Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism. Limited data support the clinical benefit of antithrombotic prophylaxis.
In this double-blind, multicenter ...trial, we evaluated the efficacy and safety of the ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients receiving chemotherapy for cancer. Patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were randomly assigned to receive subcutaneous semuloparin, 20 mg once daily, or placebo until there was a change of chemotherapy regimen. The primary efficacy outcome was the composite of any symptomatic deep-vein thrombosis, any nonfatal pulmonary embolism, and death related to venous thromboembolism. Clinically relevant bleeding (major and nonmajor) was the main safety outcome.
The median treatment duration was 3.5 months. Venous thromboembolism occurred in 20 of 1608 patients (1.2%) receiving semuloparin, as compared with 55 of 1604 (3.4%) receiving placebo (hazard ratio, 0.36; 95% confidence interval CI, 0.21 to 0.60; P<0.001), with consistent efficacy among subgroups defined according to the origin and stage of cancer and the baseline risk of venous thromboembolism. The incidence of clinically relevant bleeding was 2.8% and 2.0% in the semuloparin and placebo groups, respectively (hazard ratio, 1.40; 95% CI, 0.89 to 2.21). Major bleeding occurred in 19 of 1589 patients (1.2%) receiving semuloparin and 18 of 1583 (1.1%) receiving placebo (hazard ratio, 1.05; 95% CI, 0.55 to 1.99). Incidences of all other adverse events were similar in the two study groups.
Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding. (Funded by Sanofi; ClinicalTrials.gov number, NCT00694382.).
A number of novel oral anticoagulants that directly target factor Xa or thrombin have been developed in recent years. Rivaroxaban and apixaban (direct factor Xa inhibitors) and dabigatran etexilate ...(a direct thrombin inhibitor) have shown considerable promise in large-scale, randomised clinical studies for the management of thromboembolic disorders, and have been approved for clinical use in specific indications. Rivaroxaban is licensed for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery, the treatment of deep-vein thrombosis and prevention of recurrent venous thromboembolism, and for stroke prevention in patients with non-valvular atrial fibrillation. Based on the clinical trial data for rivaroxaban, feedback on its use in clinical practice and the authors' experience with the use of rivaroxaban, practical guidance for the use of rivaroxaban in special patient populations and specific clinical situations is provided. Although most recommendations are in line with the European summary of product characteristics for the approved indications, additional and, in several areas, different recommendations are given based on review of the literature and the authors' clinical experience.
The peri-operative management of patients on oral anticoagulants (OACs) is a common clinical problem. Our aim was to determine the incidence of major bleeding during peri-operative administration of ...treatment-dose enoxaparin and the impact of the extensiveness of the procedure on the risk of bleeding.
We performed a prospective cohort study of 260 patients at 24 North American sites on OACs for atrial fibrillation or a history of deep vein thrombosis (DVT) requiring invasive or surgical procedures whose treating physician felt that bridging therapy was required. Warfarin was withheld, and once-daily s.c. enoxaparin (1.5 mg kg(-1)) was given peri-operatively. Patients were followed for 28 days after OAC was therapeutic.
Major bleeding was observed in nine of 260 patients (3.5%, 95% CI: 1.6-6.5). The bleeding risk varied markedly by extensiveness of procedure: the incidence of major bleeding for invasive procedures, minor surgery and major surgery was 0.7% (95% CI: 0.02-3.7), 0% (95% CI: 0-5.0), and 20.0% (95% CI: 9.1-35.7), respectively. There were five thromboembolic events in total (1.9%, 95% CI: 0.6-4.4). There were four arterial events (2.3%, 95% CI: 0.6-5.7) in 176 patients with atrial fibrillation, and one venous event (1.0%, 95% ci: 0.03-5.7) in 96 patients with prior DVT/ CONCLUSIONS: Bridging therapy with once-daily therapeutic-dose enoxaparin administered primarily in an outpatient setting has a low incidence of major bleeding for patients undergoing invasive procedures and minor surgery. Further studies are needed to optimize the bridging strategy for patients undergoing major surgery.
Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies ...are critical to future RCT success.
The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design.
No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval CI 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%).
The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT.
BAY 59-7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery.
In a ...multicenter, parallel-group, double-blind, double-dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59-7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12-24 h postsurgery). Treatment was continued until mandatory bilateral venography 5-9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non-fatal pulmonary embolism and all-cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment.
Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59-7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59-7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5-10 mg b.i.d. doses compared with higher doses of BAY 59-7939.
Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.
Low-molecular-weight heparins are attractive alternatives to unfractionated heparin (UFH) for management of unstable angina/non-Q-wave myocardial infarction (UA/NQMI).
Patients (n=3910) with UA/NQMI ...were randomized to intravenous UFH for >/=3 days followed by subcutaneous placebo injections or uninterrupted antithrombin therapy with enoxaparin during both the acute phase (initial 30 mg intravenous bolus followed by injections of 1.0 mg/kg every 12 hours) and outpatient phase (injections every 12 hours of 40 mg for patients weighing <65 kg and 60 mg for those weighing >/=65 kg). The primary end point (death, myocardial infarction, or urgent revascularization) occurred by 8 days in 14.5% of patients in the UFH group and 12.4% of patients in the enoxaparin group (OR 0.83; 95% CI 0.69 to 1.00; P=0. 048) and by 43 days in 19.7% of the UFH group and 17.3% of the enoxaparin group (OR 0.85; 95% CI 0.72 to 1.00; P=0.048). During the first 72 hours and also throughout the entire initial hospitalization, there was no difference in the rate of major hemorrhage in the treatment groups. During the outpatient phase, major hemorrhage occurred in 1.5% of the group treated with placebo and 2.9% of the group treated with enoxaparin (P=0.021).
