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SummaryAnnual costs for venous thromboembolism (VTE) have been defined within the United States (US) demonstrating a large opportunity for cost savings. Costs for the European Union-28 (EU-28) have never been defined. A literature search was conducted to evaluate EU-28 cost sources. Median costs were defined for each cost input and costs were inflated to 2014 Euros (€) in the study country and adjusted for Purchasing Power Parity between EU countries. Adjusted costs were used to populate previously published cost-models based on adult incidence-based events. In the base model, annual expenditures for total, hospital-associated, preventable, and indirect costs were €1.5–2.2 billion, €1.0–1.5 billion, €0.5–1.1 billion and €0.2–0.3 billion, respectively (indirect costs: 12 % of expenditures). In the long-term attack rate model, total, hospital-associated, preventable, and indirect costs were €1.8–3.3 billion, €1.2–2.4 billion, €0.6–1.8 billion and €0.2–0.7 billion (indirect costs: 13 % of expenditures). In the multiway sensitivity analysis, annual expenditures for total, hospital-associated, preventable, and indirect costs were €3.0–8.5 billion, €2.2–6.2 billion, €1.1–4.6 billion and €0.5–1.4 billion (indirect costs: 22 % of expenditures). When the value of a premature life-lost increased slightly, aggregate costs rose considerably since these costs are higher than the direct medical costs. When evaluating the models aggregately for costs, the results suggests total, hospital-associated, preventable, and indirect costs ranging from €1.5–13.2 billion, €1.0–9.7 billion, €0.5–7.3 billion and €0.2–6.1 billion, respectively. Our study demonstrates that VTE costs have a large financial impact upon the EU-28’s healthcare systems and that significant savings could be realised if better preventive measures are applied.

Introduction Pulmonary embolism (PE) is a potentially life-threatening cardiovascular emergency with a high mortality rate. Rapid diagnosis and treatment are important in optimising clinical outcomes in patients with PE, and anticoagulants are the mainstay of treatment. Traditionally, anticoagulant therapy involves parenteral anticoagulants, overlapping with and followed by oral vitamin K antagonists. Direct oral anticoagulants (DOACs), including the factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the direct thrombin inhibitor dabigatran etexilate, have been developed to address limitations associated with traditional anticoagulant therapy. Apixaban, dabigatran and rivaroxaban have recently been approved for the treatment of acute deep vein thrombosis (DVT) and PE and prevention of recurrent DVT or PE. Edoxaban is approved in the United States but not currently in the European Union for the treatment of DVT and PE; approval of edoxaban in Europe is anticipated in the near future. Objective To summarise the management of patients with suspected PE in accordance with recent guidelines, and to discuss the evidence behind the recent approvals of the DOACs for the treatment of PE. Discussion Diagnosis and treatment of PE is guided by clinical probability scoring systems and tools for prognostic stratification and early mortality risk evaluation. Anticoagulants remain the mainstay of treatment. Successful phase III trials have demonstrated the efficacy of the DOACs for the treatment of DVT and PE, with a potentially improved safety profile, leading to their recent approval in this indication, and giving the clinician greater choice of anticoagulant therapies in this setting. Conclusions DOACs offer an alternative and potentially simplified option for anticoagulation therapy in patients with PE compared with traditional anticoagulants and are likely to assist physicians in optimising management of patients with PE and improve clinical outcomes.

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2–54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23–4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.

Evidence from the use of traditional therapy (low-molecular-weight heparin/vitamin K antagonists) for venous thromboembolism (VTE) treatment and prevention suggests that extending treatment beyond the acute phase reduces recurrence. More recently, several non-vitamin K antagonist oral anticoagulants (NOACs) have been approved in the acute setting; accumulating evidence suggests continuing treatment with these agents beyond 12months offers additional benefits to patients with VTE. This review examines the evidence for NOAC use in longer-duration anticoagulation treatment, and discusses guidelines from major societies. Clinical data from the phase III extension studies for apixaban, dabigatran and rivaroxaban are presented, and the clinical and economic costs and benefits are examined. Evidence from other therapy areas utilising extended treatment regimens highlights the possible impact of factors relevant to extended anticoagulation therapy. Phase IV studies of NOACs are presented. US and European guidelines advise long-term therapy in certain instances, taking into account evidence on NOAC use in VTE accumulated recently. They support NOAC use where they have been selected as the initial therapy choice and therapy needs to be extended beyond 3months. The phase III extension studies demonstrate the benefits of extended NOAC use versus treatment cessation, with reduced recurrence rates versus placebo, although associated with a potential moderate increase in bleeding risk. Phase IV data are also emerging, with the recent XALIA study showing that a broad range of patients with VTE can benefit from continued rivaroxaban treatment; ongoing research will yield data on long-term use of the other NOACs in routine clinical practice.

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.

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.

SummaryStandard treatment with heparin followed by vitamin K antagonists is frequently complicated by bleeding and recurrent venous thromboembolism (VTE) in cancer patients with VTE. To compare the efficacy, safety and overall survival of long-term idraparinux treatment to standard therapy in cancer patients we conducted a post-hoc analysis in the subgroup of non-active and active cancer patients included in the Van Gogh DVT clinical trial. The cancer patients with deep venous thrombosis (DVT) and without pulmonary embolism (PE) were randomised to standard treatment or a once-weekly subcutaneous injection of idraparinux (2.5 mg), a synthetic pentasaccharide. 421 cancer patients were included. A total of 220 patients received idraparinux and 201 were allocated to standard therapy for three months (8%) or six months (92%). A recurrent VTE was observed during the first six months in 2.5% (n=5) of the idraparinux recipients compared to 6.4% (n=12) in the standard therapy group (hazard ratio 0.39, 95% confidence interval [CI]; 0.14–1.11). The rate of bleeding was comparable (odds ratio 0.89, 95% CI; 0.50–1.59). The outcomes were similar at three months after randomisation in all patients. Of the idraparinux recipients, 22.7% (n=50) died during the study period compared to 48 patients (23.9%) in the standard treatment group (hazard ratio 0.99, 95% CI; 0.66–1.48). In conclusion, no significant safety or survival differences were observed between cancer patients with DVT treated with idraparinux for six months compared to standard therapy. Fewer recurrent VTEs were observed in the idraparinux group; however, this was not statistically significant and also because of study limitations this should be interpreted with caution.

Neurological disorders are often associated with immobilization, thus placing patients at increased risk for venous thromboembolism (VTE). This risk is very high in patients with acute ischemic stroke and spinal cord injuries, and it remains poorly defined in patients with peripheral nervous disorders or degenerative disorders of the central nervous system. The benefit of prophylactic strategies remains often unclear. The Italian Society for Studies on Haemostasis and Thrombosis promoted the development of evidence- and consensus-based guidelines to help physicians involved in the management of neurological patients. After a comprehensive and systematic review of the literature, a panel of experts formulated recommendations for the prevention of VTE in adolescent or adult patients presenting with different neurological disorders. Patients with acute ischemic stroke should routinely receive pharmacological prophylaxis to be started within 48 hours and continued for approximately 14 days; patients with acute hemorrhagic stroke should routinely receive mechanical prophylaxis, pharmacological prophylaxis should be considered once the patient is stable; patients with neuro-muscular degenerative diseases and with other major risk factors for venous thrombosis should be considered for the administration of pharmacological or mechanical prophylaxis; patients with peripheral nerve diseases should receive mechanical prophylaxis while immobilized and in the presence of additional risk factors for VTE, patients with Guillain Barrè should be considered for pharmacological prophylaxis with low molecular weight heparin; patients with spinal cord injury should receive combined mechanical and pharmacological prophylaxis; patients with non traumatic spinal cord diseases should be considered for pharmacological prophylaxis.

