Franco Piovella

Oral rivaroxaban for symptomatic venous thromboembolism.

BACKGROUND Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. METHODS We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. RESULTS The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). CONCLUSIONS Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis: A Randomized Trial

Context Are selective inhibitors of factor Xa as good as low-molecular-weight heparin in treating deep venous thrombosis? Contribution In this large, multicenter, double-blind trial, patients with symptomatic deep venous thrombosis were randomly assigned to receive either fondaparinux ( a selective inhibitor of factor Xa) or enoxaparin given subcutaneously for at least 5 days plus an oral vitamin K antagonist for 3 months. In both groups, about 1% of the patients experienced major bleeding during initial treatment and about 4% had recurrent thromboembolic events within 3 months. Implications Fondaparinux and enoxaparin have similar safety and efficacy for initial treatment of symptomatic deep venous thrombosis. The Editors Low-molecular-weight heparin (LMWH) therapy has expanded the options for initial management of patients presenting with deep venous thrombosis (1, 2). Low-molecular-weight heparin treatment is simple and consists of once- or twice-daily subcutaneous injection of a dose adjusted only for body weight. Treating suitable patients at home, often with self-injection, is effective and safe and has become standard practice in many settings (2-4). Clinically relevant aspects of LMWH treatment of venous thromboembolism remain uncertain, which may influence usage and recurrence or bleeding. First, LMWHs differ among themselves. Second, data on whether once- or twice-daily LMWH may be superior are conflicting (5, 6), suggesting that a once-daily regimen of enoxaparin may be less effective in patients with higher body mass index and patients with cancer (7). Third, since LMWHs are eliminated in the urine and plasma levels are higher in patients with even modest renal insufficiency (8), some clinicians administer lower dosages when the patients creatinine clearance is less than 0.84 mL/s (9), despite few outcome data to guide such alterations. Finally, in addition to the clinical and economic circumstances, practical issues surround drug administration, including the patients capacity to administer the desired dosage from a fixed-volume syringe or multidose vial; these issues can affect the feasibility of early discharge and home treatment. Fondaparinux is a synthetic and selective inhibitor of factor Xa that has proven efficacy and safety for preventing venous thromboembolism in orthopedic surgery. Although laboratory observations and theory suggested that such a compound might not be effective for treating established thrombosis (10), a dose-ranging study of deep venous thrombosis treatment found that a once-daily subcutaneous injection of fondaparinux, 7.5 mg, may be effective and safe across a broad range of body weights (50 kg and 100 kg) (11). Pharmacokinetic analyses suggested that daily doses of 5 mg and 10 mg are appropriate for patients less than and more than that weight range, respectively. Moreover, the predictable and sustained anticoagulant effect of fondaparinux for 24 hours allows once-daily injection, and since fondaparinux does not cross-react with heparin-induced antibodies, platelet count monitoring may no longer be needed (12). This may further simplify treatment. Therefore, we designed this randomized, double-blind study of 2205 symptomatic patients to determine whether the efficacy and safety of a once-daily subcutaneous fixed-dose regimen of fondaparinux are similar to those of the standard therapy of a twice-daily, subcutaneous, body weightadjusted regimen of enoxaparin. Early discharge was encouraged in both treatment groups. The large sample size allowed outcome assessment in patients with a broad range of body weights and renal function. Methods Patients Consecutive patients (>18 years of age) who presented with acute symptomatic deep venous thrombosis involving the popliteal, femoral, or iliac veins or the trifurcation of the calf veins and who required antithrombotic therapy were eligible for the study. Diagnostic criteria for deep venous thrombosis were a noncompressible vein found on ultrasonography or an intraluminal filling defect found on venography (11, 13). Patients were ineligible for the study if they had symptomatic pulmonary embolism; received therapeutic doses of anticoagulants or oral anticoagulant therapy for more than 24 hours; required thrombolysis, thrombectomy, or a vena cava filter; had contraindication to anticoagulant therapy (for example, active bleeding, thrombocytopenia [platelet count < 100 109 cells/L]); had elevated serum creatinine levels (>177 mol/L [>2 mg/dL]); had contraindication to contrast medium; had uncontrolled hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg); were pregnant; or had a life expectancy of less than 3 months. After giving informed consent, patients were randomly assigned by a computerized interactive voice response system