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BACKGROUND Extended-duration thromboprophylaxis with betrixaban reduces the risk of venous thromboembolism (VTE) without increasing major bleeding rates in acutely ill medical patients as compared to standard duration enoxaparin. We aimed to assess the risk-benefit of betrixaban in patients aged ≥ 80 years enrolled in the APEX trial. METHODS APEX was a randomized, double-blind trial in which patients hospitalized for acute medical illnesses received enoxaparin 40 mg qd for 10 ± 4 days or oral betrixaban 80 mg qd for 35 to 42 days. The primary efficacy outcome was VTE, the principal safety outcome was major bleeding. Net clinical benefit (NCB) was defined by the occurrence of VTE or major bleeding. RESULTS Of 7513 patients enrolled in the APEX trial, 2781 (37%) were aged ≥ 80 years. In this subgroup, VTE or major bleeding occurred in 7.0% of betrixaban patients and in 8.4% of enoxaparin patients, for a relative risk in the NCB of 0.82 (95% confidence interval 0.62-1.10). The relative risk reduction obtained with betrixaban was similar between those aged ≥ 80 years and patients younger than 80 years (5.0% and 6.7%, respectively, NCB 0.75, 0.58-0.96, P = .024), with no significant interaction across age groups (P = .33). CONCLUSIONS Event rates were higher in medically ill patients aged ≥ 80 years enrolled in the APEX study than in patients younger than 80 years. The predefined NCB was reduced with extended betrixaban therapy in both groups with no signs of age-related interactions. However, the primary efficacy endpoint was not achieved with betrixaban for patients 80 years of age or older.

Acutely ill medical patients with cancer are at increased risk of venous thromboembolism (VTE). Thromboprophylaxis is recommended in the presence of cancer, but its safety is not known. The aim of this study was to assess the efficacy and safety of extended prophylaxis with betrixaban in cancer patients enrolled in the APEX trial. APEX was a randomized, double-blind trial comparing oral betrixaban 80 mg qd administered for 35-42 days with subcutaneous enoxaparin 40 mg qd administered for 10 ± 4 days. Patients with acute medical illness and a history of cancer or active cancer were eligible for inclusion. Primary efficacy outcome was VTE (composite of symptomatic VTE and asymptomatic proximal deep vein thrombosis); primary safety outcome was major bleeding. Of 7513 patients enrolled in the APEX trial, 959 patients (12.8%), 499 randomized to betrixaban and 460 to enoxaparin, had cancer. The primary efficacy outcome occurred in 5.7% of cancer patients treated with betrixaban and in 6.2% treated with enoxaparin (p = 0.95). No significant interaction according to the presence or absence of cancer was observed (p = 0.36). Major bleeding events occurred in 0.8% of patients in the betrixaban group and in 0% in the enoxaparin group (p = 0.13), with no significant interaction (p = 0.07). The composite of major and clinically relevant non-major bleeds was similar between the two groups (2.9% and 2.0%, respectively, RR 1.43, 95% CI 0.63-3.27). Betrixaban was similarly effective in the reduction of VTE among subjects with and without cancer. The incidence of major bleeding was similarly low.

Obesity is associated with cardiovascular complications such as diabetes and hypertension. However, obesity and high body mass index (BMI) can also be linked to improved clinical outcomes in certain patient populations. This counterintuitive observation is called the "obesity paradox." The effect of BMI on the risk of developing venous thromboembolism (VTE) in acutely ill medical patients remains unclear. In the Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial, acutely ill hospitalized medical patients were randomized to receive either extended-duration betrixaban or shorter-duration enoxaparin and followed for 77 days. A total of 7372 patients with evaluable VTE endpoints had BMI measured at baseline. The association between BMI and VTE risk was assessed after adjusting for potential confounders. The multivariable adjusted ORs of VTE risk associated with BMI levels referencing the median BMI value (15, 18.5, 28.3 [reference], 35, 40, 45) were: 2.82 (95% CI, 1.32-6.04, [change from 28.3 to 15]), 1.85 (95% CI, 1.14-2.99, [change from 28.3 to 18.5]), 1.30 (95% CI, 1.04-1.63, [change from 28.3 to 35]), 1.13 (95% CI, 0.84-1.52, [change from 28.3 to 40]), and 0.91 (95% CI, 0.57-1.47, [change from 28.3 to 45]), respectively (p = 0.022). In conclusion, acutely ill hospitalized patients with lower BMI had a higher VTE risk through 77 days, which appears to be a manifestation of the BMI paradox.

Among hospitalized medically ill patients who are at risk of venous thromboembolism (VTE), pharmacological thromboprophylaxis is recommended during the period of immobilization or acute hospital stay.1 However, the risk of VTE extends beyond the standard 10- to 14-day course of anticoagulation and persists for weeks to months after hospital discharge. About half of VTE events occur after the period of index hospitalization and may require rehospitalization.2 Rehospitalization is an end point that adversely affects the morbidity and quality of life of patients and can be a major driver of healthcare costs. Indeed, a goal of patient-centered care is to be both alive and free of hospitalization. The APEX trial (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban Trial; ClinicalTrials.gov: NCT01583218) was a double-blind randomized clinical trial that compared extended-duration (35–42 days) betrixaban with standard-duration (10±4 days) enoxaparin among acutely ill hospitalized medical patients at increased risk of VTE. A reduction in VTE by extended-duration betrixaban compared with standard-duration enoxaparin has been demonstrated,3 but the impact of extended thromboprophylaxis with betrixaban on the risk of rehospitalization associated with VTE has not been studied. It was hypothesized that betrixaban would reduce VTE-related rehospitalization. The APEX trial randomized 7513 patients to either extended-duration betrixaban or standard-duration enoxaparin for VTE prophylaxis. The full-dose regimen (betrixaban 80 mg daily) was administered to patients who had a creatinine clearance of ≥30 mL/min and were not administered a strong P-glycoprotein inhibitor. VTE-related rehospitalization was …

