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VTE prophylaxis in ambulatory patients with cancer
The increased risk of venous thromboembolism in patients with cancer is well known. Depending on the source, the incidence varies partly due to different diagnostic methods, but ranges up to 20%. This represents a twofold to sevenfold increase in risk compared to patients without cancer. The rate of VTE diagnosed at autopsy ranges up to 50% in patients with cancer. VTE is a major complication of cancer and one of the leading causes of death in patients with cancer. In addition, VTE in patients with cancer increases the costs of care for both inpatient and outpatient. Patients with cancer have a higher risk of recurrent VTE and of treatment-related bleeding complications compared to patients without cancer.
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Risk factors for VTE in patients with cancer are related to the patient, the malignancy and the cancer treatment. Patient-related risk factors include increasing age, obesity, prior history of VTE, inheritable prothrombotic mutations and others. Malignancy-related risk factors include the type of cancer (especially pancreatic, lung, brain, gynecologic cancers and others) and the presence of metastatic disease. Cancer-treatment related risk factors include recent major surgery, immobility, current hospitalization, use of erythrocyte-stimulating agents, presence of a central venous catheter and chemotherapy treatment. The increased risk for VTE has been described for usual cytotoxic chemotherapy as well as with hormonal therapy and antiangiogenic agents.
Chemotherapy and VTE
Several studies have documented an increased risk of VTE in chemotherapy-treated patients compared to patients with cancer not undergoing chemotherapy. In one study, the rate of VTE was fourfold higher in patients with cancer (compared to patients without cancer) and was sixfold higher in patients with cancer receiving chemotherapy. In another study, researchers found a twofold increase in the risk of recurrent VTE in patients with cancer and a fourfold increase in the risk in patients with cancer receiving chemotherapy. This increased risk has been described when using chemotherapy regimens containing cisplatin, fluorouracil, asparaginase, bleomycin, mitomycin and regimens for HSCT, as well as others. Mechanisms whereby chemotherapy could increase the VTE risk include blood vessel wall damage, increased expression of tissue factor, an increase in procoagulant substances and/or a decrease in natural anticoagulants, as well as other potential mechanisms.
Angiogenesis inhibitors such as thalidomide, lenalidomide and bevacizumab (Avastin, Genentech) are associated with an increased thrombotic risk. With thalidomide and lenalidomide, the rate of VTE ranges from 10% to 40% when used in conjunction with dexamethasone or chemotherapy. The reason for such elevated rates with these therapies is not fully understood. Bevacizumab, a VEGF inhibitor, has also been associated with elevated VTE rates (twofold higher than controls in one study).
Hormonal treatments for cancer can increase the VTE risk for patients. Patients treated with tamoxifen have a much higher VTE rate than control patients and the rate for patients treated with both tamoxifen and chemotherapy is higher yet. Aromatase inhibitors also produce a higher risk, although the risk is lower than that seen with tamoxifen.
Other agents often used in conjunction with chemotherapy, such as hematopoetic growth factors and erythrocyte stimulating agents, have also been associated with elevated VTE risks.
Prophylaxis
Primary prophylaxis using heparin or LMWHs have been shown in many studies to reduce VTE risk in patients with cancer undergoing major surgical procedures or while hospitalized for an acute medical illness. In most studies, the risk reduction is about 50%, independent of anticoagulant agent and type of hospitalization (surgical or medical). Heparin, all the LMWHs (enoxaparin, dalteparin, tinzaparin) and fondaparinux are all considered to have equivalent activity in primary VTE prophylaxis. Prolonged posthospitalization primary prophylaxis (four weeks) has been shown to be effective in certain high-risk cancer populations.
For patients receiving thalidomide or lenalidomide with corticosteroids or chemotherapy, studies do recommend primary VTE prophylaxis with a LMWH or adjusted-dose warfarin (to achieve INR of about 1.5). Until recently, data regarding primary prophylaxis for other ambulatory patients with cancer have been lacking.
In a recent trial, published in abstract form (Agnelli, 2008) researchers studied primary VTE prophylaxis in ambulatory patients with cancer. This group randomly assigned 1,150 patients in a 2:1 ratio to prophylaxis with nadroparin for the duration of chemotherapy (up to four months) vs. placebo. These patients all had metastatic or locally advanced cancer (lung, breast, gastric, pancreatic, colorectal, ovarian or head and neck cancer). The most common types of cancer seen were lung, breast and colorectal cancer. Nadroparin, a LMWH available in Europe under the brand name Fraxiparin, was started with the initiation of a new chemotherapy course. The dose was 3,800 U subcutaneously once daily, which is in the range of prophylaxis dosing for this agent. Nadroparin has a two-hour to five-hour half-life, which is prolonged in those with renal impairment. The primary outcome measure of this study was a composite of clinically overt venous or arterial thrombosis. The average study duration seen was about three months. The outcome and safety measures are shown in table 1.
This study, like others in primary prophylaxis in hospitalized patients with cancer, shows about a 50% reduction in VTE risk when a LMWH is used. At first glance, the incidence rate and the absolute risk reduction do not seem dramatic. The number needed to treat (NNT) in this study was 54, meaning that 54 patients were given prophylaxis in order to prevent one VTE episode during this four-month period. This compares to NNT values in the nine to 10 range for studies of primary prophylaxis in hospitalized patients with cancer. Since the elevated VTE risk in patients with cancer does not diminish over time, the NNT might be smaller with a longer study period. The rates of major and minor bleeding complications were not statistically different. The number needed to harm (NNH) was 154, meaning that there was one major bleeding complication for every 154 patients receiving prophylaxis. The number might be higher for a longer study period. The VTE incidence was particularly high for patients with lung and pancreatic cancers. The NNT for patients with lung cancer was 23.
The potential adoption of this prophylactic therapy will depend on confirmatory studies using LMWHs commercially available in this country, perhaps of longer study duration. In addition, there are other questions to consider in the risk-and-benefit analysis. Is a NNT of 54 low enough to represent a reasonable treatment option? Will patients be able to afford the medication and co-pay costs of this therapy? Are there subsets of high-risk patients that would benefit more from prophylaxis? What are the costs of treating and preventing recurrent VTEs that might otherwise have been prevented with primary prophylaxis? Although low, is the risk of bleeding complications too high in this ambulatory cancer patient population? Further research in VTE prophylaxis should help answer these questions.
Lisa K. Lohr, PharmD, BCPS, BCOP, is a Clinical Pharmacist in Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center and is a HemOnc Today Editorial Board member.
For more information:
- Blood. 2008;112:Abstract 6.
- Chest. 2008;133:381-453.
- J Clin Oncol. 2007;34:5490-5505.
- Thromb Res. 2006;118:555-568.
- Wagman LD, et al. Venous thromboembolic disease. V.2.2008. National Comprehensive Cancer Network. www.nccn.org.