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MEDICAL FRONTIERS - 52nd Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 4-7, 2010

The failure of clinicians to provide guideline-mandated venous thromboembolism (VTE) prophylaxis in the recommended doses and duration is an increasingly significant gap in clinical care because of rising rates of VTE and its complications. While several guidelines, including those from the National Comprehensive Care Network (NCCN) and the American Society of Clinical Oncology (ASCO), recommend thromboprophylaxis for all hospitalized patients and many non-hospitalized patients with active cancer who do not otherwise have contraindications, studies consistently demonstrate that large numbers of patients go unprotected.

Identifying Patient Candidates for VTE Prophylaxis

Efforts to risk-stratify patients are being undertaken to draw attention to those at greatest risk for pulmonary embolism (PE) and deep-vein thrombosis (DVT) that can alter outcome. “Cancer patients are at high risk for VTE but receive less prophylaxis than any other at-risk group of hospitalized patients,” stated Dr. Samuel Z. Goldhaber, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

Leading a symposium on the close connection between cancer and thrombosis at the ASH meeting, Dr. Goldhaber reported an uphill struggle to improve VTE prophylaxis at his own hospital despite its reputation as a leading teaching institution. In a trial he helped design, software was programmed to identify acute care patients at his hospital who were candidates for VTE prophylaxis in order to test whether an alert message would change physician behaviour.

“We should have zero patients who were eligible. After all, the program just identified those that met current guideline criteria for VTE prophylaxis. Instead we found 2500 patients who were not receiving appropriate prophylaxis,” Dr. Goldhaber told delegates. He stressed that this was not a study to test the benefits of VTE prophylaxis, which have already been proven, but to evaluate whether a change in clinician behaviour could change outcome.

In fact, the incidence of DVT and PE was reduced by 40% with this alert system (Figure 1). In the substantial proportion of physicians who did not prescribe prophylaxis, according to Dr. Goldhaber, a related study demonstrated that although they did believe that prophylaxis prevents VTE, there was concern about bleeding. But Dr. Goldhaber remarked that the benefit of prophylaxis is evidence-based, while the data do not support a major bleeding risk. Several participants in the same symposium reiterated this message.

Figure 1.

“Many oncologists report that they are not offering anticoagulants because they are worried about bleeding, but they need to rethink this,” stated Dr. Craig Kessler, Department of Hematology, Georgetown University Medical Center, Washington, DC. He cited 6 placebo-controlled trials evaluating low molecular-weight heparins (LWMH) for VTE prophylaxis in cancer patients. With the exception of a study conducted in glioma patients, for which bleeding rates were higher on LMWH (5.1% vs. 1.2%), none showed a major increase in bleeding on active therapy. Of the relative differences in bleeding, the largest difference was a study that found higher rates of bleeding on placebo (7.1% vs. 2.9%) (Sideras et al. Mayo Clin Proc 2006;81:758-67). Yet VTE rates were reduced by as much as 50% in these trials.

VTE Risk in Cancer Patients

Cancer patients have represented about 15% of those randomized in the 3 largest studies demonstrating the benefit of VTE prophylaxis in acutely ill hospitalized patients. These studies—MEDENOX evaluated enoxaparin, PREVENT evaluated dalteparin and ARTEMIS evaluated the factor Xa inhibitor fondaparinux—all associated active therapy with large reductions in VTE rates relative to placebo. However, cancer in general, and some types of cancer specifically, appear to pose a risk for VTE that may be greater than that created by diminished mobility and a procoagulant state of acute illness. Of the agents evaluated, dalteparin is the only anticoagulant with a specific indication for the treatment of VTE and for secondary VTE prophylaxis in cancer patients. It has been evaluated in both primary and secondary prevention, and it is listed in the ASCO guidelines as the preferred agent for DVT prevention in cancer patients. Guidelines from the American College of Chest Physicians (ACCP) have cited studies with dalteparin as well as other anticoagulants in providing a grade 1A recommendation for VTE prophylaxis in bedridden cancer patients and cancer patients undergoing a surgical procedure.

“VTE in cancer is a different disease than it is in other illnesses associated with acute hospitalizations,” Dr. Kessler maintained. Citing data that VTE can be identified in 20% of cancer patients and at autopsy in 50% of cancer patients who died of their malignancy, he noted that 10% of patients with idiopathic VTE develop cancer within 2 years, suggesting that malignancy itself creates a procoagulant state (Table 1). When calculating probability of death within 180 days after any hospitalization, DVT or PE raises the risk to nearly 30%. Although this is slightly below the nearly 40% risk of death associated with malignant disease, the 180-day mortality exceeds 90% in those with b
gnancy.

Table 1.

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“The question is whether activation of blood coagulation affects the biology of cancer, and we do not have that answer, but the epidemiologic evidence is suggestive that VTE is a bad prognostic sign, and the experimental evidence supports the hypothesis that antithrombotic strategies inhibit tumour growth,” reported Dr. Frederick R. Rickles, Professor of Pharmacology, George Washington University, Washington, DC. He evaluated evidence that tissue factor, which is critical to thrombin formation, helps regulate angiogenesis and generates clotting. He cited several potential interactions of cancer and clotting. For example, thrombosis appears to induce angiogenesis and induce tumour cells to migrate away from a central hypoxic zone, a potential mechanism for formation of metastases.