Hospitalized acute medically ill patients with a history of venous thromboembolism (VTE) are at increased risk for recurrent VTE. We characterized the efficacy and safety of betrixaban for prevention of recurrent VTE in these high risk patients. The APEX trial randomized 7513 acutely ill hospitalized medical patients at risk for developing VTE to receive either betrixaban for 35-42 days or enoxaparin for 10 ± 4 days to prevent VTE. This exploratory post-hoc analysis assessed the efficacy and safety of betrixaban versus enoxaparin among subjects with and without prior VTE. Time-to-multiple symptomatic VTE events was also calculated. Approximately 8% of subjects in both arms had prior VTE, which was associated with a fourfold increase in adjusted risk of VTE [MV OR 4.03, 95% CI 3.06-5.30, p 0.001]. Betrixaban reduced VTE compared with enoxaparin among subjects with prior VTE [32 (10.4%) vs. 55 (18.9%), RR 0.57, 95% CI 0.38-0.86, p = 0.006, ARR 8.5%, NNT 12] and without prior VTE [133 (3.9%) vs. 168 (4.9%), RR 0.79, 95% CI 0.64-0.99, p = 0.042, ARR 1.0%, NNT 100] (interaction p 0.05). Additionally, four subjects in the enoxaparin arm and one subject in the betrixaban arm experienced a recurrent VTE. Compared with enoxaparin, betrixaban use was associated with reduction of recurrent VTE events through the active treatment period [36 vs. 57, HR 0.63, 95% CI 0.41-0.97, p = 0.045] and through the end of study [38 vs. 71, HR 0.54, 95% CI 0.36-0.81, p = 0.004]. Prior VTE is associated with a fourfold increase in the risk of VTE among hospitalized medically ill patients. Only 12 such patients would need to be treated with betrixaban versus enoxaparin to prevent an additional VTE endpoint. Betrixaban reduced not only the first but also all recurrent VTE events in a time-to-any-event analysis.http://www.clinicaltrials.gov , Unique identifier: NCT01583218.

Among patients hospitalized with acute heart failure (HF), the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in short-term stroke prediction remains unclear. In the APEX trial, 7513 patients hospitalized for an acute medical illness were randomized to receive either extended-duration betrixaban (80 mg once daily for 35–42 days) or standard-of-care enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. Baseline NT-proBNP concentrations were obtained in 3261 patients admitted for HF. Stroke events were adjudicated by an independent clinical events committee blinded to thromboprophylaxis allocation. The association of NT-proBNP level and other risk factors and biomarkers with stroke was assessed at 77 days after randomization. In univariate analysis, the risk of stroke at 77 days was associated with baseline NT-proBNP (HR 3.63 [95% CI 1.47–8.99]; P = 0.005), D-dimer (HR 2.73 [95% CI 1.03–7.20]; P = 0.043), and hsCRP (HR 3.03 [95% CI 1.36–6.75]; P = 0.007). In multivariable analysis adjusting for hsCRP and thromboprophylaxis, NT-proBNP was associated with the risk of stroke (adjusted HR 3.64 [95% CI 1.35–9.83]; P = 0.011). The interaction of NT-proBNP with the treatment effect was not significant (Pint = 0.30). Baseline NT-proBNP concentration was associated with short-term stroke among patients hospitalized with acute HF. Stroke risk assessment models should consider incorporation of NT-proBNP measurement.

Competing risk methods are time-to-event analyses that account for fatal and/or nonfatal events that may potentially alter or prevent a subject from experiencing the primary endpoint. Competing risk methods may provide a more accurate and less biased estimate of the incidence of an outcome but are rarely applied in cardiology trials. APEX investigated the efficacy of extended-duration betrixaban versus standard-duration enoxaparin to prevent a composite of symptomatic deep-vein thrombosis (proximal or distal), nonfatal pulmonary embolism, or venous thromboembolism (VTE)-related death in acute medically ill patients (n = 7513). The aim of the current analysis was to determine the efficacy of betrixaban vs standard-duration enoxaparin accounting for non-VTE-related deaths using the Fine and Gray method for competing risks. The proportion of non-VTE-related death was similar in both the betrixaban (133, 3.6%) and enoxaparin (136, 3.7%) arms, P = .85. Both the traditional Kaplan-Meier method and the Fine and Gray method accounting for non-VTE-related death as a competing risk showed equal reduction of VTE events when comparing betrixaban to enoxaparin (HR/SHR = 0.65, 95% 0.42-0.99, P = 0.046). Due to the similar proportion of non-VTE-related deaths in both treatment arms and the use of a univariate model, the Fine and Gray method provided identical results to the traditional Cox model. Using the Fine and Gray method in addition to the traditional Cox proportional hazards method can indicate whether the presence of a competing risk, which is dependent of the outcome, altered the risk estimate.