Summary. Background: It remains unclear whether a single complete ultrasound examination, which detects calf vein thrombosis, is as safe as a baseline rapid ultrasound examination, repeated after 1 week when negative, which examines the veins in the groin and the knee. Therefore, we compared the safety and feasibility of two diagnostic ultrasound strategies, involving rapid and complete compression ultrasound (CUS) examination. Methods: Consecutive patients with suspected deep vein thrombosis (DVT) underwent clinical probability assessment. In patients with an unlikely clinical probability and a normal D-dimer finding, DVT was considered to be excluded. All others were randomized to undergo a rapid or a single complete CUS examination. Patients in whom DVT was excluded were followed for 3 months to assess the incidence of venous thromboembolism (VTE). Results: A total of 1002 patients were included. A clinical decision rule indicating DVT to be unlikely and a normal D-dimer finding occurred in 481 patients (48%), with a VTE incidence of 0.4% [95% confidence interval (CI) 0.05–1.5%] during follow-up. DVT was confirmed in 59 of the 257 patients (23%) who underwent rapid CUS examination, and in 99 of the 264 patients (38%) who underwent complete CUS examination. VTE during follow-up occurred in four patients (2.0%; 95% CI 0.6–5.1%) in the rapid CUS arm, and in two patients (1.2%; 95% CI 0.2–4.3%) in the complete CUS arm. Conclusions: A diagnostic strategy with a clinical decision rule, a D-dimer test and a CUS examination is safe and efficient. Both the rapid and the complete CUS test are comparable and efficient strategies, with differing advantages and disadvantages.

Background Evidence-based guidelines recommend that acutely ill hospitalized medical patients who are at risk of venous thromboembolism (VTE) should receive prophylaxis. Our aim was to characterize the clinical practices for VTE prophylaxis in acutely ill hospitalized medical patients enrolled in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE). Methods IMPROVE is an ongoing, multinational, observational study. Participating hospitals enroll the first 10 consecutive eligible acutely ill medical patients each month. Patient management is determined by the treating physicians. An analysis of data on VTE prophylaxis practices is presented. Results From July 2002 to September 30, 2006, 15,156 patients were enrolled from 52 hospitals in 12 countries, of whom 50% received in-hospital pharmacologic and/or mechanical VTE prophylaxis. In the United States and other participating countries, 52% and 43% of patients, respectively, should have received prophylaxis according to guideline recommendations from the American College of Chest Physicians (ACCP). Only approximately 60% of patients who either met the ACCP criteria for requiring prophylaxis or were eligible for enrollment in randomized clinical trials that have shown the benefits of pharmacologic prophylaxis actually received prophylaxis. Practices varied considerably. Intermittent pneumatic compression was the most common form of medical prophylaxis utilized in the United States, although it was used very rarely in other countries (22% vs 0.2%, respectively). Unfractionated heparin was the most frequent pharmacologic approach used in the United States (21% of patients), with low-molecular-weight heparin used most frequently in other participating countries (40%). There was also variable use of elastic stockings in the United States and other participating countries (3% vs 7%, respectively). Conclusions Our data suggest that physicians' practices for providing VTE prophylaxis to acutely ill hospitalized medical patients are suboptimal and highlight the need for improved implementation of existing evidence-based guidelines in hospitals.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which results from obstruction of the major pulmonary arteries by incompletely resolved or organized pulmonary emboli which have become incorporated into the pulmonary artery wall, eventually causing an increase in pulmonary vascular resistances. Pulmonary endarterectomy (PEA) is the treatment of choice. Careful pre- and post-operative management is essential for a successful outcome following PEA. In 1994, we started in Pavia a program in which members of a multidisciplinary team work in close interaction with the aim of increase experience in the challenging problems these patients present in the evaluative, surgical, and post-operative phases of their care. So far, 134 PEAs have been performed. Preoperatively, New York Heart Association (NYHA) class distribution was respectively 3-II, 56-III, and 75-IV; mean pulmonary artery pressure and pulmonary vascular resistances were 47 ± 13 mmHg and 1149 ± 535 dynes/sec/cm−5 respectively. The overall operative mortality has been 9.7% (in 2005 mortality rate was 4.5%). At present, 92% of the PEA patients are actively participating in the follow-up study. Follow-up visits are at 3 months after PEA, yearly for the following 5 years, and then at 7, 10, and 15 years postoperatively. Both early and late survivals were excellent. Survival rate at 3 months, 1 year, and 3 years were respectively of 89.5±2.7%, 87.3±3.0%, and 82.7±3.6%. Survival rates had not changed at 5, 7, and 10 years postoperative. Three months after PEA, 29 (58%) subjects were within NYHA class I, 18 (36%) in class II, and 3 (6%) in class III. At 1-year follow-up, 40 (80%) patients were within NYHA class I, 10 (20%) in class II. A statistically significant difference exists not only between the preoperative and the postoperative data (p Hemodynamic data from 35 patients participating to the Pavia Pulmonary Endarterectomy Program with complete 3-year follow-up. CVP mPAP CO CI PVR PVRI CVP (mmHg) central venous pressure; mPAP (mmHg) mean pulmonary artery pressure; CO (L/min) cardiac output; CI (L/min/m2) cardiac index; PVR (dynes/sec/cm-5) pulmonary vascular resistances; PVRI (dynes/sec/cm-5/m2) pulmonary vascular resistances index; RV-EF (%) right ventricle ejection fraction. RV-EF A: Before-PEA 7±6 48±12 3.3±0.9 1.8±0.5 1125±412 2027±731 15±8 B:Before discharge 5±4 25±10 5.2±1.1 2.9±0.5 289±142 505±234 32±8 C: 3 months 2±2 24±11 5.1±1.4 2.8±0.6 231±198 542±271 32±7 D: 1 year 1±2 23±12 5.0±1.1 2.7±0.6 290±191 531±343 35±8 E: 3 years 2±2 24±12 4.9±1.1 2.6±0.5 317±226 579±393 34±8 p value A vs. B: nsA vs. C, D, and E

BACKGROUND: Selecting initial anticoagulant dose by patient weight for acute pulmonary embolism and deep vein thrombosis has clinical credibility; however, uncertainty remains regarding how to dose obese patients with newer anticoagulants because outcome data are sparse. OBJECTIVES: To use the Matisse trials' comparison of sc fondaparinux once daily with control heparin therapies (intravenous unfractionated heparin for pulmonary embolism, sc enoxaparin 1 mg/kg b.i.d. for deep vein thrombosis) for initial treatment in order to compare primary outcomes (venous thromboembolism recurrence and major bleeding) in obese patients. PATIENTS AND METHODS: Primary outcomes were compared in subsets composed of patients weighing < or = and > 100 kg and with body mass index (BMI) < 30 and > or = 30 kg/m(2). Medians and ranges for weight and BMI were compared for patients suffering either recurrence or major bleeding. RESULTS: Twenty-two thousand and one patients received fondaparinux and 2217 received enoxaparin or unfractionated heparin. Four hundred and ninety-six patients (11%) weighed > 100 kg and 1216 (28%) had a BMI > or = 30. Treatment groups had similar characteristics. The upper limit in subject weight for recurrence was 166 kg (BMI 58), and for major bleeding 120 kg (BMI 39). The incidences of recurrence and major bleeding were similar for each patient subset of weight and BMI for both fondaparinux and heparin treatment groups. Among patients with a primary outcome, median weights and BMIs were also similar. CONCLUSIONS: The current recommended doses of fondaparinux and heparins for the treatment of venous thromboembolism appear to provide similar protection against recurrence and major bleeding to one another and to obese and non-obese patients

