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Studies Examine Risk Factor Prediction And Treatment Regimens For Venous Thromboembolism

December 6, 2010

The latest advances in the treatment of bleeding and clotting disorders will be presented today at the 52nd Annual Meeting of the American Society of Hematology, focusing on venous thrombeombolism (VTE), a potentially life-threatening disorder in which abnormal blood clots form in the veins and restrict the flow of blood. New studies examine risk-prediction models and cutting-edge treatment options for patients with VTE.

“This innovative research is the driving force behind the advancements in the areas of bleeding and clotting disorders,” said J. Evan Sadler, MD, PhD, moderator of the press conference, current ASH President-Elect, and Professor of Medicine at Washington University School of Medicine, St. Louis. “The results of these studies further improve our ability to diagnose and treat disorders that affect a large number of patients, such as VTE.”

This press conference will take place on Saturday, December 4, at 10:00 a.m.

Apixaban Versus Enoxaparin for Thromboprophylaxis After Joint Replacement Surgery: Pooled Analysis of Major Venous Thromboembolism and Bleeding in 8,464 Patients From the ADVANCE 2 and 3 Trials [Abstract 192]

New research identifies an improved method for preventing venous thromboembolism (VTE), the collective name for life-threatening blood clots in the deep veins of the legs and lungs. There is a high incidence of VTE among patients having hip or knee replacement surgery who have not received preventive treatment (thromboprophylaxis), which is standard care after such joint replacement surgery. Historically, thromboprophylaxis regimens with new anticoagulants that have been more effective than standard practice typically caused increased bleeding. Apixaban, a novel oral antithrombotic drug, has been evaluated in the ADVANCE studies ““ phase III randomized, double-dummy clinical trials for the prevention of VTE after hip or knee replacement surgery.

In ADVANCE-1, investigators compared the efficacy and safety of 2.5 mg oral apixaban twice daily with subcutaneous enoxaparin 30 mg twice daily, a recommended standard of care, for the prevention of VTE after total knee replacement (TKR) in 3,195 patients. The ADVANCE-2 study compared the efficacy and safety of oral apixaban 2.5 mg twice daily with subcutaneous enoxaparin 40 mg once daily for preventing VTE after TKR in 3,057 patients. The ADVANCE-3 study compared the same regimens as ADVANCE-2 but evaluated 5,407 patients post total hip replacement surgery.

Because many clinicians and some regulatory agencies do not consider blood clots within calf veins as a clinically important outcome for evaluating the benefit and risk of thromboprophylaxis, the ADVANCE researchers analyzed the pooled data from the ADVANCE-2 and 3 studies, which had a combined total of 8,464 patients, to focus on the serious blood clots in the large veins in the thigh or the lungs, collectively known as major VTE. In both studies, subcutaneous enoxaparin was administered nine to 15 hours before the operation while oral apixaban was administered 12 to 24 hours (mean 19 hours) after wound closure, typically the morning after surgery. In ADVANCE-2, study medications continued 10 to 14 days post knee replacement surgery and 32 to 38 days post hip replacement surgery in ADVANCE-3.

Results from this analysis show that apixaban was more effective than enoxaparin without increased bleeding and with the clinical advantages of oral administration and later initiation after surgery. Major VTE occurred in 23 of 3,394 (0.68 percent) evaluable patients in the apixaban group and in 51 out of 3,394 (1.50 percent) evaluable patients in the enoxaparin group. Major bleeding occurred in 31 of 4,174 (0.74 percent) patients in the apixaban group and in 32 of 4,167 (0.77 percent) in the enoxaparin group. Additionally, major bleeding at the surgical site occurred in 26 of the apixaban patients and in 27 of the enoxaparin patients.

“The results of our pooled analysis show that apixaban 2.5 mg twice daily is more effective than enoxaparin 40 mg once daily for preventing major venous thromboembolism without increasing bleeding risk for patients who undergo hip or knee replacement surgery,” said lead study author Gary E. Raskob, PhD, Dean of the College of Public Health at the University of Oklahoma Health Sciences Center. “The apixaban regimen provides orthopedic surgeons and clinical hematologists an improved method of prevention that is easier to use both in and out of the hospital.”