Background The IMPROVE score is a validated venous thromboembolism (VTE) assessment tool to risk stratify hospitalized, medically ill patients based on clinical variables. It was hypothesized that addition of D-dimer measurement to derive a new IMPROVEDD score would improve identification of at risk of VTE. Methods The association of the IMPROVE score and D-dimer ≥ 2 × the upper limit of normal (ULN) with the risk of symptomatic deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was evaluated in 7,441 hospitalized, medically ill patients randomized in the APEX trial. Based on the Cox regression analysis, the IMPROVEDD score was derived by adding two points to the IMPROVE score if the D-dimer was ≥ 2 × ULN. Results Baseline D-dimer was independently associated with symptomatic VTE through 77 days (adjusted HR: 2.22 [95% CI: 1.38–1.58], p = 0.001). Incorporation of D-dimer into the IMPROVE score improved VTE risk discrimination (ΔAUC: 0.06 [95% CI: 0.02–0.09], p = 0.0006) and reclassification (continuous NRI: 0.34 [95% CI: 0.17–0.51], p = 0.001; categorical NRI: 0.13 [95% CI: 0.03–0.23], p = 0.0159). Patients with an IMPROVEDD score of ≥2 had a greater VTE risk compared with those with an IMPROVEDD score of 0 to 1 (HR: 2.73 [95% CI: 1.52–4.90], p = 0.0007). Conclusion Incorporation of D-dimer into the IMPROVE VTE risk assessment model further improves risk stratification in hospitalized, medically ill patients who received thromboprophylaxis. An IMPROVEDD score of ≥2 identifies hospitalized, medically ill patients with a heightened risk for VTE through 77 days.

Major medical illnesses place patients at risk of venous thromboembolism (VTE). Some risk factors including age ≥75 years or history of cancer place them at increased risk of VTE that extends for at least 5 to 6 weeks following hospital admission. Betrixaban thromboprophylaxis is now approved in the United States for this indication. We estimated the annual number of acutely ill medical patients at extended risk of VTE discharged from US hospital. Major medical illnesses (stroke, respiratory failure/chronic obstructive pulmonary disease, heart failure, pneumonia, other infections, and rheumatologic disorders) and 2 common risk factors for extended VTE risk, namely, age ≥75 years and history of cancer (active or past) were examined in 2014 US hospital discharges using the first 3 discharge diagnosis codes in the National Inpatient Sample (database of acute-care hospital discharges from the US Agency for Health Care Quality and Research). In 2014, there were 20.8 million discharges with potentially at risk of nonsurgical-related VTE. Overall, 7.2 million (35%) discharges corresponded to major medical illness that warranted thromboprophylaxis according to 2012 American College of Chest Physicians (ACCP) guideline. Among them, 2.79 million were aged ≥75 years and 1.36 million had a history of cancer (aged 40-74 years). Overall, 3.48 million discharges were at extended risk of VTE. Many medical inpatients at risk of VTE according to 2012 ACCP guideline might benefit from the awareness of continuing risk and some of these patients might benefit from extended thromboprophylaxis, depending on the risk of bleeding and comorbidities.

The North American Thrombosis Forum Atrial Fibrillation Action Initiative consensus document is a comprehensive yet practical briefing document focusing on stroke and bleeding risk assessment in patients with atrial fibrillation, as well as recommendations regarding anticoagulation options and management. Despite the breadth of clinical trial data and guideline recommendation updates, many clinicians continue to struggle to synthesize the disparate information available. This problem slows the uptake and utilization of updated risk prediction tools and adoption of new oral anticoagulants. This document serves as a practical and educational reference for the entire medical community involved in the care of patients with atrial fibrillation.

Aim Asymptomatic deep vein thrombosis (DVT) diagnosed with compression ultrasound (CUS) is a common endpoint in trials assessing the efficacy of anticoagulants to prevent venous thromboembolism (VTE), but the relationship of asymptomatic thrombus to mortality remains uncertain. Methods In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35–42 days) or enoxaparin (10 ± 4 days). Asymptomatic DVT was assessed once with CUS between day 32 and 47, and mortality was assessed through 77 days. Results A total of 309 asymptomatic DVTs were detected through CUS. Of these, 133 (4.27%) subjects were in the betrixaban group, and 176 (5.55%) subjects were in the enoxaparin group (relative risk = 0.77, 95% confidence interval [CI] = 0.62–0.97, p = 0.025, number needed to treat = 79). With respect to all-cause mortality due to cardiovascular diseases, non-cardiovascular diseases and unknown causes, the number of the deaths was 5 (1.67%), 4 (1.34%) and 1 (0.33%) in the asymptomatic DVT group and 25 (0.42%), 33 (0.56%) and 11 (0.19%) in the no DVT group, respectively. Subjects with an asymptomatic DVT had an almost threefold increase in the risk of all-cause mortality compared with subjects without DVT (hazard ratio = 2.87, 95% CI = 1.48–5.57, p = 0.001). A positive linear trend was observed between greater thrombus burden and mortality during the follow-up (p = 0.019). Conclusion Asymptomatic DVT was associated with approximately threefold increased risk of short-term all-cause mortality in patients hospitalized with an acute medical illness within the prior 77 days. A positive linear trend was observed between greater thrombus burden and mortality during the follow-up.

