New advances in thrombosis help further understanding of disease prevention

Several studies presented during the 45th Annual Meeting of the American Society of Hematology shed light on some promising new therapies that are in the pipeline for the treatment of thrombosis, as well as some potential risk factors, and may provide hope for the numerous patients suffering from this condition.

Thrombosis, or more specifically deep vein thrombosis (DVT), is a dangerous medical condition in which the formation of a blood clot blocks circulation in the deep veins of the lower limbs that are primarily responsible for returning deoxygenated blood to the heart. A number of factors contribute to one’s risk of developing a clot, including age, obesity, major surgery, trauma or immobility, genetic factors, oral contraceptives, or hormone replacement therapy. Risk is higher when more than one risk factor is present. Blood clots can become potentially fatal if the clot breaks loose from the wall of the vein and migrates from the leg to the lungs, called pulmonary embolus (PE). When this happens, clots block a pulmonary artery or one of its branches, disrupting the lung’s blood flow and the addition of oxygen to the blood.

Drugs used to treat deep vein thrombosis fall into three general classes: (1) anticoagulants, which inhibit blood coagulation and serve to weaken already formed clots, preventing further expansion; (2) thrombolytic agents, which actually help to dissolve clots; and (3) antiplatelet agents, which decrease activation of platelets and prevent new clots from being formed.

“Since we are aware of the risk factors, deep vein thrombosis should be a preventable occurrence,” said Jim George, M.D. Vice President of the American Society of Hematology and Professor of Medicine at the University of Oklahoma Health Sciences Center, Oklahoma City. “Current therapies, though somewhat effective, still have many limitations and undesirable side effects. Technological advancements in this area and new treatment options with increased safety and efficacy are greatly needed.”

Hormone Therapy and Venous Thrombosis: Final Results of the Women’s Health Initiative Trial of Estrogen Plus Progestin

The Women’s Health Initiative (WHI) is a large-scale, 15-year research program that includes multiple clinical trials designed to assess the most common causes of death, disability, and poor quality of life in postmenopausal women – cardiovascular disease, cancer, and osteoporosis. One of the WHI studies was a clinical trial that included 16,608 women aged 50 to 79 who were randomized to receive either conjugated equine estrogen (0.625 mg per day) and medroxyprogesterone acetate (2.5 mg per day) or placebo. The trial ended early (5.2 years) after finding that the associated health risks of estrogen plus progestin (E+P) outweighed the potential benefits of the treatment. Researchers continue to analyze and report on data from this trial while they complete other WHI studies.

The final results related to deep vein thrombosis and pulmonary embolism from this trial showed that women experienced a two-fold increased risk of developing this potentially fatal condition while using E+P. Thrombosis risk factors were similar for the E+P and placebo-assigned women – one third of the women were 50 to 59 years old; 22 percent were 70 to 79 years old; 84 percent were white; 35 percent were overweight [body mass index (BMI) 25 to 29]; and one third were obese (BMI = 30). Thrombosis occurred in 167 women in the E+P arm compared to 76 with placebo, a 2.1 fold increased risk [95 percent confidence interval (CI) 1.6 to 2.7]; the risk increase was similar for deep vein thrombosis and pulmonary embolism. The primary determinants of risk of thrombosis were increasing age and obesity. The risk of thrombosis with E+P was higher earlier in the study, with a four-fold increased risk in the first year.

“While our results showed that estrogen plus progestin did not increase the risk of thrombosis to a larger degree among older or obese women, age and body mass index were the primary determinants of increased absolute risk of thrombosis,” said Mary Cushman, M.D., of the University of Vermont, Burlington, Vt., lead investigator of this study. “Researchers have known that the use of hormones – both birth control pills and estrogen – increase a woman’s risk of venous thrombosis, however in this study, we were able to identify the compounding risk factors that put women at an even greater risk.”

In a nested case control study on venous thrombosis in this E+P trial, the WHI researchers reported the associations of genetic variants with thrombosis risk. They identified 147 women in the WHI study who developed thrombosis, and compared them to 513 controls. Factor V Leiden was associated with thrombosis risk, and appeared to lead to a further increased risk in combination with E+P; the prevalence of Factor V Leiden among cases and controls was 13.8 percent and 4.6 percent, respectively. Compared to women without Factor V Leiden and assigned to placebo, women with Factor V Leiden assigned to E+P had a 6.7-fold increased risk of thrombosis (95 percent CI 3.1 – 14.5). The prothrombin 20210A variant was not common enough to draw conclusions; prevalences were 3.6 percent and 4.2 percent for E+P and placebo, respectively. Factor V Leiden is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk of venous thromboembolism. Factor V Leiden, inactivated at a rate approximately ten times slower than normal factor V, increases a woman’s risk for venous thrombosis. Prothrombin 20210A is associated with elevated prothrombin levels (plasma protein produced in the liver in the presence of vitamin K and converted into thrombin by the action of various activators in the clotting of blood) and an increased risk for venous thrombosis.

