3 anticoagulant studies may change current medical practice

December 06, 2009

(NEW ORLEANS, December 6, 2009) - Blood clotting, or coagulation, is an important process that prevents excessive bleeding when a blood vessel is injured. Sometimes, however, clots form on the inside of vessels without an obvious injury or do not dissolve naturally, a potentially life-threatening situation requiring treatment. Research presented today at the 51st Annual Meeting of the American Society of Hematology reveals that the practice of using the anticoagulants aspirin and heparin with the hope of preventing clots in placental blood vessels is ineffective for preventing unexplained, recurrent miscarriages. Two other studies look at treatments for venous thromboembolism, a common and sometimes deadly clotting disorder.

"Anticoagulants are one of the most common types of medications in use today and help prevent and treat a wide variety of health conditions," said Bradford S. Schwartz, MD, moderator of the press conference highlighting this research and Professor of Medicine and Biochemistry, and Dean of the University of Illinois College of Medicine at Urbana-Champaign. "That's why it's so critical that studies examining both newer formulations and old standbys, like aspirin, provide practitioners with the most up-to-date evidence to ensure that they are being used appropriately and that the best option is chosen for each individual patient."

This press conference will take place on Sunday, December 6, at 8:00 a.m.

Dabigatran Etexilate Versus Warfarin in the Treatment of Venous Thromboembolism [Abstract #1]

A new study provides welcome news for patients with a common clotting disorder known as venous thromboembolism (VTE). According to the Venous Disease Coalition, 1 million Americans experience VTE every year, which occurs when an abnormal clot forms in a vein and restricts the flow of blood, causing pain and swelling. In some cases, the clot may detach from its point of origin and travel through the heart to the lungs, causing a potentially fatal condition known as a pulmonary embolism.

Currently, patients with VTE are treated with a blood thinner known as warfarin, which has many burdensome interactions with other medications and foods and requires frequent monitoring of the dosage. However, this study shows that an oral drug called dabigatran etexilate, which does not have these disadvantages, is as safe and effective as warfarin for combating VTE.

To compare the two drugs, an international team of researchers conducted a randomized, double-blind trial of 2,539 patients with acute VTE. For six months, roughly half of the patients in the trial (1,274) were given a fixed dose of 150 mg of dabigatran etexilate twice daily, while the other half (1,265 patients) were given warfarin once daily in doses adjusted to an International Normalized Ratio (INR) of 2.0 to 3.0. INR is a blood test needed to monitor the effects of warfarin therapy to ensure an adequate, yet safe, dose is taken; in this study, the test was performed, on average, every 11 days.

The improvement seen in both groups from the treatments was similar. After six months of treatment, only 2.4 percent of the dabigatran etexilate group (30 patients) and 2.2 percent of the warfarin group (27 patients) experienced recurrent VTE. The safety of the two drugs was also comparable. In the dabigatran etexilate arm, 207 patients experienced bleeding (including 20 patients with major bleeding) versus 280 patients in the warfarin arm (including 24 with major bleeding). Other possible side effects, including death, acute coronary syndromes, and abnormalities in liver function tests, were infrequent in the two groups.

"We are excited by these findings and feel that they will change the standard of care for venous thromboembolism, which affects a large number of our patients," said lead study author Sam Schulman, MD, Professor of Medicine, Thrombosis Service, McMaster Clinic and Hamilton General Hospital in Ontario, Canada. "This study found that dabigatran is a safe and effective anticoagulant that does not require the routine monitoring or dose adjustments that are necessary with warfarin. In other words, patients can receive the same results in a more convenient manner."

Dr. Schulman will present this study during the Plenary Scientific Session on Sunday, December 6, at 2:00 p.m. in Hall F.

Aspirin and Aspirin Combined With Low-Molecular-Weight Heparin in Women with Unexplained Recurrent Miscarriage: A Randomized Controlled Multicenter Trial (ALIFE Study)
[Abstract #488]

Recurrent miscarriages are extremely traumatic and stressful for women, and, according to the American Society for Reproductive Medicine, the cause is unknown in more than 50 percent of cases (American Society for Reproductive Medicine. Patient's Fact Sheet on Recurrent Pregnancy Loss. Available at: http://www.asrm.org/Patients/FactSheets/recurrent_preg_loss.pdf). Though treatments to avoid these tragedies remain elusive, some practitioners suspect that abnormal clots in the blood vessels that nourish the placenta are responsible for many recurrent miscarriages, and thus they have increasingly used aspirin and low-molecular-weight heparin to prevent further miscarriages, even though evidence to support their use is not available. Both medications are blood thinners and are used to prevent clots in the placenta that could cut off the supply of nutrients to a growing baby, or to decrease the risk of other pregnancy complications that might be causing the miscarriages.