To assess the efficacy and safety of betrixaban for venous thromboembolism (VTE) prophylaxis among critically ill patients. The APEX trial randomized 7513 acutely ill hospitalized patients to betrixaban for 35–42 days or enoxaparin for 10 ± 4 days. Among those, 703 critically ill patients admitted to the intensive care unit were included in the analysis, and 547 patients who had no severe renal insufficiency or P-glycoprotein inhibitor use were included in the full-dose stratum. The risk of VTE, bleeding, net clinical benefit (composite of VTE and major bleeding), and mortality was compared at 35–42 days and at 77 days. At 35–42 days, extended betrixaban reduced the risk of VTE (4.27% vs 7.95%, P = 0.042) without causing excess major bleeding (1.14% vs 3.13%, P = 0.07). Both VTE (3.32% vs 8.33%, P = 0.013) and major bleeding (0.00% vs 3.26%, P = 0.003) were decreased in the full-dose stratum. Patients who received betrixaban had more non-major bleeding than enoxaparin (overall population: 2.56% vs 0.28%, P = 0.011; full-dose stratum: 3.32% vs 0.36%, P = 0.010). Mortality was similar at the end of study (overall population: 13.39% vs 16.19%, P = 0.30; full-dose stratum: 13.65% vs 16.30%, P = 0.39). Compared with shorter-duration enoxaparin, critically ill medical patients who received extended-duration betrixaban had fewer VTE without more major bleeding events. The benefit of betrixaban was driven by preventing asymptomatic thrombosis and offset by an elevated risk of non-major bleeding. The APEX trial did not stratify by intensive care unit admission and the present study included a highly selected population of critically ill patients. These hypothesis-generating findings need to be validated in future studies. http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

Hypoalbuminemia is a common finding and independent predictor for unfavorable prognosis. The prognostic value of albumin measurement for short-term VTE prediction in hospitalized patients remains unclear. In the APEX trial (ClinicalTrials.gov identifier: NCT01583218), medical inpatients were randomized to receive either extended-duration betrixaban or shorter-duration enoxaparin and followed for 77 days. Baseline albumin concentrations were obtained in 7266 subjects with evaluable VTE endpoints. The association of baseline albumin to VTE was assessed, with adjustment for patient characteristics, thromboprophylaxis, and biomarkers for fibrinolysis and inflammation (ie, D-dimer and C-reactive protein [CRP]). VTE risk refinement was evaluated by incorporation of albumin to well-validated risk assessment models. A stepwise increase in the risk of VTE (P < .0001) was observed with lower levels of albumin. Patients at the bottom albumin quartile (

Background Anemia is a common finding and independent predictor for adverse outcomes in hospitalized patients with medical illness. It remains unclear whether anemia is a risk factor for venous thromboembolism and whether the presence of anemia can refine risk assessment for prediction of venous thromboembolism, thereby adding incremental utility to a validated model. Methods In the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban trial (APEX), 7513 hospitalized medical patients were randomized to receive either betrixaban or standard-of-care enoxaparin for thromboprophylaxis. Baseline hemoglobin concentrations were obtained in 6861 patients, with a follow-up of 77 days. Symptomatic venous thromboembolism events, including symptomatic deep vein thrombosis, pulmonary embolism, and venous thromboembolism–related mortality, were compared between low-hemoglobin and normal-hemoglobin groups (normal range: 12.5-17.0 g/dL for males and 11.0-15.5 g/dL for females). The relationship between anemia and venous thromboembolism events was assessed by fitting a univariable and multivariable logistic regression model composed of thromboprophylaxis and risk factors. Venous thromboembolism risk refinement by hemoglobin measurement was evaluated in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) risk assessment model. Results Low hemoglobin at baseline was associated with a greater risk of symptomatic venous thromboembolism (relative risk [RR] 1.94 [95% confidence interval, 1.27-2.98]; P = .002), symptomatic deep vein thrombosis (RR 2.29 [1.12-4.68]; P = .019), and nonfatal pulmonary embolism (RR 2.63 [1.22-5.65]; P = .010) but not venous thromboembolism–related mortality (RR 1.47 [0.71-3.04]; P = .30). After adjusting for thromboprophylaxis, history of previous venous thromboembolism, intensive or coronary unit admission, and D-dimer, low hemoglobin (as a categorical or continuous variable) remained associated with an increased likelihood of venous thromboembolism (adjusted odds ratio 1.71 [95% confidence interval, 1.09-2.69]; P = .020). Low hemoglobin also improved risk discrimination and reclassification after inclusion in the IMPROVE model. Conclusions Anemia was independently associated with a greater risk of symptomatic venous thromboembolism among acutely ill medical patients despite the provision of thromboprophylaxis. Hemoglobin measurement also improved risk stratification by the IMPROVE venous thromboembolism risk score.

Acute medical illnesses are associated with a prolonged elevation in inflammatory markers that predisposes patients to thrombosis beyond the duration of their hospital stay. In parallel, both observational and randomized data have demonstrated a rate of postdischarge venous thromboembolic events that often exceeds that observed in the hospital setting. Despite this significant residual risk of venous thromboembolic events following discharge among acute medically ill patients, no therapeutic strategies have been recommended to address this unmet need. Available randomized trials have demonstrated the efficacy of extending the duration of thromboprophylaxis with available anticoagulants; however, the efficacy is offset, at least in part, by an increase in bleeding events. Identification of the optimal therapeutic strategies, treatment duration, and risk assessment tools that reconcile both efficacy and safety of extended-duration thromboprophylaxis among acute medically ill patients is an area of ongoing investigation.