that recorded information about patients before treatment assignment. Randomization was stratified by center in balanced blocks of 4 patients. The respective institutional review boards approved the study protocol, and an independent data safety monitoring board monitored the study. We assessed 5141 patients for eligibility: 2205 patients were randomly assigned to study groups, 2416 patients were excluded, and 520 patients declined to participate (Figure). The most common reasons for exclusion were the use of therapeutic anticoagulation for more than 24 hours, thrombolytic therapy, or vena cava filter (580 patients); contraindication to anticoagulant therapy (395 patients); symptomatic pulmonary embolism (387 patients); and a life expectancy of less than 3 months (228 patients). Figure. Flow of patients through the study. Treatment Regimens The patients allocated to fondaparinux (Arixtra, NV Organon, Oss, the Netherlands, and Sanofi-Synthlabo, Paris, France) received a once-daily subcutaneous injection of 5.0 mg if they weighed less than 50 kg, 7.5 mg if they weighed between 50 and 100 kg, or 10.0 mg if they weighed more than 100 kg. They also received twice-daily subcutaneous injections of placebo that appeared identical to enoxaparin. The patients allocated to enoxaparin (Lovenox, Clexane, Aventis Pharmaceuticals, Bridgewater, New Jersey) received a twice-daily subcutaneous dose of 1 mg/kg of body weight and a once-daily subcutaneous injection of placebo that appeared identical to fondaparinux. Although home treatment with the study drug was allowed, the treating physician made this decision and the drug had to be administered by a home care service. In both groups, vitamin K antagonist therapy was started as soon as possible but within 72 hours of initiation of fondaparinux or enoxaparin therapy. The investigator chose the type of vitamin K antagonist therapy according to local hospital practice. The same type of vitamin K antagonist was recommended for all patients in a particular center. During initial treatment, prothrombin times were measured at least every other day and the dose of vitamin K antagonist was adjusted to maintain the international normalized ratio between 2.0 and 3.0. Double-blind, initial treatment was continued for at least 5 days and until the international normalized ratio was greater than 2.0 for 2 consecutive days. Treatment with vitamin K antagonists was continued for 3 months, and the international normalized ratio was determined at least once per month. Surveillance and Follow-up All patients were contacted daily during initial treatment and at 1 and 3 months. At each contact, patients were evaluated for symptomatic recurrence of deep venous thrombosis or pulmonary embolism and bleeding and were informed about the symptoms and signs of these conditions. They were instructed to report to the study center on an emergency basis if any of these conditions occurred. If recurrent deep venous thrombosis or pulmonary embolism was suspected, the protocol required objective testing for confirmation. Outcome Assessment The primary efficacy outcome was the incidence of symptomatic recurrent venous thromboembolism during the 3-month study period. Symptomatic recurrent venous thromboembolism was defined as objectively documented recurrent deep venous thrombosis or pulmonary embolism or death in which pulmonary embolism was a contributing cause or could not be excluded. Without objective test results to adequately confirm or exclude recurrent venous thromboembolism, this diagnosis was accepted if the physician managed the patient with therapeutic doses of LMWH for more than 2 days, thrombolysis, a vena cava filter, or thrombectomy (3, 13). The criteria for the objective diagnosis of recurrent deep venous thrombosis were a new noncompressible venous segment or a substantial increase ( 4 mm) in diameter of the thrombus during full compression in a previously abnormal segment on ultrasonography (14, 15) or a new intraluminal filling defect found on venography. The criteria for the objective diagnosis of pulmonary embolism were an intraluminal filling defect on spiral computed tomography or pulmonary angiography, cut-off of a vessel of more than 2.5 mm in diameter on pulmonary angiography, perfusion defect of at least 75% of a segment with corresponding normal ventilation (high-probability lung scan), nondiagnostic lung scan associated with new deep venous thrombosis documented by ultrasonography or venography, or pulmonary embolism confirmed by autopsy. The main safety outcomes were major bleeding during the initial treatment period and 3-month mortality. Bleeding was defined as major if it was clinically overt and associated with a decrease in the hemoglobin level of 20 g/L or more, led to transfusion of 2 or more units of red blood cells or whole blood cells, was retroperitoneal or intracranial, occurred in a critical organ, or contributed to death. Bleeding episodes that were clinically relevant but not major (for example, epistaxis that required intervention or spontaneous macroscopic hematuria) were an additional safety outcome. The cause of deat