Objective diagnosis and treatment are important in optimizing clinical outcomes in patients with venous thromboembolism (VTE), and anticoagulants are the mainstay of treatment. Traditionally, anticoagulant therapy involves parenteral anticoagulants, overlapping with and followed by oral vitamin K antagonists. Recently, direct oral anticoagulants (DOACs), including the Factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the direct thrombin inhibitor dabigatran etexilate, have been developed to address limitations associated with traditional anticoagulant therapy. DOACs have recently been approved for the treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE). Successful phase III trials have demonstrated their efficacy for the treatment of DVT and PE, with a potentially improved safety profile. Recent evidence suggests that women bleed more compared to men when treated with DOACs for VTE without differences in treatment efficacy. Future clinical trials should include outcomes stratified by sex, and should investigate the clinical impact of this sex-related safety difference.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease that results from obstruction of the major pulmonary arteries by incompletely resolved or organized pulmonary emboli that have become incorporated into the pulmonary artery wall, eventually causing an increase in pulmonary vascular resistance. From 0.1 to 4.0% of patients recovering from acute pulmonary embolism develop CTEPH. Without intervention, CTEPH is a progressive and lethal disease for which there is no effective medical therapy. Pulmonary endarterectomy (PEA) is the treatment of choice. Careful pre- and postoperative management is essential for a successful outcome after PEA. Lung transplantation is indicated only in few cases when PEA is not feasible. In 1994, we started a program (in Pavia, Italy) in which members of a multidisciplinary team work closely with the aim of increasing experience in the challenging problems these patients present in the evaluative, surgical, and postoperative phases of their care. To date, 134 PEAs have been performed. Preoperatively, New York Heart Association (NYHA) class distribution was three class II, 56 class III, and 75 class IV patients, respectively; mean pulmonary artery pressure and pulmonary vascular resistance values were 47 +/- 13 mm Hg and 1149 +/- 535 dyn/s/cm (-5), respectively. The overall operative mortality has been 9.7% (4.5% in 2004). Survival at 3-month, 1-year, and 3-year follow-up was 89.5 +/- 2.6%, 87.8 +/- 2.9%, and 83.3 +/- 3.5%, respectively; this last rate was unchanged up to 10 years. After PEA, mean pulmonary artery pressure and pulmonary vascular resistance values were 25 +/- 9 mm Hg and 322 +/- 229 dyn/s/cm (-5), respectively, and these results were stable over time. At the 3-year follow-up, 94% of patients were in NYHA class I or II and were being treated with oral anticoagulants only.

Summary. Background: Although hormone replacement therapy (HRT) is associated with an increased risk of deep vein thrombosis (DVT), it is not clear if the risk differs in users of combined estrogen-progestin HRT and estrogen-only HRT. Methods: We prospectively studied postmenopausal women with suspected DVT in whom HRT use status was ascertained and who subsequently had objective diagnostic testing to confirm or exclude DVT. Cases were patients with idiopathic DVT, in whom there were no DVT risk factors, and controls were patients without DVT, in whom there were also no DVT risk factors. The risk of DVT was determined in users of estrogen-progestin HRT and estrogen-only HRT by comparing the prevalence of current HRT use in cases with idiopathic DVT and controls without DVT (reference group). Multivariable regression analysis was done to adjust for factors that might confound an association between HRT use and the risk of DVT. Results: One thousand one hundred and sixty-eight postmenopausal women with suspected DVT were assessed, from whom 95 cases of idiopathic DVT and 610 controls without DVT and no DVT risk factors were identified. Estrogen-only HRT was associated with an increased risk for DVT that was not statistically significant [odds ratio (OR) = 1.22; 95% confidence interval (CI) 0.57, 2.61]. Estrogen-progestin HRT was associated with a greater than 2-fold increased risk for DVT (OR = 2.70; 95% CI 1.44, 5.07). Conclusion: The risk of developing DVT may be higher in users of combined estrogen-progestin HRT than in users of estrogen-only HRT.

Background: To simplify the diagnostic strategy of patients suspected for venous thromboembolism, the use of D-dimer tests has been advocated. Very important for the safety of such diagnostic strategies would be the capacity to recognise false-normal D-dimer results, in order to prevent inadequately withholding anticoagulant treatment in patients who actually have the disease. Insight in the causes of false-normal D-dimer results would therefore be necessary. We hypothesised that certain patient characteristics are associated with relatively low plasma D-dimer levels and, therefore, could increase the risk of false-normal results. Methods: Consecutive patients with an objectively confirmed venous thromboembolic event and an independently obtained false-normal SimpliRED D-dimer test result were included in the study. For each patient, two controls with objectively confirmed venous thromboembolism and an adequate abnormal D-dimer result were selected. Baseline patient characteristics, obtained by standardised questionnaires, were compared between the two groups of patients. Results: In total, 686 patients had a venous thromboembolic event and 47 of these patients had a false-normal SimpliRED result. Therefore, the overall sensitivity of the SimpliRED test for venous thromboembolism was 94% (95% CI: 92–95%). Although the prevalence of certain clinical characteristics was significantly higher in patients with a false-normal D-dimer result than in the controls [odds ratios for (LMW)heparin treatment and symptoms lasting more than 10 days: 5.1 (95% CI: 1.5–18.7) and 3.2 (95% CI:1.4–7.4), respectively], the prevalence of these characteristics was also high in the control group with an adequate abnormal D-dimer. Combining two or more of these characteristics had a low prevalence and did not further improve the ability to identify those patients with a false-normal D-dimer test at presentation. Conclusions: Although these findings clearly indicate an association between certain baseline clinical characteristics and the occurrence of a false-normal SimpliRED test, the clinical utility for these characteristics is limited.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) can be successfully treated surgically by pulmonary thromboendarterectomy (PTE) but there are few data on mid-term cardiopulmonary function, particularly on exertion, and clinical benefits following pulmonary PTE. Methods: A 2 year follow up study was undertaken of clinical status, haemodynamic and lung function indices, gas exchange, and exercise tolerance in 38 patients of mean (SD) age 50 (15) years who had undergone PTE. Results: In-hospital mortality was about 10%. Before PTE all the patients were severely impaired (NYHA classes III–IV). There was no time difference in the improvement in the parameters: nearly all the improvement in cardiac output, gas exchange, and clinical status was achieved in the first 3 months as a result of the relief of pulmonary obstruction. At 3 months the percentage of patients with normal cardiac output and PaO2 and of those with reduced clinical impairment increased to 97%, 59%, and 87%, respectively, without any further change. Only mean pulmonary artery pressure (mPAP), carbon monoxide transfer factor (TLCO), and exercise tolerance improved gradually during the second year, probably due to the recovery of the damaged small vessels. TLCO was overestimated before PTE but afterwards the trend was similar to that of mPAP. Conclusions: At mid term only a few patients did not have a satisfactory recovery because of lack of operative success, hypertension relapse, or the effect of preoperative hypertension on vessels in non-obstructed segments. Most of the patients, even the more compromised ones, had excellent long lasting results.