Background The aim of this study was to evaluate the effect of betrixaban on the occurrence of deep vein thrombosis (DVT) and also the extent of thrombus and to assess the association of baseline D-dimer with subsequent thrombus burden. Methods In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35–42 days) or enoxaparin (10 ± 4 days). D-dimer concentration was measured at baseline, and mandatory lower-extremity compression ultrasonography (CUS) was performed at 35 to 42 days. The thrombus burden of DVT was assessed by the number of non-compressible vascular segments in six target proximal veins and compared between treatment groups and D-dimer categories (≥2 × upper limit of normal [ULN] versus Results Compared with enoxaparin, extended-duration betrixaban reduced the DVT risk at 35 to 42 days (any-dose: relative risk [RR] = 0.76 [95% confidence interval: 0.61–0.94]; p = 0.013; full-dose: RR = 0.70 [0.55–0.90]; p = 0.005). Patients who received betrixaban were more likely to have a lower thrombus burden (p = 0.012 for any-dose and p = 0.001 for full-dose). Elevated D-dimer at baseline was independently associated with a 2.12-fold increased risk of developing DVT (p Conclusion Extended-duration betrixaban reduced the number of venous segments with thrombosis at 35 to 42 days compared with enoxaparin. A positive D-dimer was associated with a greater extent of thrombus burden among acutely ill medical patients who developed DVT despite receiving thromboprophylaxis. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. ClinicalTrials.gov identifier: NCT01583218.

Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis.Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients.

Background— Whether heart failure (HF) increases the risk of venous thromboembolism (VTE) is not well established. In the phase III MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabAN with enoxaparin) trial, extended-duration rivaroxaban was compared with standard-duration enoxaparin followed by placebo for VTE prevention in 8101 hospitalized acutely ill patients with or without HF. The aim of this analysis was to evaluate the relationship between HF severity and the risk of VTE in MAGELLAN patients. Methods and Results— Hospitalized patients diagnosed with HF were included according to New York Heart Association class III or IV at admission (n=2593). HF severity was determined by N-terminal probrain natriuretic peptide (NT-proBNP) plasma concentrations (median 1904 pg/mL). Baseline plasma D-dimer concentrations ranged from 0.6 to 1.7 μg/L for the less and more severe HF subgroups. Patients with more severe HF had a greater incidence of VTE versus patients with less severe HF, with a significant trend up to Day 10 (4.3% versus 2.2%; P =0.0108) and Day 35 (7.2% versus 4.1%; P =0.0150). Multivariable analysis confirmed that NT-proBNP concentration was associated with VTE risk up to Day 10 ( P =0.017) and D-dimer concentration with VTE risk up to Day 35 ( P =0.005). The association between VTE risk and HF severity that was observed in the enoxaparin/placebo group was not seen in the extended-duration rivaroxaban group. Conclusions— Patients with more severe HF, as defined by high NT-proBNP plasma concentration, were at increased risk of VTE. NT-proBNP may be useful to identify high short-term risk, whereas elevated D-dimer may be suggestive of high midterm risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00571649.

D-Dimer is a biomarker of fibrin formation and degradation. While a D-dimer within normal limits is used to rule out the diagnosis of deep venous thrombosis and pulmonary embolism among patients with a low clinical probability of venous thromboembolism (VTE), the prognostic association of an elevated D-dimer with adverse outcomes has received far less emphasis. An elevated D-dimer is independently associated with an increased risk for incident VTE, recurrent VTE, and mortality. An elevated D-dimer is an independent correlate of increased mortality and subsequent VTE across a broad variety of disease states. Therefore, medically ill subjects in whom the D-dimer is elevated constitute a high risk subgroup in which the prospective evaluation of the efficacy and safety of antithrombotic therapy is warranted.

SummaryThe EXCLAIM study enrolled hospitalised acutely ill medical patients with age >40 years and recently-reduced mobility into a trial of extended-duration anticoagulant thromboprophylaxis. This post-hoc analysis evaluated the impact of age on patient outcomes. After completion of open-label therapy with enoxaparin 40 mg once-daily (10 ± 4 days), eligible patients underwent randomisation to receive double-blind therapy of enoxaparin (n=2,975) or placebo (n=2,988) for 28 ± 4 days. During follow-up, the venous thromboembolism (VTE) risk increased with age in both treatment groups. In patients with age >75 years, those who received extended-duration enoxaparin had lower incidence of VTE (2.5% vs 6.7%; absolute difference [AD] [95% confidence interval]: −4.2% [−6.5, −2.0]), proximal deep-vein thrombosis (2.5% vs 6.6%; AD −4.1 % [−6.2, −2.0]), and symptomatic VTE (0.3% vs 1.5%; AD −1.2% [−2.2, −0.3]), in comparison to those who received placebo. In patients with age ≤75 years, those who received enoxaparin had reduced VTE (2.4% vs 2.8%; AD −0.4% [−1.5, 0.7]) and symptomatic VTE (0.2% vs 0.7%; AD −0.6% [−1.0, −0.1]) in comparison to those who received placebo. In both age subgroups, patients who received enoxaparin had increased rates of major bleeding versus those who received placebo: age >75 years (0.6% vs 0.2%; AD +0.3% [−0.2, 0.9], respectively); age ≤75 years (0.7% vs 0.2%; AD +0.5% [0.1, 0.9]). Patients in both age subgroups that received enoxaparin had similar low bleeding rates (0.6% and 0.7%, respectively). VTE risk increased with age, though the bleeding risk did not. Patients with age >75 years had a more favourable benefit-to-harm profile than younger patients.

