The largest study ever to examine the preventive use of blood-thinning medication to help prevent deadly blood clots in patients with cancer undergoing chemotherapy presented December 7 during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA.
Additional research being featured at the press conference includes studies that examine the use of three different investigational blood-thinning medications that belong to a new class of therapies called Factor Xa inhibitors. These studies evaluated the effectiveness of these medications in preventing blood clots: following major orthopedic surgery; in patients with atrial fibrillation; and in patients with deep-vein thrombosis.
Blood clotting, or coagulation, is an important process that prevents excessive bleeding when a blood vessel is injured. Usually, the body naturally dissolves the clot when the injury has healed; however, when a clot does not dissolve naturally, it can become extremely dangerous. Deep-vein thrombosis, a type of blood clot that typically forms in a major vein of the leg, and pulmonary embolism, which occurs when a blood clot detaches from its point of origin and travels to the lungs where it becomes wedged and prevents adequate blood flow, are known collectively as venous thromboembolism.
"Venous thromboembolism is a serious public health problem that affects almost 1 million Americans each year and is responsible for more deaths each year than breast cancer, HIV disease, and motor vehicle crashes combined," said J. Evan Sadler, MD, moderator of the press conference and Professor of Medicine and of Biochemistry and Molecular Biophysics, Washington University Medical School, St. Louis, MO. "The hematology community is committed to continuously improving treatments for these patients, and the exciting research presented today is another step forward in finding ways to eliminate this preventable leading cause of death."
Certain conditions can elevate a person's risk of clotting, including atrial fibrillation (an abnormal heart rhythm), previous heart attack, long periods of inactivity, some medications, and genetic or disease-related factors. Treatment typically consists of anticoagulants that help prevent clots from forming, medications that dissolve blood clots, catheter-directed thrombolysis (a surgical procedure where clot-dissolving medication is directed toward the blood clot), and thrombectomy, the surgical removal of a blood clot. Recognizing the deadly impact blood-clotting disorders have on millions of Americans every year, the American Society of Hematology has developed a new resource, www.bloodthevitalconnection.org, to help educate the public about these and other common blood diseases.
A Randomized Double-Blind Placebo-Controlled Study on Nadroparin for Prophylaxis of Thromboembolic Events in Cancer Patients Receiving Chemotherapy: The PROTECHT Study [Abstract #6]
Giancarlo Agnelli, MD, University of Perugia, Perugia, Italy
This study is the largest to determine that the preventive use of an antithrombotic medication can reduce the incidence of thromboembolic events in patients with cancer. It is well known that patients with cancer who receive chemotherapy are at high risk for developing deadly blood clots, but few large studies have confirmed whether the preventive use of a blood-thinning medication can reduce these events.
This multicenter, placebo-controlled, clinical outcome-based study was designed to evaluate the efficacy of nadroparin, a low-molecular-weight heparin, for the preventive treatment of thromboembolic events in cancer patients receiving chemotherapy. The primary outcome of the study was the combined occurrence of clinically overt venous or arterial thromboembolic events (i.e., deep-vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, and unexplained death of possible thromboembolic origin). Major bleeding was the main safety parameter.
In this study, 1,166 patients with advanced lung (279), colon (235), breast (165), ovarian (143), stomach (98), rectal (87), pancreatic (53), head and neck (36), and other cancers (54) were randomized to one of two treatment arms: once-daily subcutaneous injections of nadroparin (3,000 IU) or placebo. Twice as many patients were enrolled into the nadroparin group than the placebo group. Treatment was started on the first day of the current cycle of chemotherapy and was maintained for the overall duration of chemotherapy treatment or up to a maximum of four months.
Only 16 of the 769 patients treated with nadroparin had a thromboembolic event (2.1 percent) compared with 15 of the 381 patients (3.9 percent) in the placebo group, a 47.2 percent reduction in the risk of developing a thromboembolic event for the patients in the treatment arm. The drug also appeared to be safe as only five patients in the nadroparin group (0.7 percent) experienced a major bleeding episode, and the incidence of minor bleeding in the treatment arm was similar to that of the placebo group.
Venous thromboembolism occurred 11 times in both the nadroparin and placebo groups. Fifteen of these events occurred in patients with lung cancer (4 percent in the nadroparin arm and 8.8 percent in the placebo arm). Patients with pancreatic cancer also experienced a high overall rate of thromboembolic events (7.5 percent). While this study confirms that nadroparin reduces the incidence of thromboembolic events in cancer patients receiving chemotherapy, because of the disproportionately higher incidence of events in lung and pancreatic cancer patients, further studies should focus on patients in these two high-risk populations.
Idrabiotaparinux, a Biotinylated Long-Acting Anticoagulant, in the Treatment of Deep-Venous Thrombosis (EQUINOX Study): Safety, Efficacy, and Reversibility by Avidin [Abstract #32]
Harry Roger Buller, MD, PhD, Academic Medical Center, Amsterdam, Netherlands
This clinical trial found that six months of treatment with idrabiotaparinux, an anticoagulant and indirect Factor Xa inhibitor that links indraparinux to biotin, showed comparable efficacy to idraparinux alone with a trend toward less bleeding in patients with deep-vein thrombosis. Additionally, an infusion of avidin after the last idrabiotaparinux treatment led to a rapid reversal of the anti-Factor Xa activity, or the anticoagulant effect of the drug, which was sustained for at least five days. This study builds on previous research that showed similar efficacy and safety between once-weekly subcutaneous injections of indaparinux with standard treatment (low-molecular-weight heparin followed by a vitamin K antagonist) in the treatment of deep-vein thrombosis.
A total of 757 patients with symptomatic and confirmed deep-vein thrombosis were randomized to receive weekly subcutaneous injections of 3 mg idrabiotaparinux (385 patients) or 2.5 mg idraparinux (370 patients) for six months. The primary objective of the study was to determine whether idrabiotaparinux works in a similar manner to idraparinux (i.e., bioequipotency). The secondary objective of the study was occurrence of clinically relevant bleeding, death, or symptomatic recurrent venous thromboemolism at the end of six months of therapy.
A final objective included the reversal of the anticoagulant effect of idrabiotaparinux, as there are medically relevant instances, such as prior to surgery, when there is the need to reverse the effects of an anticoagulant. The reversal of the anticoagulant effect was measured after a 30-minute intravenous infusion of avidin (100 mg), a hen egg protein that binds with biotin to reverse the Factor Xa inhibiting activity of idrabiotaparinux. At the end of the initial six-month treatment with idrabiotaparinux, a subset of patients was re-randomized to receive avidin (those in the idrabiotaparinux arm) or placebo (those in both the idrabiotaparinux and idraparinux arms to preserve blinding). Avidin or placebo was infused between two and five hours after the last injection of idrabiotaparinux or idraparinux.
Anti-Factor Xa activity was measured just prior to the infusion, just after the infusion, and then every day for five days to ensure that the reversibility remained unchanged.
The study found that there was less clinically relevant bleeding (5.2 percent versus 7.3 percent) and less major bleeding (0.8 percent versus 3.8 percent) in those treated with idrabiotaparinux as compared with idraparinux. Rates of recurrent venous thromboembolism (2.3 percent versus 3.2 percent) and fatal or non-fatal pulmonary embolism (1.6 percent versus 1.8 percent) were similar with both idrabiotaparinux and idraparinux.