To test the effectiveness of these controversial treatments, a team of researchers from the Netherlands conducted a multicenter, randomized clinical trial of 364 women between the ages of 18 and 42 who were attempting to conceive or were less than six weeks pregnant. The women had previously experienced at least two unexplained miscarriages by the 20th week of pregnancy. Because the researchers were focused on miscarriages with unexplained causes, women with previous venous or arterial thromboembolism (clotting disorders), endocrine disorders, or other indications for anticoagulant treatment during pregnancy were excluded from the study.

"The study clearly demonstrates that aspirin combined with heparin and aspirin alone do not prevent recurrent, unexplained miscarriages and that we should not needlessly put these women through the inconvenience and risks associated with these blood-thinning medications," said lead study author Stef P. Kaandorp, MD, research fellow in the Department of Obstetrics and Gynecology at the Academic Medical Center in Amsterdam. "These results are extremely important because they will likely change the way some women at high risk for another miscarriage have been treated."

During the study, three treatment groups were compared: aspirin and nadroparin (a low-molecular-weight heparin), aspirin alone, and placebo. Oral medication was administered once a day beginning on the day of inclusion in the study through 36 weeks of gestational age, or until miscarriage, ectopic pregnancy, or premature delivery. Patients on the oral regimens received either placebo pills or 100 mg of calcium carbasalate (a salt formulation of aspirin equivalent to 80 mg of aspirin). Women who were to receive low-molecular-weight heparin received subcutaneous injections once a day of 2,850 international units of nadroparin from six weeks of gestational age through 12 hours before delivery.

The intention-to-treat analysis of the study showed that the live birth rate did not differ significantly among the three treatment groups: 54.5 percent of those in the aspirin and nadroparin group had a live birth (67 women), compared with 50.8 percent in the aspirin group (61 women), and 57 percent of the placebo group (69 women). Side effects, most notably skin reactions, also occurred more often in women assigned to the aspirin and nadroparin group.

Dr. Kaandorp will present this study during an oral session on Monday, December 7, at 3:00 p.m. in Room 275-277.

Once-Daily Oral Rivaroxaban Versus Placebo in the Long-Term Prevention of Recurrent Symptomatic Venous Thromboembolism, the EINSTEIN-Extension Study [Abstract #LBA-2]

Venous thromboembolism (VTE), a condition in which a blood vessel is blocked by a clot, is a common and potentially life-threatening disorder. In the United States, there are more than 200,000 new cases of VTE that occur annually (American Heart Association. Venous Thromboembolism and Pulmonary Embolism - Statistics. Available at: http://www.americanheart.org/downloadable/heart/1200598191688FS29VTE08.pdf. Accessed November 24, 2009). Treatment for acute VTE typically consists of an anticoagulant, such as a vitamin K inhibitor, for a period of six to 12 months. Following this, the decision to continue the treatment to prevent future clots is controversial. Long-term use of vitamin K inhibitors carries the risk of serious side effects, such as major bleeding, and requires regular laboratory monitoring to optimize the dose while reducing these risks. As an alternative, the safety and efficacy of rivaroxaban, an oral anticoagulant that does not require continued monitoring and dose adjustment, was studied for long-term therapy and found to be safe and effective.

Researchers enrolled 1,197 patients in a double-blind trial involving 280 study sites in 28 countries. Prior to enrollment, the study participants had completed six to 12 months of anticoagulant treatment for acute VTE and were randomized to receive either 20 mg of rivaroxaban once daily (602 patients) or placebo (594 patients) for an additional six to 12 months.

Treatment with rivaroxaban was found to be both safe and effective. Only eight patients (1.3 percent) on rivaroxaban showed signs of recurrent VTE events, compared with 42 patients (7.1 percent) in the placebo arm. In the rivaroxaban arm, four patients (0.7 percent) experienced major bleeding, though none of these events were fatal or at a critical site. Non-major bleeding, such as a nose bleed, skin hematoma (a swelling of blood), or blood in the urine, occurred in 32 patients (5.4 percent) taking rivaroxaban. In the placebo arm, there were no incidences of major bleeding, though seven patients (1.2 percent) experienced non-major bleeding. After the study medication was stopped, six symptomatic recurrent VTE events occurred in each group during a one-month observational period.

"The results of this study are very compelling," said lead study author Harry R. Büller, MD, PhD, Professor of Medicine in the Department of Vascular Medicine at the Academic Medical Center in Amsterdam. "For these patients in danger of having another VTE event, rivaroxaban lowered their risk by 82 percent without significantly increasing their risk of major bleeding. This once-daily pill provides the clinician with a simple option for patients in whom continued anticoagulant treatment is indicated."

Dr. Büller will present this study in the Late-Breaking Abstracts Session on Tuesday, December 8, at 7:30 a.m. in Hall F.
American Society of Hematology

The American Society of Hematology (www.hematology.org) is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology. ASH provides Blood: The Vital Connection (www.bloodthevitalconnection.org), a credible online resource addressing bleeding and clotting disorders, anemia, and cancer. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online.

American Society of Hematology

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