Special-topic “Medicine”: Prevention of Venous Thromboembolism
In this article we will explore this topic as deeply as possible. We will try to publish more such articles as we believe will be of interest to many doctors and profound study the details in the medical field and the field of diseases in general.
Prophylaxis with warfarin significantly, and cost-effectively, reduced the incidence of VTE compared to placebo, with no increased risk of major bleeding. Despite these interesting findings, additional studies are required before recommendations can be made regarding thromboprophylaxis use in cancer patients receiving chemotherapy.
Hormonal manipulation also affects the thrombosis risk. The rate of VTE increases by twofold to fivefold among women whose breast cancer has been treated with the selective estrogen receptor modulator tamoxifen. This risk was greater in postmenopausal women and when tamoxifen was combined with chemo-therapy. In a double-blinded clinical trial of the primary prevention of breast cancer, 13,000 women were randomized to receive tamoxifen or placebo for 5 years. The risk of DVT was increased in the tamoxifen group compared with those receiving placebo (0.13% vs 0.08% per year, respectively), as was the risk of PE (0.07% vs 0.02% per year, respectively). 
The use of the aromatase inhibitor anastrozole is associated with approximately half the risk of VTE compared with that for tamoxifen use. In a clinical trial of 1,017 women with advanced breast cancer who were randomized to receive tamoxifen or anastrozole, the respective rates of VTE were 6.5% and 3.6%, respectively, after a median follow-up period of 18 months. Among > 6,000 postmenopausal women with early breast cancer who were followed up over a median duration of 33 months, VTE occurred in 5.3% of those treated with tamoxifen, and in 3.1% of those treated with anastrozole. We are not aware of any clinical trials that have studied the use of VTE prophylaxis among cancer patients receiving hormonal manipulation therapy.
Several studies have assessed the role of anticoagulants in the primary prevention of VTE in cancer patients without another indication for anticoagulant therapy. In stage IV breast cancer patients, low-dose warfarin therapy (INR range, 1.3 to 1.9) reduced the risk of VTE when used in the long term.
However, in the Fragmin Advanced Malignancy Outcome Study (FAMOUS), in which 382 patients with advanced cancer received dalteparin, 5,000 U SC once daily, or placebo for approximately 9 months, the rates of symptomatic VTE did not differ significantly (3.4% vs 2.4%, respectively). Since VTE was a secondary end point in this study, it may have been underpowered to detect this outcome. For the primary outcome, survival at 1 year, there was also no significant improvement with the long-term use of LMWH.
The presence of a CVC is an independent risk factor for upper extremity DVT in the general population. It is also well-known that cancer patients with indwelling CVCs sometimes develop symptomatic thrombosis of the axil-lary/subclavian veins, producing arm swelling and discomfort, predisposing them to catheter-related sepsis and the need to replace the catheter.
For the prevention of CVC-associated VTE, prophylaxis with fixed-dose warfarin, 1 mg daily, was compared to no prophylaxis in one clinical trial. Using screening venography of the upper limb at 90 days, DVT was reduced from a rate of 37.5% among control subjects to 9.5% among warfarin recipients. However, two subsequent clinical trials failed to show any benefit from a 1-mg daily dose of warfarin compared to no prophylaxis.
The safety of unmonitored mini-dose warfarin in cancer patients is also questionable. For example, among 95 patients with central lines for chemotherapy who were given warfarin, 1 mg daily, 33% had an INR of > 2.0, 27% had an INR of > 3.0, and 7% had an INR of > 5.0. Bleeding was observed in eight patients, seven of whom had an elevated INR.
LMWH also has been assessed for the prevention of catheter-associated thrombosis. In one study, cancer patients with CVCs were randomly allocated to receive dalteparin, 2,500 U SC once daily, or no prophylaxis for 90 days, followed by upper extremity venography. The study was prematurely stopped after 8 of 13 control patients developed thrombosis compared to only 1 patient assigned to receive LMWH (p = 0.002).
These findings were challenged by those of another clinical trial in which 425 cancer patients receiving chemotherapy through a CVC were randomized to receive dalteparin, 5,000 U SC once daily, or placebo. Clinically relevant VTE occurred in 3.7% and 3.4%, respectively, of the dalteparin and placebo recipients. To date, this study has been presented only in abstract form. Although this area remains controversial, neither mini-dose warfarin nor prophylactic LMWH can be recommended as prophylaxis for cancer patients with indwelling CVCs.
Furthermore, the incidence of venous thrombosis requiring catheter removal was only 3.4% (1.14 per 1,000 catheter-days) among 351 patients with a peripherally inserted central catheter who were not receiving thromboprophylaxis. These studies suggest that the risk of clinically important VTE related to CVCs may be too low to warrant routine prophylaxis.
In summary, the appropriate thromboprophylaxis of hospitalized cancer patients with additional VTE risk factors provides an important opportunity to reduce the burden of this disease. The prevention of VTE in these patients is important, not only because cancer patients have a particularly high risk for VTE, but also because VTE is often more difficult to diagnose in oncology patients, and the treatment of VTE may be less effective, and associated with more bleeding complications.
Cancer patients undergoing surgery should receive aggressive thromboprophylaxis, as recommended in the sections on general, gynecologic, urologic, and neurologic surgery in this article. Cancer patients who are immobile or are bedridden with an acute medical illness also should receive prophylaxis using the guidelines for medical patients. However, we do not believe that ambulatory cancer patients require VTE prophylaxis.