Enoxaparin is superior to UFH for reducing a composite of death and serious cardiac ischemic events during the acute management of UA/NQMI patients without causing a significant increase in the rate of major hemorrhage. No further relative decrease in events occurred with outpatient enoxaparin treatment, but there was an increase in the rate of major hemorrhage.
We have previously demonstrated that a clinical model can be safely used in a management strategy in patients with suspected pulmonary embolism (PE). We sought to simplify the clinical model and ...determine a scoring system, that when combined with D-dimer results, would safely exclude PE without the need for other tests, in a large proportion of patients. We used a randomly selected sample of 80% of the patients that participated in a prospective cohort study of patients with suspected PE to perform a logistic regression analysis on 40 clinical variables to create a simple clinical prediction rule. Cut points on the new rule were determined to create two scoring systems. In the first scoring system patients were classified as having low, moderate and high probability of PE with the proportions being similar to those determined in our original study. The second system was designed to create two categories, PE likely and unlikely. The goal in the latter was that PE unlikely patients with a negative D-dimer result would have PE in less than 2% of cases. The proportion of patients with PE in each category was determined overall and according to a positive or negative SimpliRED D-dimer result. After these determinations we applied the models to the remaining 20% of patients as a validation of the results. The following seven variables and assigned scores (in brackets) were included in the clinical prediction rule: Clinical symptoms of DVT (3.0), no alternative diagnosis (3.0), heart rate >100 (1.5), immobilization or surgery in the previous four weeks (1.5), previous DVT/PE (1.5), hemoptysis (1.0) and malignancy (1.0). Patients were considered low probability if the score was <2.0, moderate of the score was 2.0 to 6.0 and high if the score was over 6.0. Pulmonary embolism unlikely was assigned to patients with scores < or =4.0 and PE likely if the score was >4.0. 7.8% of patients with scores of less than or equal to 4 had PE but if the D-dimer was negative in these patients the rate of PE was only 2.2% (95% CI = 1.0% to 4.0%) in the derivation set and 1.7% in the validation set. Importantly this combination occurred in 46% of our study patients. A score of <2.0 and a negative D-dimer results in a PE rate of 1.5% (95% CI = 0.4% to 3.7%) in the derivation set and 2.7% (95% CI = 0.3% to 9.0%) in the validation set and only occurred in 29% of patients. The combination of a score < or =4.0 by our simple clinical prediction rule and a negative SimpliRED D-Dimer result may safely exclude PE in a large proportion of patients with suspected PE.
Thromboembolic disorders are major causes of morbidity and mortality. It is well-recognised that the pathogenesis is different for arterial and venous thrombosis; however, both involve coagulation ...activation. Anticoagulants are used for the prevention and treatment of a wide variety of thromboembolic and related conditions. Agents with anti- inflammatory properties in addition to anticoagulation may be particularly beneficial. Traditional anticoagulants, although effective, are associated with certain limitations. Understanding the pathological processes associated with thrombosis and the rational target for anticoagulation is essential, not only for the development of safer and more effective agents, but also for better clinical management of patients who require anticoagulation therapy. In recent years, new oral agents that target single enzymes of the coagulation cascade have been developed--some of those are in advanced stages of clinical development. Based on scientific rationale, both factor Xa and thrombin are viable targets for effective anticoagulation.
Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low-molecular-weight heparin (LMWH) for at least 3-6 ...months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE.
Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6 and 7-12.
Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding.
Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.
When warfarin is interrupted for surgery, low-molecular-weight heparin is often used as bridging therapy. However, this practice has never been evaluated in a large prospective study. This study was ...designed to assess the efficacy and safety of bridging therapy with low-molecular-weight heparin initiated out of hospital.
This was a prospective, multicenter, single-arm cohort study of patients at high risk of arterial embolism (prosthetic valves and atrial fibrillation with a major risk factor). Warfarin was held for 5 days preoperatively. Low-molecular-weight heparin was given 3 days preoperatively and at least 4 days postoperatively. Patients were followed up for 3 months for thromboembolism and bleeding. Eleven Canadian tertiary care academic centers participated; 224 patients were enrolled. Eight patients (3.6%; 95% CI, 1.8 to 6.9) had an episode of thromboembolism, of which 2 (0.9%; 95% CI, 0.2 to 3.2) were judged to be due to cardioembolism. Of these 8 episodes of thromboembolism, 6 occurred in patients who had warfarin deferred or withdrawn because of bleeding. There were 15 episodes of major bleeding (6.7%; 95% CI, 4.1 to 10.8): 8 occurred intraoperatively or early postoperatively before low-molecular-weight heparin was restarted, 5 occurred in the first postoperative week after low-molecular-weight heparin was restarted, and 2 occurred well after low-molecular-weight heparin was stopped. There were no deaths.
Bridging therapy with subcutaneous low-molecular-weight heparin is feasible; however, the optimal approach for the management of patients who require temporary interruption of warfarin to have invasive procedures is uncertain.
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