“Before we start testing for these genetic disorders prior to prescribing E+P, we will need to study this area further,” Cushman said.

Enoxaparin Treatment Improves the Gestational Outcome of Pregnant Women with Thrombophilia and Recurrent Pregnancy Loss: The LIVE-ENOX Study

It is estimated that recurrent pregnancy loss affects two to five percent of all couples desiring pregnancy. Historically, the cause of recurrent pregnancy loss was unknown in most couples. Recent research has shown a possible link between maternal thrombophilia, a blood disorder in which there is an increased risk of thrombosis, and recurrent pregnancy loss. LIVE-ENOX is a multi-center, randomized trial that investigated the use of an anticoagulant therapy, enoxaparin, for improving pregnancy outcomes in patients with thrombophilia and recurrent pregnancy loss. Results showed that enoxaparin, administered in doses of either 40 mg/day or 80 mg/day, appears safe and comparably effective in the prevention of pregnancy loss for thrombophilic women with recurrent pregnancy loss. Data also demonstrated an apparent reduction in the incidence of preeclampsia and placental abruption, two complications of pregnancy that are known to negatively affect birth outcomes.

“Loss of pregnancy is a physically and emotionally challenging ordeal. When pregnancy loss is repetitive, these feelings are magnified,” explains Benjamin Brenner, M.D., of the Rambam Medical Center, Haifa, Israel, lead investigator of the study. “Results from this study may give hope to the thousands of couples who are still in need of an effective treatment for thrombophilia-related recurrent pregnancy loss.”

Women with thrombophilia and recurrent pregnancy loss were enrolled at five to 10 weeks of gestation and grouped according to the number of previous pregnancy losses and length of pregnancies before previous losses (three or more pregnancy losses in first trimester, two or more losses in second trimester, or one or more losses in third trimester), and type of thrombophilia. Treatment with enoxaparin was given throughout the pregnancy and postpartum period. The primary efficacy endpoint was delivery of a live, healthy baby. The safety endpoints were bleeding episodes in newborns and mothers and thrombocytopenia in mothers, a blood condition leading to increased bleeding and decreased clotting ability. Treatment with enoxaparin significantly increased the rate of live births compared to patients’ historical rates of live birth (81.4 percent versus 28.2 percent for 40 mg and 76.5 percent versus 28.3 percent for 80 mg). Treatment with enoxaparin was also shown to decrease the rate of preeclampsia and placental abruption. No instances of maternal or neonatal bleeding were observed. Enoxaparin is safe and effective for prevention of pregnancy loss in women with thrombophilia.

A Phase II Randomized, Double-Blind, Five-Arm, Parallel Group, Dose-Response Study to a New Oral Directly-Acting Factor Xa Inhibitor, Razaxaban, for the Prevention of Deep Vein Thrombosis in Knee Replacement Surgery – on Behalf of the Razaxaban Investigators

Venous thromboembolism, a dangerous condition in which blood clots break away from the site of formation, become lodged in a blood vessel, and obstruct blood flow, is a common complication for major joint replacement surgeries. There is a need for new antithrombotic drugs that are safer and more effective than those currently available. Researchers from orthopedic clinics in the U.S., Canada, and Australia conducted a phase II randomized, double-blind, controlled, dose-response study to investigate razaxaban, a new oral, directly acting inhibitor of coagulation factor Xa. Results showed that razaxaban administered at 25 mg twice a day (bid) appears to reduce the risk of venous thromboembolism after major orthopedic surgery with similar safety compared to current standard therapy, enoxaparin (a low molecular weight heparin), administered at 30 mg bid.

“This new oral agent interacts directly with factor Xa, eliminating the need for anti-thrombin III, a common target in the coagulation pathway for most antithrombotic drugs,” said Michael Rud Lassen, M.D., of Hoersholm Hospital, Denmark, lead investigator of the study. “Razaxaban shows future promise as an additive drug and may help to reduce thrombosis in patients undergoing major orthopedic surgery.”