Objective: In a recent multi-center trial of gadolinium contrast-enhanced magnetic resonance angiography (Gd-MRA) for diagnosis of acute pulmonary embolism (PE), two centers utilized a common MRI platform though at different field strengths (1.5T and 3T) and realized a signal-to-noise gain with the 3T platform. This retrospective analysis investigates this gain in signal-to-noise of pulmonary vascular targets. Methods: Thirty consecutive pulmonary MRA examinations acquired on a 1.5T system at one institution were compared to 30 consecutive pulmonary MRA examinations acquired on a 3T system at a different institution. Both systems were from the same MRI manufacturer and both used the same Gd-MRA pulse sequence, although there were some protocol adjustments made due to field strength differences. Region-of-interests were manually defined on the main pulmonary artery, 4 pulmonary veins, thoracic aorta, and background lung for objective measurement of signal-to-noise, contrast-to-noise, and bolus timing bias between centers. Results: The 3T pulmonary MRA protocol achieved higher spatial resolution yet maintained significantly higher signal-to-noise ratio (≥13%, p = 0.03) in the main pulmonary vessels relative to 1.5T. There was no evidence of operator bias in bolus timing or patient hemodynamic differences between groups. Conclusion: Relative to 1.5T, higher spatial resolution Gd-MRA can be achieved at 3T with a sustained or greater signal-to-noise ratio of enhanced vasculature.

Objective Post-thrombotic syndrome causes considerable morbidity. The Home-LITE study showed a lower incidence of post-thrombotic syndrome and venous ulcers after 3 months of treating deep vein thrombosis with the low-molecular-weight heparin tinzaparin versus oral anticoagulation. This systematic review examined whether long-term treatment of deep vein thrombosis using low-molecular-weight heparin, rather than oral anticoagulation, reduces development of post-thrombotic syndrome. Methods We identified 9 articles comparing treatment of deep vein thrombosis using long-term low-molecular-weight heparin with any comparator, which reported outcomes relevant to the post-thrombotic syndrome assessed ≥ 3 months post-deep vein thrombosis. Results Pooled analysis of 2 studies yielded an 87% risk reduction with low-molecular-weight heparin in the incidence of venous ulcers at ≥ 3 months ( P = .019). One study showed an overall odds ratio of 0.77 ( P = .001) favoring low-molecular-weight heparin for the presence of 8 patient-reported post-thrombotic syndrome signs and symptoms. Pooled analysis of 5 studies showed a risk ratio for low-molecular-weight heparin versus oral anticoagulation of 0.66 ( P 0001) for complete recanalization of thrombosed veins. Conclusion These results support the lower incidence of post-thrombotic syndrome and venous ulcers observed in Home-LITE. Long-term treatment with low-molecular-weight heparin rather than oral anticoagulation after a deep vein thrombosis may reduce or prevent development of signs and symptoms associated with post-thrombotic syndrome. Post-thrombotic syndrome and associated acute ulcers may develop more rapidly after deep vein thrombosis than previously recognized.

This is a literature review on prevention of deep vein thrombosis and pulmonary embolism. Criteria for clinical trials are listed, diagnostic techniques are discussed, and nine approaches for preventing venous thromboembolism are outlined. Choices for primary prophylaxis in hip surgery and major knee surgery are presented.

Patients with acute medical illnesses are at increased risk of venous thromboembolism (VTE), a significant cause of morbidity and mortality. Thromboprophylaxis is recommended in these patients but questions remain regarding the optimal duration of therapy. The aim of this study is to determine whether oral rivaroxaban is non-inferior to standard-duration (approximately 10 days) subcutaneous (s.c.) enoxaparin for the prevention of VTE in acutely ill medical patients, and whether extended-duration (approximately 5 weeks) rivaroxaban is superior to standard-duration enoxaparin. Patients aged 40 years or older and hospitalized for various acute medical illnesses with risk factors for VTE randomly receive either s.c. enoxaparin 40 mg once daily (od) for 10 +/- A 4 days or oral rivaroxaban 10 mg od for 35 +/- A 4 days. The primary efficacy outcomes are the composite of asymptomatic proximal deep vein thrombosis (DVT), symptomatic DVT, symptomatic non-fatal pulmonary embolism (PE), and VTE-related death up to day 10 + 4 and up to day 35 + 4. The primary safety outcome is the composite of treatment-emergent major bleeding and clinically relevant non-major bleeding. As of July 2010, 8,101 patients from 52 countries have been randomized. These patients have a broad range of medical conditions: approximately one-third were diagnosed with acute heart failure, just under one-third were diagnosed with acute infectious disease, and just under one-quarter were diagnosed with acute respiratory insufficiency. MAGELLAN will determine the efficacy, safety, and pharmacological profile of oral rivaroxaban for the prevention of VTE in a diverse population of medically ill patients and the potential of extended-duration therapy to reduce incidence of VTE

For a majority of patients with venous thromboembolism (VTE), initial treatment is straightforward and necessitates the immediate initiation of a parenteral anticoagulant (eg, heparin or low molecular weight heparin), simultaneous initiation of long-term therapy (eg, vitamin K antagonist), and discontinuation of the parenteral anticoagulant after 5 days assuming that the vitamin K antagonist is therapeutic. This standardized approach is based on numerous pivotal clinical trials completed over the past 3 decades. Yet, advances in standardized VTE treatment continue to evolve and include issues related to the selection and dosing of parenteral anticoagulants (eg, relative efficacy and dosing in the obese patient, patients with renal impairment, and pregnant patients), optimal location of initial care delivery, use of dosing initiation nomograms for vitamin K antagonists with the potential of gene-based dosing, and demonstration that longterm low molecular weight heparin therapy may be optimal for some patient populations (eg, those with active cancer). Further, in parallel with the evolution of VTE treatment, there have been remarkable advances in our understanding of heparin-induced thrombocytopenia, a prothrombotic complication of parenteral anticoagulant use.