The Effect of Low Molecular Weight Heparin on Survival in Patients With Advanced Malignancy

PURPOSE Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism. METHODS Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding. RESULTS In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25). CONCLUSION A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.

Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery.

Background Compression stockings are recommended for prophylaxis against venous thromboembolism in patients undergoing neurosurgery, but anticoagulant agents have not gained wide acceptance because of concern about intracranial bleeding. Methods In a multicenter, randomized, double-blind trial, we assessed the efficacy and safety of enoxaparin in conjunction with the use of compression stockings in the prevention of venous thromboembolism in patients undergoing elective neurosurgery. Enoxaparin (40 mg once daily) or placebo was given subcutaneously for not less than seven days beginning within 24 hours after surgery. The primary end point was symptomatic, objectively confirmed venous thromboembolism or deep-vein thrombosis assessed by bilateral venography, which was performed in all patients on day 8±1. Bleeding side effects were carefully assessed. Results Among the 307 patients assigned to treatment groups, 129 of the 154 patients receiving placebo (84 percent) and 130 of the 153 patients receiving enoxaparin (85 percent) had venographic studies adequate for analysis. An additional patient in the placebo group died before venography of autopsyconfirmed pulmonary embolism. In this analysis, 42 patients given placebo (32 percent) and 22 patients given enoxaparin (17 percent) had deep-vein thrombosis (relative risk in the enoxaparin group, 0.52; 95 percent confidence interval, 0.33 to 0.82; P=0.004). The rates of proximal deep-vein thrombosis were 13 percent in patients receiving placebo and 5 percent in patients receiving enoxaparin (relative risk in the enoxaparin group, 0.41; 95 percent confidence interval, 0.17 to 0.95; P=0.04). Two patients in the placebo group died of autopsy-confirmed pulmonary embolism on days 9 and 16. Major bleeding occurred in four patients receiving placebo (intracranial bleeding in all four) and four patients (intracranial bleeding in three) receiving enoxaparin (3 percent of each group). Conclusions Enoxaparin combined with compression stockings is more effective than compression stockings alone for the prevention of venous thromboembolism after elective neurosurgery and does not cause excessive bleeding. (N Engl J Med 1998; 339:80-5.)

Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: Results of a meta-analysis

PURPOSE To obtain reliable estimates of the relative efficacy and safety of low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH) in the treatment of patients with venous thromboembolism. METHODS A literature search of randomized trials evaluating LMWH and UFH for the period from 1980 to 1994 was conducted to obtain data for a meta-analysis. Studies were classified as level 1 if they were double-blind or if there was blinded assessment of outcome measures, and level 2 if they did not provide assurance of blinded outcome assessment. RESULTS In level 1 studies, the relative risk (RR) of recurrent venous thromboembolism during the first 15 days and over the entire period of anticoagulant therapy was 0.24 (95% confidence intervals [CI] 0.06 to 0.80, P = 0.02) and 0.39 (95% CI 0.30 to 0.80, P = 0.006), respectively, in favor of LMWH treatment. The RR for major bleeding was 0.42 (95% CI 0.2 to 0.9, P = 0.01), in favor of LMWH. In level 2 studies, no significant differences in the rates of recurrent venous thromboembolism or major bleeding were observed. Pooling level 1 and level 2 studies, the RR for overall mortality and mortality in cancer patients was 0.51 (95% CI 0.2 to 0.9, P = 0.01), and 0.33 (95% CI 0.1 to 0.8, P = 0.01), respectively in favor of LMWH. CONCLUSIONS LMWH are likely to be more effective than UFH in preventing recurrent venous thromboembolism, to produce less major bleeding, and to be associated with a lower mortality rate, particularly in the subgroup of patients with cancer.