Dr. Raskob will present this in an oral presentation on Monday, December 6, at 7:00 a.m. in Room 230.

Development of a Clinical Prediction Rule for Risk Stratification of Recurrent Venous Thromboembolism in Patients With Cancer-Associated Venous Thromboembolism [Abstract 475]

Patients with cancer tend to have a higher risk of venous thromboembolism (VTE) due to disease-related chemical responses that cause the clotting system to overactivate. Approximately 20 percent of all diagnosed VTE cases occur in cancer patients, affecting 1 out of 250, or approximately 6,000, cancer patients annually.1 Current medical guidelines recommend that all cancer patients with VTE be treated with long-term low-molecular-weight heparin (LMWH), an anticoagulant treatment used to prevent and treat VTE, for at least six months. Ideally, patients should receive anticoagulants for as long as the cancer is active or anticancer treatment is ongoing. On the other hand, patients with blood clots who do not have cancer are usually treated with oral anticoagulants, such as vitamin K antagonists (VKA). In patients with cancer, it is unknown whether treatment strategies should vary according to risk of recurrent VTE or whether patients with low VTE recurrence risk will receive equal benefit from the use of VKA.

Furthermore, patients with a high risk of recurrent VTE who fail standard treatment with LMWH should be evaluated for a more aggressive anticoagulation approach. This study aimed to create a risk prediction system that would lead to the identification of patients with low and high VTE recurrence risk. Identification of these patients is particularly important as it can lead to the development of better tailored treatments.

The investigators reviewed the charts of 543 cancer patients with VTE followed from 2002 to 2004 and from 2007 to 2008 at the Thrombosis Unit of the Ottawa Hospital in Ontario, Canada. Results from the analysis show that 10.1 percent of the patient population experienced a VTE recurrence during the first six months of anticoagulation treatment. In total, 343 patients received LMWH and 36 (10.1 percent) developed a recurrent VTE. The other 200 patients received VKA and 19 (9.5 percent) developed a recurrence, suggesting that treatment type did not have a significant effect on recurrence. A multivariate analysis suggested that gender, primary tumor site, tumor stage, and history of prior VTE were significant variables in predicting which patients would have a recurrence of VTE. Specifically, female gender, lung cancer, and prior history of VTE were identified as variables that increased the risk of VTE, while breast cancer and stage I disease appeared to lower the risk. From this model, a scoring system was set ranging from -3 to 3. Patients with a score of zero or less were typed as low risk, and those with a score equal to 1 or more were considered high risk. Of the 543 patients, 48 percent had a low-risk score. Since this is the first time that a study has demonstrated a difference in VTE recurrence risk in patients with cancer, the generalizability of the prediction rule has yet to be established. Therefore, the investigators plan to conduct a prospective multicenter study for validation of the rule and to evaluate different treatment strategies according to patients’ risk.

“The development of a scoring system that stratifies VTE recurrence risk in patients with cancer-associated VTE is important as it is the first step in demonstrating that such a heterogeneous population varies in terms of VTE recurrence risk,” said lead study author Martha L. Louzada, BSc, MD, a hematologist at the University of Western Ontario. “With better treatment methods, the standard of care for cancer patients can be improved as physicians will be able to better predict the risk of VTE recurrence in patients with cancer-associated VTE and plan treatment accordingly.”

Dr. Louzada will present this study in an oral presentation on Monday, December 6, at 10:30 a.m. in Hall F5. 

Oral Rivaroxaban for the Acute and Continued Treatment of Symptomatic Venous Thromboembolism. The Einstein-DVT and Einstein-Extension Study [Abstract 187]

Each year, up to 2 million Americans are affected by deep-vein thrombosis (DVT), the formation of a blood clot in a major vein, most commonly in the leg.2 Current treatment guidelines recommend prolonged therapy for a significant number of DVT patients; however, treatment often includes multiple therapies of varying doses and administration methods that require constant monitoring. Novel oral anticoagulants, which tend to have a simple fixed-dose regimen without the need for monitoring, may make extended treatment more appealing for both patients and physicians.

