Evaluation of new anti-coagulant drugs

Haematology
Evaluation of new anti-coagulant drugs
By American Society of Hematology, Dec 7, 2008 - 2:01:46 PM

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 was presented in a press conference during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA. Additional research 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.

Levels of Factor Xa activity were identical in both treatment groups throughout the six-month study. Of the 52 idrabiotaparinux patients re-randomized to receive avadin or placebo, 41 were analyzed for reversal of Factor Xa activity (23 received avidin and 18 received placebo). At the end of the 30-minute infusion of avidin, mean anti-Factor Xa activity was reduced by 77.8 percent and was sustained for at least five days as compared with 2.4 percent for the placebo group. The infusion of avidin was well-tolerated with no allergic reactions observed.

Randomized, Parallel Group, Multicenter, Multinational Study Evaluating Safety of DU-176b Compared With Warfarin in Subjects With Non-Valvular Atrial Fibrillation [Abstract #33]
Jeffrey I. Weitz, MD, Henderson Research Centre, Hamilton, Canada

The primary objective of this study was to evaluate the safety of four dosing regimens of DU-176b in patients with non-valvular atrial fibrillation. This phase II study found that two regimens (30 mg and 60 mg once-daily) of an investigational oral Factor Xa inhibitor, DU-176b, are safe in patients with non-valvular atrial fibrillation, making the drug a potential substitute for warfarin, the conventional blood-thinning agent used in such patients to prevent stroke.

Dosing of warfarin is complicated because it interacts with many commonly-used medications and even certain foods. For that reason, patients receiving warfarin require regular blood testing to monitor the international normalized ratio (INR) to ensure that an adequate yet safe dose of warfarin is given.

A total of 1,146 patients with atrial fibrillation were randomized to receive either one of four fixed-dose regimens of DU-176b (30 mg once-daily, 30 mg twice-daily, 60 mg once-daily, 60 mg twice-daily) or warfarin (dose-adjusted to a target INR of 2.0 to 3.0) for 12 weeks. The primary endpoints of the study were the incidence of bleeding events (major and clinically relevant non-major) and elevated liver enzymes and/or bilirubin, which might be indicative of hepatic toxicity. Secondary endpoints included major adverse cardiovascular events, stroke, systemic embolism, acute myocardial infarction, hospitalizations due to cardiovascular conditions, or cardiovascular death.

The incidence of major and clinically relevant non-major bleeding events was significantly higher in the 30 mg and 60 mg twice-daily DU-176b regimens than it was in patients given warfarin (7.8 percent, 10.6 percent and 3.2 percent, respectively). In contrast, the incidence of major and clinically relevant non-major bleeding events with the 30 and 60 mg once-daily DU-176b regimens was comparable to that with warfarin (3.0 percent, 3.8 percent, and 3.2 percent, respectively). There were no significant differences in patients with elevated liver enzymes or bilirubin across all treatment groups, and there were no significant differences in the rates of secondary endpoints.

Once-Daily Oral Rivaroxaban Compared With Subcutaneous Enoxaparin Every 12 Hours for Thromboprophylaxis After Total Knee Replacement: RECORD4 [Abstract #35]
Alexander G.G. Turpie, MD, McMaster University, Hamilton, Ontario, Canada

This study concluded that investigational rivaroxaban, an oral Factor Xa inhibitor, is more efficacious than a current standard of therapy, enoxaparin, for the prevention of venous thromboembolism following total knee replacement surgery without significantly increasing the risk of bleeding. Coupled with previous research that demonstrated that post-operative rivaroxaban was more effective than pre-operative enoxaparin in preventing deep-vein clotting, along with an easier method of administration (oral versus subcutaneous injection), this study may change the way physicians prevent serious blood clots in patients undergoing major orthopedic surgery.

In this study, a total of 3,148 patients were randomized to receive either once-daily oral rivaroxaban (10 mg) starting six to eight hours after surgery or twice-daily subcutaneous injections of enoxaparin beginning 12 to 24 hours after surgery for 10 to 14 days. Patients underwent mandatory, bilateral venography (X-ray of the vein) between days 11 and 15.

The primary endpoint of the study was the combined occurrences of deep-vein thrombosis, non-fatal pulmonary embolism, and all-cause mortality up to day 17. The main safety endpoint was major bleeding observed after one dose of the drug until two days after the end of treatment. Efficacy was determined first by a test for non-inferiority in the per-protocol population of 1,702 patients, followed by a test for superiority in the intention-to-treat population of 1,924 patients.

The results indicated that rivaroxaban significantly reduced the incidence of adverse events (the combination of blood clots and death) by 31 percent as compared with enoxaparin, with no significant increase in the rate of major bleeding events. Rivaroxaban and enoxaparin appeared equally effective at preventing major venous blood clots and pulmonary embolism

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