D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study

Abstract Objective To investigate the efficacy of using a rapid plasma D-dimer test as an adjunct to compression ultrasound for diagnosing clinically suspected deep vein thrombosis. Design D-dimer concentrations were determined in all patients with a normal ultrasonogram at presentation. Repeat ultrasonography was performed 1 week later only in patients with abnormal D-dimer test results. Main outcome measure Patients with normal ultrasonograms were not treated with anticoagulants and were followed for 3 months for thromboembolic complications. Setting University research and affiliated centres. Subjects 946 patients with clinically suspected deep vein thrombosis. Results Ultrasonograms were abnormal at presentation in 260 (27.5%) patients. Of the remaining 686 patients tested for D-dimer, 88 (12.8%) had abnormal concentrations. During follow up venous thromboembolic complications occurred in one of the 598 patients who were not treated with anticoagulants and who had an initial normal ultrasonogram and D-dimer concentration, whereas thromboembolic complications occurred in two of the 83 untreated patients who had abnormal D-dimer concentrations but a normal repeat ultrasonogram. The cumulative incidence of venous thromboembolic complications during follow up was 0.4% (95% confidence interval 0% to 0.9%). The rapid plasma D-dimer test used as an adjunct to compression ultrasonography resulted in a reduction in the mean number of repeat ultrasound examinations and additional hospital visits from 0.7 to 0.1 per patient. Conclusions Testing for D-dimer as an adjunct to a normal baseline ultrasound examination decreased the number of subsequent ultrasound examinations considerably without any increased risk of venous thromboembolic complications in patients not receiving anticoagulants. The use of ultrasound and testing for D-dimer enabled treatment decisions to be made at the time of presentation in most patients.

Factors at Admission Associated With Bleeding Risk in Medical Patients: Findings From the IMPROVE Investigators

BACKGROUND Acutely ill, hospitalized medical patients are at risk of VTE. Despite guidelines for VTE prevention, prophylaxis use in these patients is still poor, possibly because of fear of bleeding risk. We used data from the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) to assess in-hospital bleeding incidence and to identify risk factors at admission associated with in-hospital bleeding risk in acutely ill medical patients. METHODS IMPROVE is a multinational, observational study that enrolled 15,156 medical patients. The in-hospital bleeding incidence was estimated by Kaplan-Meier analysis. A multiple regression model analysis was performed to identify risk factors at admission associated with bleeding. RESULTS The cumulative incidence of major and nonmajor in-hospital bleeding within 14 days of admission was 3.2%. Active gastroduodenal ulcer (OR, 4.15; 95% CI, 2.21-7.77), prior bleeding (OR, 3.64; 95% CI, 2.21-5.99), and low platelet count (OR, 3.37; 95% CI, 1.84-6.18) were the strongest independent risk factors at admission for bleeding. Other bleeding risk factors were increased age, hepatic or renal failure, ICU stay, central venous catheter, rheumatic disease, cancer, and male sex. Using these bleeding risk factors, a risk score was developed to estimate bleeding risk. CONCLUSIONS We assessed the incidence of major and clinically relevant bleeding in a large population of hospitalized medical patients and identified risk factors at admission associated with in-hospital bleeding. This information may assist physicians in deciding whether to use mechanical or pharmacologic VTE prophylaxis.

Travel and risk of venous thrombosis.

