:

     -Dabigatran (Pradaxa)

• Factor Xa inhibitors:

     -Rivaroxaban (Xarelto)
     -Apixaban (Eliquis)
     -Edoxaban (Savaysa)


These medications are given orally at fixed doses and do not require coagulation monitoring or titration.  Compared to warfarin (which needs close INR following and can vary drastically
with the drug and dietary fluctuations common in cancer patients) or long-term low molecular weight heparin (which needs subcutaneous injections and can be cost restrictive) they are appealing alternative treatment options.

Data on treating VTE in patients with cancer

While these medications have proven noninferior in treating the broad population of patients with VTE in large phase III studies, no prospective randomized trials have been done to verify this finding in those with active cancer.  In the existing trials of the general population, only a small number of patients happened to have or develop cancer during the study periods.  

A recent systematic review and meta-analysis in CHEST identified only 6 studies have been done using a direct oral anticoagulant versus a vitamin K antagonist that included patients with active cancer that objectively assessed VTE recurrence rates and bleeding.1  In these studies, the number of patients with active cancer were few, ranging from 2.5% to 9.4% (totaling 1,028 patients).  Further limiting our use of this evidence is that the comparator groups in these studies used heparin bridged to warfarin, instead of LMWH (which is the preferred VTE treatment in patients with active cancer - CHEST guidelines grade 2B for LMWH preferred over VKA).2

Efficacy of direct oral anticoagulants

Of these six studies, two were with dabigatran, two with rivaroxaban, and one each with apixaban and edoxaban.  Since the number of patients with active cancer who experienced a recurrent VTE was so small, the data was looked at in aggregate (combined analysis of all direct oral anticoagulants) in a recent meta-analysis.  Overall, recurrence rates of VTE were 23 of 595 (3.9%) in the direct oral anticoagulant group compared with 32 of 537 (6%) in the comparator group.  This means there was a comparable, but nonsignificant reduction in recurrent VTE with direct oral anticoagulants (OR 0.63; 95% CI, 0.37-1.10).

Bleeding rates of direct oral anticoagulants

The bleeding rates that occurred in cancer patients in these six studies were also assessed in aggregate.  Major bleeding occurred in 19 of 587 (3.2%) treated with direct oral anticoagulants compared to 22 of 527 (4.2%) treated with the heparin-warfarin bridge comparator.  This, again, was a nonsignificant reduction in the direct oral anticoagulant group (OR 0.77; 95% CI, 0.41-1.44).

Take home points:

• No prospective randomized controlled trials exist to support or refute the use of direct oral anticoagulants for treating VTE in patients with cancer
• A meta-analysis of the available randomized controlled trials' active cancer patients found similar VTE recurrence rates (noninferior compared to heparin-warfarin bridge).  This is consistent with the overall study group (cancer + no cancer).
• This meta-analysis also found a nonsignificant reduction in major bleeding (again, comparable to the overall VTE study group
• Limitations of this data include that the direct oral anticoagulants were compared to heparin-warfarin bridge, not LMWH which is the current guideline-recommended treatment for patients with VTE and active cancer

References:

1. Vedovati MC, Germini F, Agnelli G, et al.  Direct oral anticoagulants in patients with VTE and cancer: A systematic review and meta-analysis.  CHEST  2015;147(2):475-83.
2. Kearon C, Akl EA, Comerota AJ, et al.  Antithrombotic therapy for VTE disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.  CHEST  2012;141(2):e419s-494s.

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