Semuloparin, an ultralow-molecular-weight heparin, reduced the incidence of venous thromboembolic events when given prophylactically to patients with a variety of metastatic or locally advanced solid tumors, according to a report in the Feb. 16 issue of the New England Journal of Medicine.
Semuloparin prevented both deep vein thrombosis and pulmonary embolism (PE) without raising the risk of major bleeding in patients undergoing chemotherapy for lung, pancreatic, stomach, colon, rectal, bladder, or ovarian cancer. It did not improve overall survival, however, said Dr. Giancarlo Agnelli of the department of internal medicine at the University of Perugia (Italy) and his associates.
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Dr. Giancarlo Agnelli
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The investigators assessed the safety and efficacy of semuloparin because this patient population has a high incidence of venous thromboembolism (VTE). They conducted the SAVE-ONCO trial (NCT00694382), which was sponsored by semuloparin’s manufacturer, Sanofi-Aventis, at 395 medical centers in 47 countries.
A total of 3,212 patients were randomly assigned to receive daily subcutaneous injections of either semuloparin (1,608 patients) or placebo (1,604 patients), beginning on the first day of chemotherapy and continuing until chemotherapy was stopped or changed to a different regimen. The concomitant use of antiplatelet agents and nonsteroidal anti-inflammatory drugs (NSAIDs) was permitted at the treating physician’s discretion.
The mean duration of treatment was 3.5 months. The reasons for discontinuing treatment were similar between patients receiving semuloparin and those receiving placebo – chiefly adverse events (15.9% and 17.5%, respectively) and the patient’s request to discontinue treatment (18.1% and 17.4%, respectively).
The primary efficacy outcome – a composite end point of any symptomatic deep vein thrombosis in the lower or upper limbs, any nonfatal pulmonary embolism, or death related to VTE – occurred in 1.2% of the semuloparin group, a significantly lower rate than the 3.4% rate in the placebo group.
Semuloparin significantly reduced the incidence of deep vein thrombosis, fatal PE, and nonfatal PE. This benefit was seen across all groups of patients categorized by cancer stage, cancer site, and geographic region, Dr. Agnelli and his colleagues reported (N. Engl. J. Med. 2012;366:601-9).
The treatment benefit also was consistent across numerous baseline risks for VTE, such as personal or family history of VTE; use of a central venous catheter; obesity; age of 75 years or more; presence of chronic respiratory or heart failure; presence of venous insufficiency or varicose veins; and use of hormone therapy.
However, semuloparin did not improve overall survival. Mortality was 43.4% in the semuloparin group and 44.5% in the placebo group.
The overall rate of major and clinically relevant nonmajor bleeding was 2.8% with semuloparin and 2.0% with placebo, a nonsignificant difference. Two fatal bleeding events occurred with semuloparin and four with placebo. "Five episodes of nonfatal bleeding in a critical area or organ were noted, all in the semuloparin group," the researchers said.
Serious adverse events developed in 26.3% of patients taking semuloparin and 25.5% of those taking placebo, a nonsignificant difference. In particular, there were no cases of heparin-induced thrombocytopenia, and the rates of thrombocytopenia were comparable between the semuloparin and placebo groups (7.1% and 7.6%, respectively).
"Current guidelines recommend antithrombotic prophylaxis for patients with cancer who are admitted to the hospital for medical illness (administered for the duration of the hospital stay) and for patients who have undergone surgery for cancer (extended for up to 5 weeks) but not for routine use in ambulatory patients receiving chemotherapy. This study suggests a benefit from antithrombotic prophylaxis with semuloparin in patients receiving chemotherapy for cancer," Dr. Agnelli and his associates said.
This study was supported by Sanofi, manufacturer of semuloparin. Dr. Agnelli and his associates reported ties to numerous industry sources.
Interpreting the Findings
The findings by Agnelli et al. indicate that many cancer patients "can probably avert hospitalization for deep vein thrombosis and pulmonary embolism and might live longer, if they accept an increased risk of bleeding and its subsequent treatment," said Dr. Elie A. Aki and Dr. Holger J. Schünemann.
According to the SAVE-ONCO data, if 1,000 cancer patients used a prophylactic dose of ultralow-molecular-weight heparin, "over a period of 12 months death would be averted in approximately 30 patients, venous thromboembolism would be averted in 20, and 1 would have a major bleeding episode," they noted.
Elie A. Akl, M.D., Ph.D., is in the department of medicine, State University of New York at Buffalo, and the departments of clinical epidemiology and biostatistics at McMaster University, Hamilton, Ont. Holger J. Schünemann, M.D., Ph.D., is in the departments of medicine and clinical epidemiology and biostatistics at McMaster University. They reported no relevant financial conflicts of interest. These remarks were taken from their editorial accompanying the report of Dr. Agnelli and his colleagues (N. Engl. J. Med. 2012;366:661-2).
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