Objective: To evaluate the safety of withholding anticoagulant treatment from patients with clinically suspected deep vein thrombosis but normal findings on compression ultrasonography. Design: Compression ultrasonography was done with a simplified diagnostic procedure limited to the common femoral vein in the groin and the popliteal vein extending down to the trifurcation of the calf veins. Patients with normal ultrasonography findings at presentation were retested 1 week later. Main outcome measure: The incidence of venous thromboembolic complications during follow up for 6 months in patients in whom anticoagulant treatment was withheld on the basis of normal results on two ultrasonography tests 1 week apart. Setting: University research centres in four hospitals. Results: A total of 1702 patients were included in the study. Abnormal results on compression ultrasonography at presentation or at 1 week were found in 400 and 12 patients, respectively, for a prevalence of deep vein thrombosis of 24%. None of the patients were lost to follow up. Venous thromboembolic complications during the week of serial testing occurred in a single patient and in eight patients during 6 months9 follow up, resulting in a cumulative rate of venous thromboembolic complications of 0.7% (95% confidence interval 0.3% to 1.2%). The mean number of extra hospital visits and additional tests required per initially referred patient was 0.8. Conclusion: It is safe to withhold anticoagulant treatment from patients with clinically suspected deep vein thrombosis who have a normal result on compression ultrasonography at the time of presentation and at 1 week. Key messages Clinical diagnosis of suspected deep vein thrombosis is notoriously unreliable and objective diagnostic tests are indicated to confirm or refute the presence of this condition Ultrasonography with vein compressibility of the common femoral and popliteal vein is the non-invasive test of choice for the diagnostic management of patients with suspected deep vein thrombosis It is safe to withhold anticoagulant treatment from patients with suspected deep vein thrombosis who have normal results on compression ultrasonography on presentation and on a single repeat test 1 week later With the simplified compression ultrasound strategy the number of repeat tests can be safely reduced to a single test performed a week after presentation Most patients with deep vein thrombosis can be identified at presentation, making this strategy convenient to patients and less costly

Background Low-molecular-weight heparin is known to be safe and effective for the initial Treatment of patients with proximal deep-vein thrombosis. However, its application to patients with pulmonary embolism or previous episodes of thromboembolism has not been studied.Methods We randomly assigned 1021 patients with symptomatic venous thromboembolism to fixed-dose, subcutaneous low-molecular-weight heparin (reviparin sodium) or adjusted-dose, intravenous unfractionated heparin. Oral anticoagulant therapy with a coumarin derivative was started concomitantly and continued for 12 weeks, Approximately one third of the patients had associated pulmonary embolism, The outcome events studied over the 12 weeks were symptomatic recurrent venous thromboembolism, major bleeding, and death. We sought to determine whether low-molecular-weight heparin is at least equivalent to unfractionated heparin in patients with venous thromboembolism.Results Twenty-seven of the 510 patients assigned to low-molecular-weight heparin (5.3 percent) had recurrent thromboembolic events, as compared with 25 of the 511 patients assigned to unfractionated heparin (4.9 percent). The difference of 0.4 percentage point indicates that the two therapies have equivalent value according to our predetermined definition of equivalence. Sixteen patients assigned to low-molecular-weight heparin (3.1 percent) and 12 patients assigned to unfractionated heparin (2.3 percent) had episodes of major bleeding (P=0.63), and the mortality rates in the two groups were 7.1 percent and 7.6 percent, respectively (P=0.89).Conclusions Fixed-dose, subcutaneous low-molecular-weight heparin is as effective and safe as adjusted-dose, intravenous unfractionated heparin for the initial management of venous thromboembolism, regardless of whether the patient has pulmonary embolism or a history of venous thromboembolism. (C) 1997, Massachusetts Medical Society.

Background: Endothelin (ET) is an endothelium-derived multifunctional peptide that produces a potent, long-lasting vasoconstric- tion. Nitric oxide (NO), besides being the most important endothelium- derived relaxant factor in blood vessels, is supposed to be involved in regulating the interactions among endothelium, adhesive molecules, and leukocytes. Methods:We investigated the possible occurrence and distribution of ET and constitutive nitric oxide synthase (NOs), the enzyme that generates NO from L-arginine, in bovine lymphatic vessels and primary culture of lymphatic endothelium by using immunocytochemistry. Results:Specific immunostaining with both ET and endothelial constitu- tive NOs antisera was detectable at light and electron microscopic levels in the endothelial cell layer of lymphatic vessels, whereas no immunostain- ing could be observed in the muscular and adventitial layers. The immuno- reaction showed a diffuse pattern throughout the cytoplasm of endothe- lial cells. Primary cultures of endothelial cells isolated from lymphatic vessels also displayed cytoplasmic ET- and NOs-like immunoreactivities. The endothelial nature of cell monolayers was confirmed by the positive reaction to the von Willebrand factor, a reliable marker of endothelial cells, and by ultrastructural features of cultured cells. Conclusions: These findings suggest that the endothelium is a major source of ET and NO in lymphatic vessels. Interestingly, the lymphatic endothelium maintains the capability of producing such vasoactive sus- tances also in vitro, thus suggesting that lymphatic endothelial cells in culture may be used in studies concerning the role of the endothelium in the generation of vasoactive molecules. According to previous functional studies, the occurrence of ET and NOs immunoreactivities in lymphatic vessel endothelium supports the view that lymphatic endothelium may play an important role in the regulation of lymphatic vascular tone and in the production of vascular contractile activity promoting lymph flow. Anat. Rec. 248:490-497, 1997. r 1997 Wiley-Liss, Inc.

Background. An intravenous course of standard (unfractionated) heparin with the dose adjusted to prolong the activated partial-thromboplastin time to a desired length is the standard initial in-hospital treatment for patients with deep-vein thrombosis, but fixed-dose subcutaneous low-molecular-weight heparin appears to be as effective and safe. Because the latter treatment can be given on an outpatient basis, we compared the two treatments in symptomatic outpatients with proximal-vein thrombosis but no signs of pulmonary embolism. Methods. We randomly assigned patients to adjusted-dose intravenous standard heparin administered in the hospital (198 patients) or fixed-dose subcutaneous low-molecular-weight heparin administered at home, when feasible (202 patients). We compared the treatments with respect to recurrent venous thromboembolism, major bleeding, quality of life, and costs. Results. Seventeen of the 198 patients who received standard heparin (8.6 percent) and 14 of the 202 patients who received low-molecular-weight heparin (6.9 percent) had recurrent thromboembolism (difference, 1.7 percentage points; 95 percent confidence interval, -3.6 to 6.9). Major bleeding occurred in four patients assigned to standard heparin (2.0 percent) and one patient assigned to low-molecular-weight heparin 10.5 percent; difference, 1.5 percentage points; 95 percent confidence interval, -0.7 to 2.7). Quality of life improved in both groups, Physical activity and social functioning were better in the patients assigned to low-molecular-weight heparin. Among the patients in that group, 36 percent were never admitted to the hospital at all, and 40 percent were discharged early. This treatment was associated with a mean reduction in hospital days of 67 percent, ranging from 29 percent to 86 percent in the various study centers. Conclusions. In patients with proximal-vein thrombosis, treatment with low-molecular-weight heparin at home is feasible, effective, and safe.

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 [Cl] 0.06 to 0.80, P = 0.02) and 0.39 (95% Cl 0.30 to 0.80, P = 0.006), respectively, in favor of LMWH treatment. The RR for major bleeding was 0.42 (95% Cl 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% Cl 0.2 to 0.9, P = 0.01) and 0.33 (95% Cl 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.