Patients undergoing elective primary total knee replacement surgery were randomly assigned to one of four dose groups for razaxaban (25 mg, 50 mg, 75 mg, or 100 mg bid) or enoxaparin (30 mg administered subcutaneously bid). Treatment with razaxaban started eight hours after surgery and standard therapy was started 12 to 24 hours after surgery. Treatment was continued for 10 days and then venography (radiographic demonstration of a vein after the administration of a contrast agent) of both legs was performed to see whether clots had developed in the veins.

The primary efficacy outcome of this study measured the incidence of a venous thromboembolism during treatment. The safety analysis measured all bleeding incidents (major and non-major), thrombocytopenia (decrease in the number of platelets), and death. An independent medical committee that was unaware of treatment assignment determined the incidence of all events.

Of the 656 patients treated and included in the safety analysis, 438 were eligible for efficacy analysis. Efficacy results showed a dose-dependent relationship; patients taking razaxaban had a lower rate of venous thromboembolism than those with standard therapy (8.6 percent – 25 mg bid; 6.0 percent – 50 mg bid; 3.6 percent – 75 mg bid; and 1.4 percent – 100 mg bid versus 15.9 percent – enoxaparin 30 mg bid). Safety results showed an opposite dose-dependent relationship. Patients on the higher doses of razaxaban seemed to experience a higher incidence of major bleeding over that of standard therapy (0.7 percent – 25 mg bid; 4.1 percent – 50 mg bid; 3.5 percent – 75 mg bid; and 5.8 percent – 100 mg bid versus 0.0 percent – enoxaparin 30 mg bid). The three highest doses of razaxaban were stopped before the intended sample size of 150 patients was reached, due to increased reports of bleeding. In this study, the lowest dose of razaxaban, 25 mg bid, demonstrated potential for increased efficacy and similar safety compared to current standard treatment.

Randomized, Double-Blind Comparison of Ximelagatran, an Oral Direct Thrombin Inhibitor, and Warfarin to Prevent Venous Thromboembolism (VTE) after Total Knee Replacement (TKR): EXULT B

Total knee replacement surgery, like many other major orthopedic surgeries, continues to be hampered by venous thromboembolism events, such as deep vein thrombosis and pulmonary embolism. Without any preventive medication, harmful blood clots occur in two thirds of all total knee replacement surgery patients. Anticoagulants that are currently approved in the U.S. for prevention of venous thromboembolism are still associated with unacceptably high rates of deep vein thrombosis and require regular dosage monitoring to prevent major bleeding events.

“Oral anticoagulants that are currently available have many limitations. There is a great need for new therapies with increased safety and efficacy,” said Charles Francis, M.D., of the University of Rochester, Rochester, N.Y., lead investigator of the study. “The results from this study encourage us to continue looking at ximelagatran as a preventive treatment for this serious complication in total knee replacement surgery.”

The trial, led by Dr. Francis, compares the safety and efficacy of ximelagatran, a novel oral direct thrombin inhibitor, to warfarin for prevention of venous thromboembolism in total knee replacement patients. As a direct thrombin inhibitor, ximelagatran in its activated form selectively inhibits free and clot-bound thrombin, a key enzyme in the body’s coagulation pathway. Results showed that ximelagatran given 24 hours after total knee replacement surgery appeared to have increased efficacy and similar safety, without the need for coagulation monitoring or dose adjustment, when compared to warfarin.

The study, a double-blind, double-placebo phase III trial, compared a fixed dose of ximelagatran (36 mg twice a day [bid]) and warfarin (target INR 2.5; range 1.8-3.0). The 2,303 patients were randomized to either oral ximelagatran and warfarin placebo, or warfarin and ximelagatran placebo for seven to 12 days following surgery. Efficacy was measured by the number of subjects with confirmed venous thromboembolism and/or all-cause mortality. Safety was measured by rates of bleeding events (major and minor) and surgical wound assessment up to two days after the last dose of study drug was administered. The efficacy population was made up of 1,949 patients (982 received ximelagatran; 967 received warfarin). A slightly higher rate of venous thromboembolism and death was observed in patients receiving warfarin (31.9 percent) over patients on ximelagatran (22.5 percent). There was no statistically significant difference in safety between the two treatments. Ximelagatran provides better protection against venous thromboembolism without need for dose monitoring and with no increase in complications.