This study analyzed data from the Einstein-DVT and the Einstein-Extension studies. The Einstein-DVT study compared rivaroxaban, an oral anticoagulant, with enoxaparin followed by oral vitamin K antagonist (VKA), the current standard therapy for DVT, for either three, six, or 12 months. The purpose of this study was to investigate the efficacy and safety of rivaroxaban and determine whether the new therapy was at least as effective as and easier to use than current treatment. Patients diagnosed with acute DVT without symptomatic pulmonary embolism (PE) were randomized to receive either oral rivaroxaban (1,731 patients) or enoxaparin (1,718 patients). In the Einstein-Extension study, patients that completed six to 12 months of anticoagulant treatment were randomized to receive rivaroxaban (602 patients) or placebo (594 patients) for an additional six to 12 months. In this study, the investigators sought to prove that rivaroxaban was superior to no treatment (placebo), with the exception of bleeding risk. For both studies, the primary efficacy outcome was recurrent non-fatal or fatal symptomatic VTE, and the principal safety outcome was major or clinically relevant non-major bleeding in Einstein-DVT and major bleeding the Einstein-Extension study.

Results from the Einstein-DVT study revealed 36 (2.1 percent) VTE events in the rivaroxaban group versus 51 (3.0 percent) cases of VTE in the enoxaparin/VKA treatment group. In both groups, major or clinically relevant non-major bleeding occurred in 8.1 percent of subjects while major bleeding occurred in 0.8 percent (one fatal) and 1.2 percent (five fatal) of the rivaroxaban and enoxaparin/VKA patients, respectively.

Results from the Einstein-Extension study demonstrated eight (1.3 percent) VTE events among rivaroxaban recipients and 42 events (7.1 percent) in the placebo group. Major bleeding occurred in 0.7 percent (none fatal) of rivaroxaban recipients and in none of the placebo patients. Clinically relevant non-major bleeding occurred in 5.4 percent of rivaroxaban and 1.2 percent of placebo recipients, respectively. Results from both studies prove rivaroxaban is an effective therapy against DVT and reduces major bleeding risk.

“These study outcomes may possibly change the way that patients with DVT are treated,” said lead study author Harry R. Bller, MD, PhD, Professor of Medicine at the Academic Medical Center at the University of Amsterdam in Amsterdam, Netherlands. “This new treatment regimen of oral rivaroxaban can potentially make blood clot therapy easier than the current standard treatment for both the patient and the physician with a single-drug and simple fixed-dose approach.”

Dr. Bller will present this study in an oral presentation on Monday, December 6, at 7:00 a.m. in Room 230.

Outpatient Treatment in Patients With Acute Pulmonary Embolism: The Hestia Study [LBA 1]

Pulmonary embolism (PE), which occurs when a blood clot detaches from its point of origin and travels to the lungs where it prevents adequate blood flow, affects approximately 200,000 people per year in the United States.3 Currently, patients with PE are initially treated in the hospital with low-molecular-weight heparin (LMWH), but several previous studies suggest that outpatient treatment may also be effective and safe for some PE patients. Clinicians need a way to identify those patients who may benefit from outpatient treatment, but validated selection criteria for this purpose are lacking.

With the goal of providing clinicians with a reliable evaluation tool, a group of researchers developed the Hestia criteria, an 11-point questionnaire, and studied its efficacy and safety in determining eligibility for outpatient treatment for patients with acute PE. A total of 297 patients in 12 hospitals in the Netherlands were identified with the Hestia criteria and treated on an outpatient basis with weight-adjusted therapeutic doses of LMWH followed by vitamin K antagonists (VKA). They were sent home from the hospital within 24 hours after being diagnosed with PE. Venous thromboembolism re-occurred in six patients (2 percent; PE in five patients and DVT in one), two patients experienced major bleeding (0.7 percent), and three patients died in the three months following treatment, although none as a result of fatal PE.

“Results from this study show that the Hestia criteria are efficacious and safe in helping doctors determine which acute PE patients can receive outpatient anticoagulant treatment safely,” said Menno Huisman, MD, PhD, Associate Professor of Medicine, Chair, Section of Vascular Medicine in the Department of Medicine at Leiden University Medical Center in Leiden, Netherlands. “This set of criteria serves as an easy-to-use model for clinicians who treat PE patients.”

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