HAMILTON, ONTARIO—Today, most patients diagnosed with acute venous thromboembolism (VTE) are treated initially with unfractionated heparin or low-molecular-weight heparin (LMWH) and then given long-term oral anticoagulant therapy. But this is not an ideal regimen for cancer patients, in whom controlling levels of an orally administered anticoagulant can be difficult. Reasons include the drug interactions, malnutrition, vomiting, and liver dysfunction associated with cancer treatment; the interruptions in therapy due to chemotherapy-induced thrombocytopenia; and poor venous access, which can compound these problems by making laboratory monitoring difficult. However, many of the properties of LMWHs, especially injectability and pharmacokinetic predictability, make them desirable in this setting.

Thus, a team of investigators from McMaster University in Hamilton, Ontario, led by Agnes Y. Lee, MD, sought to determine whether secondary prophylaxis with the LMWH dalteparin might provide a more effective, practical alternative for cancer patients with acute VTE. Their findings, published in a recent issue of the New England Journal of Medicine, show that dalteparin monotherapy reduces the risk of recurrent VTE by 52% compared with prophylaxis with a coumarin derivative.1 The new treatment was not associated with an increased risk of bleeding.

A MORE EFFECTIVE ALTERNATIVE

“This is a very important advance in the supportive care of cancer patients,” Dr. Lee said, emphasizing that current VTE rates in these patients are unacceptable—about one in 200 will develop a VTE, and about one in four will in turn develop a VTE recurrence despite receiving oral anticoagulant therapy. “Recurrent VTE not only compromises the patient’s quality of life even further, but may interfere with cancer treatment, lead to more [frequent] hospitalization, and escalate health care costs,” Dr. Lee explained. By safely preventing VTE events as well as eliminating the need for painful venipunctures and routine laboratory visits, dalteparin may help to address these issues.

The study was a multicenter, open-label trial that took place at 48 clinical centers in eight countries. All of the enrolled patients were adults with active cancer (other than skin cancer) and newly diagnosed, symptomatic, proximal deep venous thrombosis (DVT), pulmonary embolism (PE), or both. They were randomly assigned to receive either subcutaneous dalteparin (200 IU/kg once daily for five to seven days) plus an oral coumarin derivative (warfarin or acenocoumarol, within 24 hours for six months) or dalteparin only (200 IU/kg once daily for the first month, followed by a daily dose of about 150 IU/kg for five months).

The primary outcome of interest was episodes of symptomatic, recurrent VTE. Secondary measures included clinically overt bleeding (major and any) and death. To minimize any potential biases of the study’s open-label design, the researchers monitored participants closely, objectively investigated all reported events, and had all of the suspected outcomes evaluated by a central committee whose members were unaware of the patients’ treatment assignments. The mean duration of treatment was 125 days in the dalteparin group and 115 days in the oral anticoagulant group.

Twenty-seven of the 336 patients in the dalteparin group and 53 of the 336 patients in the coumarin group had a recurrent thromboembolic event (hazard ratio for the comparison, 0.48; P = .002). The respective probabilities of recurrent thrombosis at six months were 9% and 17%.

ADEQUATE ANTICOAGULATION

According to the investigators, several lines of evidence suggested that the patients receiving the coumarin derivative had adequate anticoagulation and that the recurrent VTEs seen developed despite the maintainance of acceptable international normalized ratios (INRs). First, the target INR goal was met (mean, 2.5 ± 0.75) and the INR was estimated to be in the therapeutic range a satisfactory 46% of the time (it was below this range 30% of the time and above it 24% of the time). Second, the recurrent VTE rate in the coumarin group was comparable to rates reported in large, prospective cohort studies. Furthermore, VTE events occurred even when the INR was above 2.0 (60% of the recurrences).

Major bleeding (defined as that associated with death, occurring at a critical site, resulting in transfusion of at least two units of blood, or leading to a drop in hemoglobin of at least 2.0 g/dL) was observed in 19 patients in the dalteparin group and in 12 patients in the oral-anticoagulant group; the difference, however, was not significant. There was a minor, though statistically insignificant, difference between the groups in the rate of any bleeding (14% and 19%, respectively).

As with the occurrence of thromboembolic events, major bleeding tended to happen when physiologic control was compromised. For example, two patients in the dalteparin group were thrombocytopenic at the time of major bleeding, and six patients in the oral anticoagulant group had an INR of more than 3.0.

CLEARLY “SUPERIOR”

At randomization, the majority of patients in both groups had metastatic disease (67%) originating from a solid tumor. The breast was the most common primary site, followed by the colorectal area, the lung, and the genitourinary tract.

Dr. Lee said that it is unlikely that the efficacy of dalteparin varies with tumor type, but she acknowledged that her group’s study was not designed or powered to address this question. “It was very clear, however, that dalteparin was superior to oral anticoagulant in patients with metastatic disease,” Dr. Lee added, given the strength of the association (P < .005; unpublished data).

Mortality at six months was slightly lower in the dalteparin group than in the oral anticoagulant group (130 deaths versus 136 deaths; respective rates, 39% and 41%). However, 90% of the deaths in each group were due to progressive cancer, and the between-group differences were not statistically significant.

Dr. Lee stated that a post hoc analysis, as well as new evidence from randomized placebo-controlled trials, showed that certain LMWHs improve survival in cancer patients without metastatic disease. Research will be required “to confirm these provocative findings,” she said. For now, the superior efficacy of dalteparin lies in its immediate quality-of-life benefits.

—Verna L. Schwartz, MS

Reference
1. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003; 349:146-153.

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