Individual studies of LMWH in patients with cancer have yet to show an independent survival benefit from this therapy, but a meta-analysis of 4 LMWH studies cited by Dr. Rickles did associate a significant 12% (P=0.015) reduction in mortality at 1 year (Kuderer et al. Cancer 2007;110:1149-60). The meta-analysis of 9 studies in the same publication did not associate warfarin with a mortality benefit, although a combination of all anticoagulation studies did demonstrate significance (P=0.003). Studies more specifically designed to evaluate the ability of LMWH to improve survival in cancer patients, including a study called FRAGMATIC testing dalteparin in newly diagnosed lung cancer patients, are underway and may resolve whether LMWH agents can reduce mortality when properly dosed in an adequately powered trial.

One of the most significant studies to demonstrate the benefit of LMWH and its superiority to warfarin compared these strategies as secondary prevention in cancer patients with recurrent VTE. In this study, called CLOT (Comparison of Low molecular weight heparin versus Oral anticoaguLant Therapy), the probability of a recurrent thromboembolism was reduced by 52% (HR 0.48; P=0.002) for dalteparin relative to warfarin over 6 months of follow-up (Lee et al. N Engl J Med 2003;249:146-53). There was no significant difference in the rate of major bleeding or bleeding of any kind. The mortality was lower but not significantly different in the dalteparin arm (39% vs. 41%).

Importance of Cancer Site and Other Risk Predictors

Despite the guidelines, one hesitation for not administering VTE prophylaxis or for providing prophylaxis at low doses or for shorter periods than that recommended is that only a minority of cancer patients eventually develop a clinically significant clot. This has led to substantial efforts toward better risk stratification to increase the rate of prophylaxis among those who need it most. For example, site of cancer appears to be important. In one study, the OR of developing a VTE was relatively low in prostate (2.2%) and breast (4.9%) cancers but climbed steeply in cancers of the gastrointestinal tract (20.3%) and lung (22.2%) (Blom et al. JAMA 2005;293:715-22). It is notable that hematologic cancers, for which the OR was a reported 28.0, pose one of the greatest risks for VTE.

“Subgroups of cancer patients at high risk for VTE can be identified based on clinical risk factors and biomarkers, and I think these may be important for drawing attention to those who are in urgent need of anticoagulant therapy,” stated Dr. Alok A. Khorana, Vice-Chief, Division of Hematology/Oncology, Wilmot Cancer Center, University of Rochester, New York. According to Dr. Khorana, a risk model with 5 factors that was developed at his institution is among those validated for risk prediction. The 5 factors are elevated platelet count, low hemoglobin levels, elevated leukocyte count, obesity and the site of cancer (for which the highest scores were given to cancers of the stomach or pancreas) (Khorana et al. Blood 2008;111:4902-7).

While these and comparable ongoing efforts are expected to be useful for identifying cancer patients at high risk for their first VTE, there is also work being performed to risk-stratify patients who may require more aggressive anticoagulation after an initial VTE.

New data presented at the ASH meeting by a Canadian team of investigators led by Dr. Martha L. Louzada, Division of Hematology, University of Western Ontario, London, suggest that risk scoring may be useful. In their study, VTE recurrence among 543 cancer patients was reviewed retrospectively. Of these, 55 had a VTE recurrence. On multivariate analysis, gender, primary tumour site, tumour stage and history of prior VTE were significant variables and used to develop a risk scoring method.

“A better understanding of the patient characteristics that influence the risk for recurrence may enable tailored treatment for the patient with cancer-associated VTE,” Dr. Louzada explained. Assigning numerical scores to these risk factors, she reported that 48% of the patients in her study population had a risk score of =0, which was associated with a VTE recurrence of 4.5%. In contrast, those with a score of =1 had a VTE recurrence of 19% or higher. Although she called for further validation studies, she suggested that this approach might be relevant to individualize anticoagulation therapy.

Weight-based Dosing Option

One way to tailor therapy would be to employ weight-based dosing. Although LMWH, unlike warfarin, does not require monitoring of prothrombin time, weight-based dosing has the potential to both increase efficacy in heavier patients and reduce bleeding risk in patients of lower weight. This approach has been facilitated, particularly in the outpatient setting, by premeasured vials that can be prescribed according to weight. Simple methods like this may encourage physicians to prescribe anticoagulation treatment more readily while improving compliance among patients who self-administer the therapy. While these benefits have not been demonstrated in a trial, strategies of this kind are being pursued because of the frequency with which those most in need of VTE prophylaxis are not receiving therapy.

“The ACCP guidelines state that every hospital should develop a formal strategy to prevent VTE, but this is not being done uniformly,” reported Dr. Goldhaber, who foresees several trends conspiring to exacerbate the problem without a change in orientation. Relative to non-cancer hospitalized patients, where rates of VTE have remained relatively constant over the past 20 years, the rates in cancer patients, which have always been higher, have climbed substantially. Until relatively recently, cancer patients typically responded to their anti-cancer therapy or died, so the risk of VTE was limited (Figure 2). Currently, particularly with new targeted agents that control tumour growth, patients are experiencing extended periods of survival with active cancer. In these patients, VTE may be a threat to an otherwise favourable prognosis.

“As cancer therapies improve, quality life-years will be extended, and treatments for the complications of cancer, including VTE, wil
ce for optimal care,” Dr. Goldhaber told delegates.

Figure 2.

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Summary

Current guidelines mandate use of anticoagulants in patients hospitalized with cancer as well as in cancer patients who remain at high risk for VTE after discharge. The preferred therapy is LMWH, of which dalteparin is the only approved agent. LMWH has been shown to be more effective than warfarin for preventing recurrent VTE. The major obstacle to VTE prevention is physician compliance to guidelines and several initiatives have been developed to alter behaviour, including hospital-based strategies to raise rates of prescriptions in appropriate candidates. While more education about the evidence-based value of LMWH for VTE prophylaxis in cancer patients is needed, risk stratification strategies are being pursued to help physicians recognize those patients most in need of protection.