Anticoagulant Treatment for Cancer Patients with DVT: Risks of Recurrent Venous Thromboembolism or Bleeding are High

Abstract & Commentary

Synopsis: Recurrent venous thromboembolism and/or bleeding occur in a subset of patients treated with anticoagulant therapy for deep vein thrombosis (DVT). In this report of 842 consecutive patients with DVT, 181 of whom had underlying cancer, it was shown that the presence of underlying malignancy increased the risk of recurrent DVT and hemorrhagic complications, despite standard and presumed therapeutic levels of anticoagulation. Furthermore, these risks correlated with the extent of the underlying cancer. Possibilities for improvement using the current paradigms of anticoagulation seem limited, and research investigating new treatment strategies is warranted.

Source: Prandoni P, et al. Blood. 2002;100:3484-3488.

The current study from the university hospital of Padua, Italy, was designed to assess the risk for recurrent venous thrombosis or bleeding during anticoagulant treatment in patients with or without underlying cancer. In a prospective analysis, 842 consecutive patients with laboratory (venography or compression ultrasound) confirmed DVT were followed for 12 months to determine the rate of recurrent DVT or bleeding. Of these, 181 were known to have cancer at the time of diagnosis of DVT. The 12-month cumulative incidence of recurrent DVT in cancer patients was 20.7% (95% CI, 15.6-25.8) vs 6.8% (95% CI, 3.9-9.7) in patients without cancer. Thus, the hazard ratio for recurrent DVT in patients with cancer compared to those without was 3.2 (95% CI, 1.9-5.4). The 12-month incidence of major bleeding was 12.4% (95% CI, 6.5-18.2) in patients with cancer and 4.9% (95% CI, 2.5-7.4) in patients without cancer for a hazard ratio of 2.2 (95% CI, 1.2-4.1).

The recurrence of venous thrombosis and bleeding complications were both related to the extensiveness of the cancer. Overall, the risk for recurrences was 2-3 fold increased in patients with less extensive cancer (ie, stage I or II), whereas in patients with more advanced disease (stage III or IV) the increased risk was almost 5-fold. Similarly, the risk of hemorrhage was not increased in those with early cancer (compared with noncancer patients) but was 5-fold greater in patients with extensive underlying cancer.

Comment by William B. Ershler, MD

The importance of this study is that it established in a prospective analysis what clinicians have long predicted—patients with cancer have a high risk for recurrent DVT and also treatment associated bleeding.1-3 The compared groups (those with or without underlying malignancy) were comparable in every regard, and because they were consecutive patients (ie, not selected or derived from a screening program) and because all were treated with a prescribed anticoagulation protocol, the data are very strong.

In this study, both groups (patients with or without underlying cancer) had comparable intensity of anticoagulant therapy) and in approximately 75% of both groups, the level of anticoagulation was maintained in the suggested therapeutic range (INR between 2 and 3, unless thrombocytopenic, at which time the target INR was 1.5-2). In fact, the analysis revealed that the increased risk of recurrent DVT or bleeding was not due to a change in intensity of anticoagulation therapy in the cancer group, or associated with more frequent nontherapeutic (over or under) INRs.

The correlation of recurrent DVT or major bleed with the extensiveness (stage) of the underlying malignancy supports the contention that the cancer itself contributes to anticoagulant treatment failure (recurrent DVT) or complication (bleeding). Possible mechanisms that would explain these associations include bleeding at the site of cancer, procoagulant states induced by the cancer, and decline in general condition leading to immobilization.

Thus, the Padua group has confirmed that recurrent DVT and hemorrhagic complications are more frequent in DVT patients with underlying malignancy, and that these both occur more commonly in those with advanced disease, even at a presumed therapeutic level of anticoagulation. What the research has not been able to provide is a suggestion on how to avoid these complications. Certainly, less intensive anticoagulation will result in more recurrent DVTs and more intensive anticoagulation will result in more bleeding. Placement of inferior vena cava filters may reduce the risk of pulmonary embolus, but the risk of recurrent DVTs will remain, or perhaps even be increased.3,4 The Padua study did not include enough patients with cancer to determine if certain types are more likely to be associated with anticoagulation failure or complication. Accordingly, more research is clearly needed to identify those at highest risk, and to examine new treatment strategies to reduce these untoward complications.

Dr. Ershler is INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, D.C.

References

1. Prandoni P, et al. Ann Intern Med. 1996;125:1-7.

2. Carson JL, et al. N Engl J Med. 1992;326:1240-1245.

3. Simioni P, et al. Blood. 2000;96:3329-3333.

4. Decousus H, et al. N Engl J Med. 1998;338:409-415.