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PRIORITY PRESS - 51st Annual Meeting of the American Society of Hematology

New Orleans, Louisiana / December 5-8, 2009

Both cancer and its treatments induce a hypercoagulable state that raises the risk of venous thromboembolism (VTE), including the risk for symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE). The evidence that VTE, which is one of the most significant causes of in-hospital mortality, occurs in up to 20% of hospitalized cancer patients has led to a series of published guidelines to encourage physician intervention. The consensus among guidelines is strong, including general agreement on the duration of prophylaxis, choice of preferred treatment and appropriate steps for treatment when VTE occurs.

Consensus Among Guidelines

“VTE is very common across a broad range of cancers and the risk is exacerbated by many types of cancer therapies. What the guidelines tell us is that prophylaxis is needed and that low molecular-weight heparins (LMWH) are the appropriate first-line agents,” stated Dr. Ajay Kakkar, Thrombosis Research Unit, Barts and the London School of Medicine, London, UK. Although there is an exception for patients at high risk of bleeding events, Dr. Kakkar cited overwhelming evidence of benefit from anticoagulation studies using unfractionated heparin (UFH) and LMWH. When the two are compared, once-daily LMWH does at least as well as three times daily UFH “whatever the end point we use,” such as VTE, DVT, PE or death.

The ASCO guidelines published two years ago (Lyman et al. J Clin Oncol 2007;25:5490-505) are now supported by guidelines from, among others, the European Society of Medical Oncology (ESMO), the National Comprehensive Cancer Network (NCCN) and the American College of Chest Physicians (ACCP). When members of these guideline panels as well as others, such as the French and Italian national oncology organizations, recently convened to discuss commonalities and disagreements, the consensus was that all hospitalized (but only selected ambulatory cancer patients) should receive VTE thromboprophylaxis (Khorana et al. J Clin Oncol 2009;27:4919-26). LMWH was uniformly identified as the preferred method of thromboprophylaxis.

Corroborative Findings on VTE Prophylaxis from the Literature

In general, the studies associating thromboprophylaxis with benefit in medically treated patients is derived from investigations that included both cancer and non-cancer patients. One of these, called PREVENT (Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial), associated the LMWH dalteparin with a 45% (P=0.0015) reduction in the risk of VTE with a very low increased risk of bleeding (Leizorovicz et al. Circulation 2004;110:874-9). Another, called MEDENOX (MEDical Patients With ENOXaparin), showed similar benefit with the LMWH enoxaparin (Samama et al. N Engl J Med 1999;341:793-800). When patients were stratified by underlying condition, protection against VTE from LMWH relative to placebo was at least as good in cancer patients as in the whole population.

In the surgical population, the literature showing benefit from thromboprophylaxis is even more persuasive and includes some studies conducted specifically in cancer patients. For example, UFH reduced the risk of PE by 85% in patients with malignant disease undergoing surgery in a study conducted more than 30 years ago (Kakkar et al. Lancet 1975;2(7924):45-51). Studies repeated with LMWH agents have demonstrated similar clinical risk reductions. In a dose-ranging study that included 1303 surgical patients with malignancy, the low rate of DVT on 2500 IU of dalteparin was even lower on a dose of 5000 IU (8.5% vs. 14.9%; P=0.001) even though bleeding was not increased significantly (Bergqvist et al. Br J Surg 1995;82:496-501). In a Canadian study comparing 5000 U heparin three times per day to 40 mg enoxaparin once daily in patients undergoing colorectal surgery, VTE rates were lower on the LMWH, approaching clinical significance (13.9% vs. 16.9%; P=0.05), while the major bleeding rates also did not differ significantly (McLeod et al. Ann Surg 2001;233:438-44).

Treatment Protocols and Timelines

While thromboprophylaxis with a LMWH agent should be offered to any hospitalized cancer patient for the duration of their admission, it should be continued for seven to 10 days after surgery in all patients and for longer in special high-risk groups, such as those with major abdominal and pelvic surgery, patients with residual disease, patients with obesity and patients with a previous history of VTE, according to Dr. Kakkar. He recommended up to four weeks of LMWH whether or not the patient remains in hospital. Mechanical prophylaxis can be combined with LMWH, particularly in very high-risk patients, but Dr. Kakkar emphasized that it is not a substitute for LMWH except in patients contraindicated for LMWH because of active bleeding.

For treatment of VTE in a cancer population, LMWH is not only more convenient than alternatives but more effective. This not only includes a reduced risk of VTE relative to UFH but a survival benefit. In a meta-analysis, mortality on LMWH vs. UFH was reduced by 38% (OR 0.62; 95% CI, 0.46-0.84) (Cochrane Syst Rev 2004;4:CD001100). When compared to warfarin, LMWH agents also generally perform better for long-term risk prevention. Although a trend for protection against recurrent VTE fell just short of significance in a study that compared enoxaparin to warfarin (10.5% vs. 21.1%; P=0.09) in a study of 138 patients (Meyer et al. Arch Intern Med 2002;162:1729-35), the difference between dalteparin and warfarin for recurrent VTE (9% vs. 17%; P=0.002) was highly significant in a study of 672 patients (Lee et al. N Engl J Med 2003;349:146-53).

Whether it is a question of efficacy or simply the difficulty of maintaining patients in the therapeutic range, “about one-third of patients with cancer will have some kind of treatment failure on warfarin,” stated Dr. Agnes Y.Y. Lee, Medical Director, Thrombosis Program, Vancouver General Hospital, University of British Columbia. She noted that warfarin is labour-intensive and has been shown to reduce patient quality of life simply because of the need for frequent monitoring. Another reason that large organizations have endorsed LMWH as the preferred drug class is that these agents do not interact with cancer treatment. Other anticoagulants, such as the factor Xa inhibitor fondaparinux or the new oral direct Xa inhibitors such as rivaroxaban, have either not been shown to offer greater efficacy than UFH or warfarin or they have not yet been studied in cancer patients.

Currently, the ACCP recommends at least three months of LMWH for treatment of VTE in cancer patients while ASCO recommends at least six months, but Dr. Lee reminded delegates that there is no clinical trial evidence that establishes when there may no longer be a benefit from VTE prophylaxis. Rather, the evidence suggests that the risk of recurrent VTE persists as long as patients remain on thrombogenic cancer therapies or who have active disease. Although Dr. Lee recommended discontinuing prolonged therapy if the risk of serious bleeding is thought to outweigh the risk of VTE recurrence, she reported that many experts now believe indefinite LMWH therapy as prophylaxis against recurrence may be appropriate.

“We have no data, but common sense suggests that anticoagulation should be continued as long as cancer is active or the patient remains on chemotherapy,” Dr. Lee confirmed. However, she also suggested that therapy should be individualized relative to risk of VTE events and to bleeding risk.

Summary

The fact that cancer induces a hypercoagulable state has been recognized for more than 100 years, but VTE is a growing source of life-threatening complications partly because of success in cancer control. As patients with more advanced disease are surviving longer, often on chronic regimens of highly thrombogenic chemotherapies, including newer anti-angiogenic agents such as bevacizumab, the incidence of VTE is increasing. This has been the impetus for ASCO and other large organizations involved in identifying standards of care to develop specific guidelines for prophylaxis and treatment. For prophylaxis, all hospitalized cancer patients should receive pharmacologic protection with longer regimens for those undergoing surgery. For those who develop VTE, treatment regimens should be continued for as long as the patient has active disease. In both cases, LMWH is the preferred anticoagulant.