Duration of anticoagulation can be categorised into initial treatment, lasting 3, 6 or 12 months, and long-term treatment beyond 12 months. There is a strong rationale for anticoagulation treatment beyond the acute phase in many patients with venous thromboembolism (VTE), being the risk of recurrent VTE after stopping anticoagulation high, particularly for unprovoked deep vein thrombosis (DVT). Several non-vitamin K antagonist oral anticoagulants (NOACs) have been approved in the acute setting; accumulating evidence suggests continuing treatment with these agents beyond 12 months offers additional benefits to patients with VTE. Apixaban, dabigatran and rivaroxaban have been studied in this setting in a series of phase III extension studies (AMPLIFY-EXT, RE-MEDY and RE-SONATE, and EINSTEIN EXT, respectively). AMPLIFY-EXT evaluated patients who had completed 6-12 months of anticoagulation treatment with apixaban. Patients received either a further 12 months of apixaban at a dose of 2.5 mg or 5 mg twice daily, or placebo. Recurrent VTE or mortality from any cause were 3.8%, 4.2% and 11.6%, respectively (relative risk [95% confidence interval (CI)] vs placebo: 0.33 [0.22-0.48] and 0.66 [0.25-0.53], respectively); for major bleeding, rates were 0.2%, 0.1% and 0.5%, respectively (relative risk [95% CI] vs placebo: 0.49 [0.09-2.64] and 0.25 [0.03-2.24], respectively). In RE-MEDY, patients received either dabigatran (150 mg twice daily) or warfarin for 6-36 months after at least 3 months of prior anticoagulation treatment. Recurrent or fatal VTE occurred in 1.8% of patients treated with dabigatran versus 1.3% of warfarin-treated patients (P=0.01 for non-inferiority); major bleeding rates were lower with dabigatran (0.9% vs 1.8%) but this difference was not statistically significant. In the RE-SONATE study, dabigatran (150 mg twice daily) or placebo was administered for up to 12 months. Recurrent or fatal VTE was significantly lower with dabigatran (0.4% vs 5.6%; P In EINSTEIN EXT, patients who had completed 6-12 months of rivaroxaban or VKA anticoagulation treatment were randomised to receive either rivaroxaban or placebo for 6 or 12 months. Extended rivaroxaban treatment was associated with a significantly lower rate of recurrent VTE (1.3% vs 7.1%, respectively; P The phase III extension studies demonstrate the benefits of extended NOAC use versus treatment cessation, with reduced recurrence rates versus placebo, although associated with a potential moderate increase in bleeding risk; in addition, based on outcomes in patients given placebo, it is clear that not prescribing anticoagulation treatment is not a viable approach. VTE is associated with substantial costs, and recurrent episodes increase costs further. The costs are attributable to hospitalisation, treatment facility and staff and outpatient management. The lack of routine coagulation monitoring needed with use of NOACs may simplify patient management, thereby further reducing the burden on healthcare providers and patients. US and European guidelines advise long-term therapy in certain instances. They support NOAC use where they have been selected as the initial therapy choice and therapy needs to be extended beyond 3 months. In addition to clinical trials of extended anticoagulation, assessment of this therapy in routine clinical practice is essential, in order to confirm whether the results of clinical trials apply to a broad range of patients beyond the highly controlled setting of a clinical study. Phase IV data are now emerging (Dresden Noacs Registry, Xalia Study, Einstein Choice Study, Start Register) and are supportive of the findings from phase III studies. Future studies involving all NOACs will be valuable in determining the safety and effectiveness of long-term NOAC use in a wider patient population. Disclosures Piovella: GlaxoSmithKline: Speakers Bureau; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER/BMS: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

SummaryThe optimal duration of oral anticoagulant therapy for patients with acute proximal deep vein thrombosis (DVT) is uncertain. Based on the hypothesis that a normal impedance plethysmogram (IPG) following DVT defines a group of patients at low risk of recurrent venous thromboembolism (VTE), a trial was conducted to evaluate the efficacy of only four weeks of warfarin. Patients with venographically confirmed acute proximal DVT who had received four weeks of warfarin after initial heparin and whose four week IPG was normal were allocated to either continue warfarin (targeted International Normalized Ratio 2.0 to 3.0) for a further eight weeks or receive placebo. Patients with an abnormal four week IPG received warfarin for a further eight weeks. Based on clinical characteristics at the time of the qualifying thrombosis, all patients were classified as having either continuing or transient risk factors for recurrent VTE. During the eight weeks following randomization, nine (8.6%) of the 105 placebo patients developed recurrent VTE compared to one (0.9%) of the 109 warfarin patients, P = 0.009. Over the entire 11 months of follow-up, 12 placebo patients developed recurrence compared to seven warfarin patients, P = 0.3. Nineteen of the 192 patients with an abnormal four week IPG experienced recurrence during the nine months after discontinuing warfarin.In the 301 patients who received three months of warfarin in the randomized trial or in the cohort study, all 26 recurrent events were in the 212 patients with continuing risk factors.In conclusion, an IPG four weeks after proximal DVT is not a useful predictor for recurrent VTE; whereas the presence of continuing risk factors is a very strong predictor. Four weeks of oral anticoagulants may be all that is required in patients without continuing risk factors. Patients with continuing risk factors may require more than three months of oral anticoagulants.

Background: Some patients with acute VTE who may previously have been exposed to heparin products have unrecognized antibodies implicated in heparin-induced thrombocytopenia (HIT). Antibody prevalence and patient consequences upon exposure to heparin, low-molecular-weight heparin, and fondaparinux are uncertain. Methods: In this secondary analysis, we tested patients in the Matisse VTE studies at study entry for heparin-dependent antibodies and further tested patients with enzyme-linked immunosorbent assay (ELISA)-positive results for platelet-activating antibodies. We compared the risk of HIT (> 50% fall in platelet count, heparin-dependent antibodies, no contradicting features) between patients treated with heparin (either unfractionated or low molecular weight [enoxaparin]) vs those who received fondaparinux. Comparison groups for thrombocytopenia occurrence comprised patients with ELISA-positive, platelet-activating, antibody-positive results; ELISA-positive, but platelet-activating antibody-negative results; and randomly selected antibodynegative results. Results: A total of 127 of 3,994 patients (3.2%) had ELISA-positive results at baseline, but only 14 (0.4%; 95% CI, 0.2%-0.6%) had platelet-activating antibodies. Among these 14, four treated with unfractionated or low-molecular-weight heparin developed HIT compared with zero of 10 fondaparinux-treated patients (OR, 95; 95% CI, 8-1,123; P

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.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.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.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.

Background: Few studies have assessed the effect of prothrombotic blood abnormalities on the risk of deep vein thrombosis (DVT) with hormone replacement therapy (HRT). Methods: We studied postmenopausal women with suspected DVT in whom HRT use and prothrombotic blood abnormalities were sought. Cases had unprovoked DVT and controls had no DVT and without DVT risk factors. The risk of DVT was determined in women with and without prothrombotic abnormalities. Results: A total of 510 postmenopausal women with suspected DVT were assessed; 57 cases and 283 controls were identified. Compared to HRT, nonusers without the factor V Leiden mutation, the risk of DVT was increased in estrogen-progestin HRT users (odds ratio [OR], 3.2; 95% confidence interval [CI]: 1.2-8.6) and in nonusers with the factor V Leiden mutation (OR, 5.3; 1.9-15.4) and appears multiplied in users of estrogen-progestin HRT with the factor V Leiden mutation (OR, 17.1; 3.7-78). Compared to HRT, nonusers with normal factor VIII, the risk of DVT was increased in estrogen-progestin HRT users with normal factor VIII (OR, 2.8; 1.0-7.9) and in HRT nonusers with the highest factor VIII quartile (OR, 6.0; 2.1-17), and appears to be multiplied in women who are users of estrogen-progestin HRT with the highest factor VIII quartile (OR, 17.0; 3.6-80). Conclusions: In postmenopausal women who are estrogen-progestin HRT users, the presence of the factor V Leiden mutation or an elevated factor VIII level appears to have a multiplicative effect on their overall risk of DVT, increasing it 17-fold compared to women without these blood abnormalities who are HRT nonusers.

The endothelium constitutes a specialized organ, with unique metabolic properties. Since the introduction of in vitro culture techniques, studies on the function of endothelial cells have rapidly increased and our knowledge has been greatly enhanced. It is now established that endothelial cells can either promote hemostasis or exert antithrombotic activities. These activities are in well controlled balance. Injuries to the intimal vascular monolayer may play a role in the pathogenesis of atherosclerosis and its complications. Two types of endothelial cell injury have been described: a denuding injury, secondary to endothelial cell necrosis and desquamation, which triggers platelet/subendothelial interactions, and a non-denuding injury, which induces new endothelial properties and the loss of intimal thromboresistance. Thrombosis may complicate atherosclerosis at different stages. A role for inflammatory mediators in the pathogenesis of thrombosis has been stressed recently and this may have implications for future directions in the study of atherothrombotic disease.