Summary In 1998 the term economy class syndrome was coined to describe the association between travel and thrombosis. A fair risk estimate, however, has not been done. We report the results of a prospective study, in which we kept the effect of bias to a minimum. We compared travel history in 788 patients with venous thrombosis with that of controls with similar symptoms but in whom the disease had been excluded. For air travel alone, the odds ratio was 1·0 (95% CI 0·3–3·0); also, no association was recorded for other methods of transportation. We have shown that, there is no increased risk of deep vein thrombosis among travellers.

Predictive and Associative Models to Identify Hospitalized Medical Patients at Risk for VTE

BACKGROUND Acutely ill hospitalized medical patients are at risk for VTE. We assessed the incidence of VTE in the observational International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) study and derived VTE risk assessment scores at admission and associative VTE scores during hospitalization. METHODS Data from 15,156 medical patients were analyzed to determine the cumulative incidence of clinically observed VTE over 3 months after admission. Multiple regression analysis identified factors associated with VTE risk. RESULTS Of the 184 patients who developed symptomatic VTE, 76 had pulmonary embolism, and 67 had lower-extremity DVT. Cumulative VTE incidence was 1.0%; 45% of events occurred after discharge. Factors independently associated with VTE were previous VTE, known thrombophilia, cancer, age > 60 years, lower-limb paralysis, immobilization ≥ 7 days, and admission to an ICU or coronary care unit (first four were available at admission). Points were assigned to each factor identified to give a total risk score for each patient. At admission, 67% of patients had a score ≥ 1. During hospitalization, 31% had a score ≥ 2; for a score of 2 or 3, observed VTE risk was 1.5% vs 5.7% for a score ≥ 4. Observed and predicted rates were similar for both models (C statistic, 0.65 and 0.69, respectively). During hospitalization, a score ≥ 2 was associated with higher overall and VTE-related mortality. CONCLUSIONS Weighted VTE risk scores derived from four clinical risk factors at hospital admission can predict VTE risk in acutely ill hospitalized medical patients. Scores derived from seven clinical factors during hospitalization may help us to further understand symptomatic VTE risk. These scores require external validation.

Deep-vein thrombosis rates after major orthopedic surgery in Asia. An epidemiological study based on postoperative screening with centrally adjudicated bilateral venography

Summary.  Background: The incidence of postsurgical venous thromboembolism is thought to be low in Asian ethnic populations. Objective: We studied the incidence of deep‐vein thrombosis (DVT) in Asian patients undergoing major orthopedic surgery of the lower limbs. Patients/methods: We performed a prospective epidemiological study in 19 centers across Asia (China, Indonesia, South Korea, Malaysia, Philippines, Taiwan, and Thailand) in patients undergoing elective total hip replacement (THR), total knee replacement (TKR) or hip fracture surgery (HFS) without pharmacological thromboprophylaxis. The primary endpoint was the rate of DVT of the lower limbs documented objectively with bilateral ascending venography performed 6–10 days after surgery using a standardized technique and evaluated by a central adjudication committee unaware of local interpretation. Results: Overall, of 837 Asian patients screened for this survey, 407 (48.6%, aged 20–99 years) undergoing THR (n = 175), TKR (n = 136) or HFS (n = 96) were recruited in 19 centers. DVT was diagnosed in 121 of 295 evaluable patients [41.0%, (95% confidence interval (CI): 35.4–46.7)]. Proximal DVT was found in 30 patients [10.2% (7.0–14.2)]. Total DVT and proximal DVT rates were highest in TKR patients (58.1% and 17.1%, respectively), followed by HFS patients (42.0% and 7.2%, respectively), then THR patients (25.6% and 5.8%, respectively). DVT was more frequent in female patients aged at least 65 years. Pulmonary embolism was clinically suspected in 10 of 407 patients (2.5%) and objectively confirmed in two (0.5%). Conclusions: The rate of venographic thrombosis in the absence of thromboprophylaxis after major joint surgery in Asian patients is similar to that previously reported in patients in Western countries.