Purpose To determine the effectiveness of venous compression stockings or compression bandages on the reduction of postthrombotic syndrome in patients with deep venous thrombosis. Methods We attempted to identify all published trials in all languages identified by PubMed through June 2009. Meta-analysis was performed. Results Based on 5 randomized trials of patients with deep venous thrombosis comparing treatment with venous compression to controls, mild-to-moderate postthrombotic syndrome occurred in 64 of 296 (22%) treated with venous compression, compared with 106 of 284 (37%) in controls (relative risk=0.52). Severe postthrombotic syndrome occurred in 14 of 296 (5%) treated, compared with 33 of 284 (12%) controls (relative risk=0.38). Any postthrombotic syndrome occurred in 89 of 338 (26%) treated, compared with 150 of 324 (46%) controls (relative risk=0.54). Conclusion Venous compression reduced the incidence of postthrombotic syndrome, particularly severe postthrombotic syndrome. Venous compression in patients with deep venous thrombosis would seem to be indicated for this purpose. There was, however, wide variation in the type of stockings used, time interval from diagnosis to application of stockings, and duration of treatment. Further investigation, therefore, is needed.

The purpose of this investigation is to show trends in the duration of hospitalization of patients with pulmonary embolism (PE) and deep venous thrombosis (DVT). The number of patients discharged from short-stay non-Federal hospitals throughout the United States with a primary diagnostic code for PE or DVT from 1979 through 2005 was obtained from the National Hospital Discharge Survey. By 2005, 13% of patients with PE were discharged in 1 to 2 days, 30% in 3 to 4 days, 26% in 5 to 6 days, and 31% in ≥7 days. Regarding DVT, by 2005, 26% of patients with DVT were discharged in 1 to 2 days, 34% were discharged in 3 to 4 days, 20% were discharged in 5 to 6 days, and 19% were discharged in ≥7 days. The data indicate that large proportions of patients with a primary diagnosis of PE and of DVT are being discharged before adequate heparin can be administered and before warfarin can become antithrombotic. Others have reported an increased mortality among patients with PE discharged in ≤4 days. If patients are to be discharged before adequate heparin can be administered, outpatient treatment with low-molecular-weight heparin (LMWH) for at least 5 days and until the international normalized ratio (INR) is ≥2.0 for 24 hours is recommended or extended outpatient treatment with LMWH may be considered.

Background: The safety and efficacy of new anticoagulants are often initially tested for venous thromboembolism (VTE) prevention in patients undergoing major orthopedic surgery. Concern among surgeons about the risks for bleeding may result in suboptimal use of thrombophylaxis. Objective: To evaluate the definitions used to define bleeding outcomes in studies of new anticoagulants and to examine the influence the definition has on the perceived bleeding risk of thromboprophylaxis. Methods: The MedLine database was searched for phase III studies of new anticoagulants versus the standard comparator, enoxaparin, in patients undergoing major orthopedic surgery. Results: The definitions for major bleeding outcomes varied widely both across and within clinical trial programs of new anticoagulants. Studies which did not include surgical site bleeding in their definition for major bleeding showed lower major bleeding rates in comparison to those that did include this outcome. Other factors that influenced the rate of major bleeding included the timing of prophylaxis initiation in relation to surgery and the dose of anticoagulant therapy. The wide range of definitions used for major bleeding made it difficult to compare bleeding risk among studies of new anticoagulants. Conclusions: The definitions of bleeding events that clinical trials of thromboprophylaxis use in their assessment of new anticoagulants strongly influences each drug’s perceived safety profile and may underestimate bleeding risks. Clinical studies of new anticoagulants urgently need standardization of bleeding definitions to allow intertrial comparability and to ensure consistent reporting of clinically relevant outcomes.

The clinical diagnosis of pulmonary embolism (PE) is difficult in coronary care units (CCUs) because many findings of PE are similar to those of acute coronary syndromes and heart failure. Immobilization of only 1 or 2 days may predispose to PE. Heart failure and acute myocardial infarction add to the risk. Dyspnea may be absent or occur only with exertion. The onset of dyspnea may occur over seconds to days. Orthopnea occurs with PE as well as heart failure. When the clinical probability and results of objective testing are discordant, the posttest probability of PE may be neither sufficiently high nor sufficiently low to permit therapeutic decisions. Objective scoring systems for clinical assessment have not been developed for patients in a CCU. d-dimer is likely to be of little value for the exclusion of PE in CCUs, because elevations occur with heart failure, unstable angina, and myocardial infarction. Computed tomographic pulmonary angiography with venous phase imaging of the low pelvic and proximal leg veins (computed tomographic venography) is recommended for imaging. Scintigraphy in women aged50 years with normal or nearly normal results on chest x-ray may be the preferred imaging test to reduce the risk for radiation. Echocardiography with leg ultrasonography is a rapidly obtainable combination of bedside tests that may be useful for young patients and patients in extremis. In conclusion, the choice of diagnostic test depends on the clinical probability of PE, the condition of the patient, the availability of diagnostic tests, the risks of iodinated contrast material, radiation exposure, and cost.

Although effective, vitamin K antagonists (VKAs) are challenging to use because of their slow onset and offset of action, narrow therapeutic window, multiple dietary and drug interactions, and unpredictable anticoagulant effect. Accordingly, it is recognized that there is an unmet need for an oral thrombotic inhibitor that does not require monitoring and has a rapid onset of action. There is also an unmet need in the field of thromboprophylaxis against venous thromboembolism (VTE) in high-risk patients. The topic of this Supplement is the evidence for the use of dabigatran in high-risk orthopedic patients, namely patients with hip and knee athroplasty. An oral therapy with an immediate reliable and predictable anticoagulant effect without the need for coagulation monitoring and without any long-term hepatic or safety concerns will be a major advance in the management of patients with various thrombotic disorders.