The treatment of venous thromboembolism (VTE) in cancer patients remains controversial.The Italian Society for Thrombosis and Haemostasis (SISET) commissioned a project to develop clinical practice guidelines for the therapy of VTE in patients with malignancies.Key questions about the treatment of VTE in patients with malignancies were formulated by a multidisciplinary working group consisting of experts in clinical medicine and research. After a systematic review and discussion of the literature, recommendations were formulated and graded according to the supporting evidence. For those questions for which the literature search did not yield any definitive answer (absence of evidence evidence of low quality, and contradictory evidence), a formal consensus method was used to issue clinical recommendations.The results of the available literature on VTE treatment in cancer patients were reviewed and clinical recommendations were drafted.We describe the results of a systematic literature review and an explicit approach to consensus techniques which resulted in recommendations for the key therapeutic issues in cancer patients with VTE.

Enoxaparin is the most frequently used low-molecular weight heparin in the world, given in order to prevent venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery (MOS). Fondaparinux is an effective and safe alternative. The aim of our study was to compare the cost-effectiveness of enoxaparin and fondaparinux in the extended thromboprophylaxis of patients undergoing MOS in Italy. A decision-tree model was developed: probabilities of symptomatic events were derived from the published trials; use of resources in Italy was evaluated by means of a questionnaire administered to a panel of experts. Only the direct costs of VTE (acute treatment of events and of complications) were considered. Cost units were derived from the current cost of drugs, and from the Italian National Healthcare tariffs in 2007. Incremental cost-effectiveness ratios were analysed at three time points: 30 days, 1 year and 5 years. The higher cost of fondaparinux was counterbalanced by reduced rates of early DVT, early PE and prophylaxis-related major bleeding. If compared with enoxaparin, after 30 days of extended prophylaxis, fondaparinux is associated with a savings ofeuro48.83 per patient; at the end of the first year, the savings increased toeuro72.13, and after 5 years, the savings areeuro74.36. One-way sensitivity analysis shows that the results are robust to the variation in unit costs for VTE-related care, or in event rates for both treatments. In conclusion, our model shows that, when administered for extended prophylaxis of VTE following MOS, fondaparinux is more effective and cost saving than enoxaparin.

In the initial treatment of venous thromboembolism (VTE) fondaparinux, a pentasaccharide, is a good alternative to heparin. Whether this is also true for cancer patients is unknown. We performed two post-hoc analyses of two randomized studies to compare efficacy, safety and overall survival of fondaparinux to standard initial (low-molecular-weight) heparin (LMWH) treatment in cancer patients with venous thromboembolism. Two hundred thirty-seven cancer patients with deep venous thrombosis (DVT) were initially treated with fondaparinux or enoxaparin. Two hundred forty cancer patients with pulmonary embolism (PE) received fondaparinux or unfractionated heparin. The initial treatment was followed by vitamin K antagonists. In DVT patients, the three-month recurrence rate was 5.4% in the enoxaparin recipients compared to 12.7% in those treated with fondaparinux [absolute difference 7.3%, 95% CI 0.1, 14.5]. A recurrence was observed in 8.9% of the PE patients treated with fondaparinux compared to 17.2% in the unfractionated heparin recipients [absolute difference -8.3, 95% CI -16.7, 0.1]. In both studies no difference in bleeding and overall survival was observed. Regarding overall survival and bleeding fondaparinux is comparable to enoxaparin and unfractionated heparin in cancer patients. No significant differences in recurrent VTE were observed when comparing fondaparinux with unfractionated or LMWH. Because of study limitations these results should be considered hypothesis-generating.

SummaryIn the initial treatment of venous thromboembolism (VTE) fondaparinux, a pentasaccharide, is a good alternative to heparin. Whether this is also true for cancer patients is unknown. We performed two post-hoc analyses of two randomized studies to compare efficacy, safety and overall survival of fondaparinux to standard initial (low-molecular-weight) heparin (LMWH) treatment in cancer patients with venous thromboembolism. Two hundred thirty-seven cancer patients with deep venous thrombosis (DVT) were initially treated with fondaparinux or enoxaparin. Two hundred forty cancer patients with pulmonary embolism (PE) received fondaparinux or unfractionated heparin. The initial treatment was followed by vitamin K antagonists. In DVT patients, the three-month recurrence rate was 5.4% in the enoxaparin recipients compared to 12.7% in those treated with fondaparinux [absolute difference 7.3%, 95% CI 0.1, 14.5]. A recurrence was observed in 8.9% of the PE patients treated with fondaparinux compared to 17.2% in the unfractionated heparin recipients [absolute difference –8.3, 95% CI –16.7, 0.1]. In both studies no difference in bleeding and overall survival was observed. Regarding overall survival and bleeding fondaparinux is comparable to enoxaparin and unfractionated heparin in cancer patients. No significant differences in recurrent VTE were observed when comparing fondaparinux with unfractionated or LMWH. Because of study limitations these results should be considered hypothesis-generating.

Background The benefit-risk ratio of extended fondaparinux therapy has not been assessed in patients undergoing major lower limb joint arthroplasty. Few data on the concomitant use of fondaparinux and continuous neuraxial or deep peripheral nerve blockade are available. We performed a prospective intervention study in patients undergoing major orthopedic surgery primarily designed to assess the efficacy of fondaparinux when drug administration was withheld for 48 h to permit removal of a neuraxial or deep peripheral nerve catheter. The safety and efficacy of extended fondaparinux therapy for the prevention of venous thromboembolism were also evaluated. Methods Patients received a daily subcutaneous injection of 2.5 mg fondaparinux for 3 to 5 wk postoperatively. In patients with a neuraxial or deep peripheral nerve catheter, the catheter was removed 36 h after the last fondaparinux dose. The next fondaparinux dose was administered 12 h after catheter removal. The primary end points were symptomatic venous thromboembolism and major bleeding up to 4-6 wk after surgery. Results We recruited 5704 patients. A neuraxial or deep peripheral nerve catheter was inserted in 1553 (27%) patients and 78 (1.4%) patients, respectively. The rate of venous thromboembolism was 1.0% (54 of 5387). There was no difference between patients without (1.1%) or with (0.8%) a catheter (the upper limit of the 95% confidence interval of the odds ratio, 1.49, being below the predetermined noninferiority margin of 1.75). The incidence of major bleeding was 0.8% (42 of 5382). No neuraxial or perineural hematoma was reported. Conclusions Once-daily subcutaneous injection of 2.5 mg fondaparinux given for 3 to 5 wk was effective and safe for prevention of venous thromboembolism after major orthopedic surgery. Temporary discontinuation of fondaparinux for 48 h permitted safe removal of a neuraxial or deep peripheral nerve catheter without decreasing thromboprophylatic efficacy.

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 ¼ 175), TKR (n ¼ 136) or HFS (n ¼ 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.

Objective. To determine the incidence and the prognostic factors of objectively diagnosed deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with epithelial ovarian malignancy. Methods. We reviewed the records of all patients with epithelial ovarian cancer who were diagnosed, treated, and followed-up at our institution between 1990 and 2001. Data were collected regarding age, body mass index, previous DVT and PE, menopause status, FIGO stage, grade, histology, type of surgery, residual disease, first line chemotherapy, and relapse status. Results. Of the 253 cases, the overall incidence of symptomatic venous thromboembolic events (VTE) was 16.6% (42 patients): 1.6% (4) with PE and 15% (38) with DVT. 8 events (3.2%) were detected before tumor diagnosis, 6 (2.4%) in the postoperative period, 16 (6.4%) during first line chemotherapy and 12 (4.8%) throughout the follow-up period. Risk factors associated with occurrence of VTE were: at diagnosis, history of deep vein thrombosis ( P = 0.001); during chemotherapy, older age ( P = 0.017), larger body mass index ( P = 0.019), FIGO stage 2c–4 ( P = 0.004), no surgery ( P = 0.003), and presence of residual tumor ( P = 0.026). None of the considered risk factors were found to be predictors of VTE postoperatively. The multivariate regression analysis found that residual tumor, age, and body mass index were independent prognostic factors. Conclusion. The incidence of VTE throughout the entire history of ovarian malignancy is high. Prognostic factors could be used to establish prophylaxis protocols based on risk stratification.

