New anticoagulant studies may change current medical practice including use of aspirin and heparin in VTE and to prevent miscarriages

Research presented yesterday at the 51st Annual Meeting of the American Society of Hematology, now taking place in New Orleans, reveals that the practice of using the anticoagulants aspirin and heparin with the hope of preventing clots in placental blood vessels is ineffective for stopping 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 Schwartz, 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," he said.

Dabigatran etexilate versus warfarin in venous thromboembolism

Currently, patients with VTE are treated with warfarin, which has many burdensome interactions with other medications and foods, and requires frequent monitoring of the dosage. However, a new study shows that an oral drug called dabigatran etexilate (marketed by independent German drug major Boehringer Ingelheim as Pradaxa), which does not have these disadvantages, is as safe and effective as warfarin for combating VTE. Pradaxa is currently approved in over 40 countries for the primary prevention of VTE in adults who undergo certain types of hip- or knee-replacement surgeries.

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 150mg of dabigatran etexilate twice daily, while the other half (1,265 patients) received warfarin once daily in doses adjusted to an International Normalized Ratio (INR) of 2.0 to 3.0.

The improvement seen in both groups from the treatments was similar. After six months of treatment, only 2.4% of the dabigatran etexilate group (30 patients) and 2.2% 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 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, 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," he noted.

Aspirin and aspirin combined with heparin

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% of cases. 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.

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 Kaandorp, research fellow in the Department of Obstetrics and Gynecology at the Academic Medical Center in Amsterdam, Netherlands, adding: "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 100mg of calcium carbasalate (a salt formulation of aspirin equivalent to 80mg 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% in the aspirin group (61 women), and 57% 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.

Dabigatran an alternative for acute VTE

Boehringer Ingelheim also announced results at the ASH meeting from the RE-COVER study investigating dabigatran etexilate (150mg BID) compared to dose-adjusted warfarin in patients with acute VTE.

Dabigatran etexilate met the primary outcome of the trial, six-month incidence of recurrent symptomatic VTE and related deaths, and was non-inferior to dose-adjusted warfarin in patients with acute VTE (2.4% versus 2.1%). There were 37% fewer patients treated with dabigatran etexilate (71) who experienced major or clinically relevant non-major bleeds versus those given warfarin (111). The percentage of patients experiencing major bleeds was 1.6 in the dabigatran etexilate group and 1.9 in the warfarin group. The number of patients with any bleeding was 29% lower in the group treated with dabigatran etexilate.

"The standard of care for patients with VTE is anticoagulation," said Janet Schnee, clinical program director, Boehringer Ingelheim Pharmaceuticals in the USA. "It is encouraging to see that the results of this study suggest that dabigatran etexilate has the potential to be an alternative treatment for VTE," she added.