CHICAGO – Prophylaxis with semuloparin, an experimental ultralow-molecular-weight heparin, achieved a significant 64% reduction in relative risk for venous thromboembolism events among cancer patients undergoing chemotherapy in a large, randomized, double-blind, phase III trial called SAVE-ONCO.
An intent-to-treat analysis found that the rate of venous thromboembolism (VTE) events – a composite of symptomatic deep vein thrombosis, any pulmonary embolism, and VTE-related death – was 1.2% in patients treated with semuloparin vs. 3.4% in a control group treated with placebo (hazard ratio, 0.36; P less than .0001).
Dr. Daniel J. George
Benefits trended in favor of semuloparin for all components of the composite end point, including any pulmonary embolism (odds ratio, 0.41) and VTE-related death (OR, 0.77), reported Dr. Daniel J. George, who presented the paper on behalf of Dr. Giancarlo Agnelli of Perugia (Italy) University at the annual meeting of the American Society of Clinical Oncology.
Although the incidence of clinically relevant bleeding was higher at 2.8% with semuloparin vs. 2% for placebo, Dr. George added that a safety analysis found that the incidence of major bleeding was similarly low, at 1.2% and 1.1%, respectively.
Based on the trial results, Dr. Elias Zerhouni, president of global research and development at trial sponsor Sanofi-Aventis, announced that the company plans "to submit semuloparin for regulatory filing" in the third quarter of 2011. Still investigational, the selectively engineered anticoagulant has high anti–coagulation factor Xa activity and minimal anti–coagulation factor IIa activity with a half-life of 16-20 hours.
Although it is advocated for cancer patients who are hospitalized or undergoing surgery and is not contraindicated for anticoagulation, the routine prophylaxis of ambulatory cancer patients receiving chemotherapy is not currently recommended.
"So this leaves us with the question, Which cancer patients should we now consider for thromboprophylaxis?" said Dr. George of Duke University Medical Center in Durham, N.C. "Already our guidelines suggest that those patients with cancer undergoing major surgery, or hospitalized, or acutely ill, ought to be anticoagulated with low-molecular-weight heparin during those periods of time.
"I would now submit that the SAVE ONCO data would support having patients initiating chemotherapy, in the setting of locally advanced or metastatic disease, as a third population that we could consider for thromboprophylaxis," he said.
Although discussant Dr. Vered Stearns of Johns Hopkins University in Baltimore viewed the findings favorably, she cautioned that "SAVE-ONCO should not change current practice for the overall population."
Dr. Stearns emphasized that predictive models are needed to determine which ambulatory patients are at the highest risk for VTE, "and who should be offered prophylaxis in the context of expected clinical outcomes." Biomarkers such as circulating coagulating factors are also important, she added.
"Semuloparin is an efficacious and safe agent. That’s very exciting," Dr. Stearns said. "The reduction in [VTE] events is consistent throughout the report, and my understanding is [that] the group is conducting subgroup analysis and evaluation of predictive markers that may help us select the population that would benefit from primary prophylaxis."
A multinational study, the SAVE-ONCO trial enrolled 3,200 patients who were at high risk of VTE. Participants had metastatic or locally advanced solid tumors such as lung, pancreas, stomach, colon/rectal, bladder, or ovarian tumors for which they were starting a new course of chemotherapy with minimum treatment intent of 3 months.
Patients were randomized 1:1 to standard-care chemotherapy plus either placebo or semuloparin 20 mg subcutaneously once daily for the length of their chemotherapy.
Patient characteristics were well balanced across both arms: The median age was 60 years, and 60% of patients were men. More than two-thirds had metastatic disease. Lung cancer was the most common tumor type (36%) followed by colon/rectal cancer (28%). The remainder had cancer of the stomach, ovary, pancreas, or bladder. Treatment duration was approximately 3.5 months in both groups.
In response to audience questions, Dr. George said that the study did not show a survival benefit, but "there is likely a subset of patients" for whom this made a dramatic impact in their early morbidity and mortality.
The study did not address cost, but that will be a factor if prophylaxis is introduced for a large population of cancer patients, he acknowledged, "It really comes down to safety and cost," he said.
The study was sponsored by Sanofi-Aventis. Dr. George disclosed numerous relationships with pharmaceutical companies, including consultant or advisory role, honoraria, and speakers bureau with Sanofi-Aventis. Dr. Agnelli disclosed receiving honoraria from Sanofi-Aventis and relationships with other companies. Dr. Stearns disclosed honoraria and research funding from other companies.