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.

Although patients with primary pulmonary hypertension and patients with chronic thromboembolic pulmonary hypertension with distal lesions may share similar pathophysiological characteristics, scarce information is available on the usefulness of epoprostenol in this form of secondary pulmonary hypertension. The aim of this study was to evaluate the feasibility, safety and efficacy of epoprostenol therapy in surgically untreatable patients with chronic thromboembolic pulmonary hypertension.Continuous infusive therapy with epoprostenol was undertaken in 16 patients with primary pulmonary hypertension and in 11 surgically untreatable thromboembolic pulmonary hypertension patients. The median follow-up was 12.4 months (range 6-23 months). Patients underwent clinical, echocardiographic and hemodynamic evaluation at baseline and a 6-min walk test every 3 months after beginning epoprostenol; ultrasound evaluations were repeated in a subgroup of patients.Epoprostenol therapy improved the clinical status, exercise tolerance and NYHA functional class. A greater left ventricular end-diastolic volume was recorded at echocardiography in both groups.Epoprostenol therapy may be feasible, safe and clinically effective in patients with surgically untreatable chronic thromboembolic pulmonary hypertension.

Background: The current standard initial therapies for deep venous thrombosis are low-molecular-weight heparin and unfractionated heparin. In a dose-ranging study of patients with symptomatic deep venous thrombosis, fondaparinux had efficacy and a safety profile similar to those of low-molecular-weight heparin (dalteparin). Objective: To evaluate whether fondaparinux has efficacy and safety similar to those of enoxaparin in patients with deep venous thrombosis. Design: Randomized, double-blind study. Setting: 154 centers worldwide. Patients: 2205 patients with acute symptomatic deep venous thrombosis. Intervention: Fondaparinux, 7.5 mg (5.0 mg in patients weighing 100 kg) subcutaneously once daily, or enoxaparin, 1 mg/kg of body weight, subcutaneously twice daily for at least 5 days and until vitamin K antagonists induced an international normalized ratio greater than 2.0. Measurements: The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolic complications. The main safety outcomes were major bleeding during initial treatment and death. An independent, blinded committee adjudicated all outcomes. Results: 43 (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute difference, -0.15 percentage point [95% Cl, -1.8 to 1.5 percentage points]). Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively. Limitations: Follow-up was incomplete in 0.4% of fondaparinux-treated patients and 1.0% of enoxaparin-treated patients. Conclusions: Once-daily subcutaneous fondaparinux was at least as effective (not inferior) and safe as twice-daily, body weight-adjusted enoxaparin in the initial treatment of patients with symptomatic deep venous thrombosis

BACKGROUND: The standard initial treatment of hemodynamically stable patients with pulmonary embolism is intravenous unfractionated heparin, requiring laboratory monitoring and hospitalization. METHODS: We conducted a randomized, open-label trial involving 2213 patients with acute symptomatic pulmonary embolism to compare the efficacy and safety of the synthetic antithrombotic agent fondaparinux with those of unfractionated heparin and to document noninferiority in terms of efficacy. Patients received either fondaparinux (5.0, 7.5, or 10.0 mg in patients weighing less than 50, 50 to 100, or more than 100 kg, respectively) subcutaneously once daily or a continuous intravenous infusion of unfractionated heparin (ratio of the activated partial-thromboplastin time to a control value, 1.5 to 2.5), both given for at least five days and until the use of vitamin K antagonists resulted in an international normalized ratio above 2.0. The primary efficacy outcome was the three-month incidence of the composite end point of symptomatic, recurrent pulmonary embolism (nonfatal or fatal) and new or recurrent deep-vein thrombosis. RESULTS: Forty-two of the 1103 patients randomly assigned to receive fondaparinux (3.8 percent) had recurrent thromboembolic events, as compared with 56 of the 1110 patients randomly assigned to receive unfractionated heparin (5.0 percent), for an absolute difference of -1.2 percent in favor of fondaparinux (95 percent confidence interval, -3.0 to 0.5). Major bleeding occurred in 1.3 percent of the patients treated with fondaparinux and 1.1 percent of those treated with unfractionated heparin. Mortality rates at three months were similar in the two groups. Of the patients in the fondaparinux group, 14.5 percent received the drug in part on an outpatient basis. CONCLUSIONS: Once-daily, subcutaneous administration of fondaparinux without monitoring is at least as effective and is as safe as adjusted-dose, intravenous administration of unfractionated heparin in the initial treatment of hemodynamically stable patients with pulmonary embolism

The aim of the study was to evaluate the potential usefulness of transthoracic echocardiography in differentiating patients with primary or chronic thromboembolic pulmonary hypertension and to define the capability of echocardiography to assess right-heart performance in such patients. Right-heart catheterization and ultrasound examination were performed in 111 patients with chronic thromboembolic pulmonary hypertension and in 31 patients with primary pulmonary hypertension. All echocardiographic and Doppler parameters were similar in primary and chronic thromboembolic pulmonary hypertension. A significant correlation was found between the tricuspid annular plane systolic excursion and the right ventricular fractional area change and thermodilution-derived right ventricular ejection fraction (P.001 for both). Furthermore, different patterns of the pulsed Doppler flow velocity curve into the superior vena cava were associated with different right-heart hemodynamic profiles. In conclusion, in patients with chronic pulmonary hypertension transthoracic echocardiography portends meaningful information on the capability of the right heart to confront the increased afterload but it does not permit etiologic differentiation.

Delayed thrombus regression after a first episode of deep vein thrombosis (DVT) of the inferior limbs has been implicated in the development of the post-thrombotic syndrome. Whether normalization of vein segments involved in the index DVT has prognostic significance with respect to the probability of DVT recurrence or new thrombosis is currently unknown. In this study, we prospectively monitored thrombus regression in consecutive patients with symptomatic and asymptomatic DVT. Factors affecting normalization rates and the relationship between previous normalization and DVT recurrence or new thrombosis were explored.One hundred and seventy-nine patients with a first episode of symptomatic DVT of the lower limbs (38 with cancer) and 104 patients with DVT occurring after hip replacement surgery were serially monitored by real time B-mode compression ultrasonography (C-US) over a period of 12 months (months 1, 3, 6 and 12). C-US normalization of popliteal and femoral venous segments was arbitrarily assigned to be residual thrombus occupying, at maximum compressibility, less than 40% of the vein area in the absence of compression.In patients with no DVT recurrence or new thrombosis, C-US normalization was observed at 12 months in 100% of 99 patients with post-operative DVT, in 59% of 134 cancer-free symptomatic DVT outpatients and in 23.3% of 30 symptomatic DVT outpatients with cancer (p = 0.0001). Independent negative effects on the probability of C-US normalization were observed for younger age (p0.05), for the outpatient presentation of the index DVT (p 0.017), for DVT involving the entire femoro-popliteal axis (p 0.05), and for the presence of cancer (p 0.05). DVT recurrence or new thrombosis was observed in 5 patients with post-operative DVT (4.8%), in 7 cancer-free patients with symptomatic DVT (5.0%) and in 8 patients with cancer (21.1%). Only 4 of these patients had shown normalization of their index DVT prior to the event. The presence of cancer was the only significant predictor of DVT recurrence and/or new thrombosis occurring within 3 months from the index DVT (OR = 4.90, p = 0.002). The absence of previous C-US normalization was the only predictor of recurrence or new thrombosis occurring after 3 and 6 months from the index DVT (OR 5.26, p 0.027).Absence of C-US normalization after a first episode of DVT appears to be a factor favoring recurrence or new thrombosis and may be relevant to the optimal duration of oral anticoagulant treatment.

One of the most popular features utilized to promote direct oral anticoagulants diffusion in stroke prevention in non-valvular atrial fibrillation is that these drugs do not require monitoring of their anticoagulant activity or plasma level measurements. We believe that there are clinical scenarios in which monitoring can help guide clinical management. Here we describe a clinical case in which close monitoring of thrombin inhibitor dabigatran peak plasma levels helped in maintaining the patient drug administration schedule, despite the interference of mirabegron, a beta-3 adrenergic agonist, utilized for the symptomatic treatment overactive bladder (OAB) syndrome, and of amiodarone, an effective and commonly prescribed antiarrhythmic drug. These P-glycoprotein (P-gp) inhibitors drugs may increase the blood levels and effects of dabigatran. Combining these medications may increase the risk of bleeding complications and anemia, especially when associated to mild to moderate renal insufficiency. Dabigatran etexilate is a pro-drug that has a low (3%-7%) bioavailability. Once dabigatran etexilate is absorbed, the pro-drug is hydrolyzed to the active drug, dabigatran, by carboxylesterases in the bloodstream. Dabigatran etexilate is a substrate of the efflux transporter P-gp, but dabigatran, the active drug, is not. P-gp is present on the luminal side of absorptive cells in the small intestine and takes drug molecules from the cell cytoplasm and transports them back into the intestinal lumen for excretion. An inhibitor of P-gp, as mirabegron or amiodarone, will increase bioavailability of a P-gp substrate by reducing drug efflux. Our patients suffers from persistent non-valvular atrial fibrillation, complicated by ischemic stroke. He has been assigned a dabigatran 150 mg b.i.d. treatment in may 2014. His creatinine clearance was 75 mL/min. One month later, due to OAB syndrome, he started mirabegron, a drug which might potentially increase the risk of bleeding and which generally causes to stop dabigatran administration. We decided instead to set up a monitoring plan, utilizing plasma-diluted thrombin time to measure dabigatran concentrations. Calibration material consisted of pooled normal plasma with known quantities of dabigatran. By using this calibration material, we constructed a dose-response curve ranging from 0 to 500 ng/mL of dabigatran. An examination of the published literature of the pharmacology of dabigatran indicated that the expected peak steady-state concentration of dabigatran in patients with atrial fibrillation (150 mg, 2 times daily) was approximately 180 ng/mL with a trough of approximately 90 ng/mL (12 hours after last dose). After 4 weeks of mirabegron administration, dabigatran plasma trough level of our patient was 126.4 ng/mL. We therefore decided not to modify the 150 mg b.i.d. treatment. Three weeks later, patient suffered from acute cardiac failure associated to a creatinine clearance reduction to 41 mL/min. As a consequence, mirabegron treatment was stopped. At this point, dabigatran plasma trough level was 148.6 ng/mL. Again, we decided not to modify the 150 mg b.i.d. treatment. Six weeks later, due to an elevated cardiac rate (140/min) a treatment with 300 mg o.d. of amiodarone was started. A week later dabigatran plasma trough level was 219.6 ng/mL, with a creatinine clearance of 58mL/min. We decided then to reduce the administration of dabigatran to 110 mg twice daily. After two weeks, dabigatran plasma trough level lowered to 120.2 ng/mL. Our patient is still on dabigatran treatment which has so far never been stopped. At this time, studies addressing the correlation of dabigatran concentration with risk of bleeding (overdose) or breakthrough thrombosis (underdosing) are unavailable. The lack of such studies currently limits the predictive power of the plasma-diluted thrombin time to determine hemorrhage/thrombosis risk. However, we believe that in situations like our patient’s the adoption of this assay would be a valuable tool to aid adjusting dabigatran treatment. With access to appropriate pharmacodynamic and pharmacokinetic data and relevant calibration material, the plasma–diluted thrombin time assay can easily be applied for use in the monitoring dabigatran etexilate. Disclosures No relevant conflicts of interest to declare.

Background —With the best prophylactics now available, venous thromboembolism after total knee replacement remains substantial (25% to 27%). Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent inhibitor of factor VIIa/tissue factor complex that has the potential to reduce this risk. The present study was performed to determine an efficacious and safe dose of rNAPc2 for prevention of venous thromboembolism after elective, unilateral total knee replacement. Methods and Results —This open-label, sequential dose-ranging study was conducted in 11 centers in Canada, Europe, and the United States. Five regimens were tested. Injections were administered subcutaneously on the day of surgery (day 1) and days 3, 5, and optionally, day 7. Primary efficacy outcome was a composite of overall deep vein thrombosis based on mandatory unilateral venography (day 7±2) and confirmed symptomatic venous thromboembolism recorded ≤48 hours after the last dose of rNAPc2. Primary safety outcome was major bleeding ≤72 hours after the last dose. An independent, blinded Central Adjudication Committee assessed all outcome events. Of 293 patients studied, 251 (86%) could be evaluated for primary efficacy analysis. A dosage of 3.0 μg/kg administered within 1 hour after surgery provided the best observed results, with an overall deep vein thrombosis rate of 12.2%, a proximal deep vein thrombosis rate of 1.3%, and a major bleeding rate of 2.3%. Conclusions —A randomized, double-blind trial that compared rNAPc2 with current best prophylactics is warranted based on encouraging, first-reported clinical results for a factor VIIa/tissue factor inhibitor evaluated for thrombosis prophylaxis.

Objective: To see whether degree of pulmonary hypertension or severity of cardiac failure affect the success of pulmonary thromboendarterectomy (PTE) in chronic thromboembolic pulmonary hypertension. Methods: From May 1996 to June 1999, 33 patients, all in New York Heart Association (NYHA) class 3 or 4 were treated with PTE. Preoperative hemodynamic values were: central venous pressure (CVP) 8 ^ 6 (1‐23), mean pulmonary artery pressure (mPAP) 50 ^ 10 (30‐69), cardiac output (CO) 3:3 ^ 0:9 (1.8‐5.2), pulmonary vascular resistance (PVR) 1056 ^ 344 (523‐1659), and right ventricle ejection fraction (RVEF) 12 ^ 5 (5‐21). To establish whether some hemodynamic or cardiac variables correlate with surgical failure (early death or functional non-success), these patients were divided into a low risk or a high risk group for each variable: CVP (, 9o r$9), mPAP (,50 or $50), CO ($3.5 or ,3.5), PVR ($1100 or ,1100), and RVEF ($10 or ,10). The duration of 3‐4 NYHA class period (,24 or $24 months) was also included in the study. Results: Three patients (9.1%) died in hospital, one (3.0%) underwent lung transplant shortly after PTE, and in five cases (15.2%) mPAP and PVR at the 3-month follow-up examination corresponded with our definition of functional nonsuccess (mPAP and PVR decreased by less than 40% of preoperative values). One of the five functional nonsuccess patients underwent lung transplant 3 months after the operation and another died 17 months after the operation from a non-related cause. Thus PTE was successful in 24 patients and unsuccessful in nine. None of the hemodynamic variables considered was found to be associated with the disparate outcomes. At the 3-month examination, all surviving patients were in NYHA class 1 or 2 except for three in NYHA class 3. At 2 years, hemodynamic values were: CVP 2 ^ 2 (0‐4), mPAP 16 ^ 3 (12‐21), CO 5:0 ^ 1:0 (3.4‐ 6.5), PVR 182 ^ 51 (112‐282), and RVEF 35 ^ 5 (26‐40). All differences were significant with respect to baseline values (P , 0:001). Preoperative mPAP and RVEF values had a strict linear correlation (Ra 0:45; Pa 0:014). Conclusions: None of the variables considered was correlated with early death or functional nonsuccess. Neither preoperative severity of pulmonary hypertension nor degree of cardiac failure influenced the outcome of the operation. PTE leads to hemodynamic recovery even in very compromised patients. q 2000 Elsevier Science B.V. All rights reserved.

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.

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.