The state of the art of diagnostic evaluation of hemodynamically stable patients with suspected acute pulmonary embolism was reviewed. Diagnostic evaluation should begin with clinical assessment using a validated prediction rule in combination with measurement of D-dimer when appropriate. Imaging should follow only when necessary. Although with 4-slice computed tomography (CT) and 16-slice CT, the sensitivity for detection of pulmonary embolism was increased by combining CT angiography with CT venography, it is not known whether CT venography increases the sensitivity of 64-slice CT angiography. Methods to reduce the radiation exposure of CT venography include imaging only the proximal leg veins (excluding the pelvis) and obtaining discontinuous images. Compression ultrasound can be used instead. In young women, radiation of the breasts produces the greatest risk of radiation-induced cancer. It may be that scintigraphy is the imaging test of choice in such patients, but this pathway should be tested prospectively. A patient-specific approach to the diagnosis of pulmonary embolism can be taken safely in hemodynamically stable patients to increase efficiency and decrease cost and exposure to radiation.

Acute venous disorders include deep venous thrombosis, superficial venous thrombophlebitis, and venous trauma. Deep venous thrombosis (DVT) most often arises from the convergence of multiple genetic and acquired risk factors, with a variable estimated incidence of 56 to 160 cases per 100,000 population per year. Acute thrombosis is followed by an inflammatory response in the thrombus and vein wall leading to thrombus amplification, organization, and recanalization. Clinically, there is an exponential decrease in thrombus load over the first 6 months, with most recanalization occurring over the first 6 weeks after thrombosis. Pulmonary embolism (PE) and the post-thrombotic syndrome (PTS) are the most important acute and chronic complications of DVT. Despite the effectiveness of thromboembolism prophylaxis, appropriate measures are utilized in as few as one-third of at-risk patients. Once established, the treatment of venous thromboembolism (VTE) has been defined by randomized clinical trials, with appropriate anticoagulation constituting the mainstay of management. Despite its effectiveness in preventing recurrent VTE, anticoagulation alone imperfectly protects against PTS. Although randomized trials are currently lacking, at least some data suggests that catheter-directed thrombolysis or combined pharmaco-mechanical thrombectomy can reduce post-thrombotic symptoms and improve quality of life after acute ileofemoral DVT. Inferior vena caval filters continue to have a role among patients with contra-indications to, complications of, or failure of anticoagulation. However, an expanded role for retrievable filters for relative indications has yet to be clearly established. The incidence of superficial venous thrombophlebitis is likely under-reported, but it occurs in approximately 125,000 patients per year in the United States. Although the appropriate treatment remains controversial, recent investigations suggest that anticoagulation may be more effective than ligation in preventing DVT and PE. Venous injuries are similarly under-reported and the true incidence is unknown. Current recommendations include repair of injuries to the major proximal veins. If repair not safe or possible, ligation should be performed.

Background Selection of patients for diagnostic tests for acute pulmonary embolism requires recognition of the possibility of pulmonary embolism on the basis of the clinical characteristics. Patients in the Prospective Investigation of Pulmonary Embolism Diagnosis II had a broad spectrum of severity, which permits an evaluation of the subtle characteristics of mild pulmonary embolism and the characteristics of severe pulmonary embolism. Methods Data are from the national collaborative study, Prospective Investigation of Pulmonary Embolism Diagnosis II. Results There may be dyspnea only on exertion. The onset of dyspnea is usually, but not always, rapid. Orthopnea may occur. In patients with pulmonary embolism in the main or lobar pulmonary arteries, dyspnea or tachypnea occurred in 92%, but the largest pulmonary embolism was in the segmental pulmonary arteries in only 65%. In general, signs and symptoms were similar in elderly and younger patients, but dyspnea or tachypnea was less frequent in elderly patients with no previous cardiopulmonary disease. Dyspnea may be absent even in patients with circulatory collapse. Patients with a low-probability objective clinical assessment sometimes had pulmonary embolism, even in proximal vessels. Conclusion Symptoms may be mild, and generally recognized symptoms may be absent, particularly in patients with pulmonary embolism only in the segmental pulmonary branches, but they may be absent even with severe pulmonary embolism. A high or intermediate-probability objective clinical assessment suggests the need for diagnostic studies, but a low-probability objective clinical assessment does not exclude the diagnosis. Maintenance of a high level of suspicion is critical.

This review describes the accuracy of multidetector contrast-enhanced computed tomography (CT) for the diagnosis of acute pulmonary embolism, the role of clinical assessment and of venous phase imaging in combination with it, and the approach to the diagnosis.The sensitivity of CT angiography was 83%, specificity 96% and positive predictive value 86%. Positive predictive values were 97% for pulmonary embolism in a main or lobar artery, 68% for a segmental vessel, and 25% for a subsegmental branch. A CT angiogram with concordant clinical probability assessment resulted in high predictive values, but with a discordant clinical probability, predictive value was low. The sensitivity for pulmonary embolism increased to 90% by using CT venography in combination with CT angiography.A negative D-dimer by the rapid enzyme-linked immunosorbent assay method with a low or moderate probability clinical assessment can safely exclude pulmonary embolism. Clinical probability assessment and D-dimer are recommended. In general, CT angiography in combination with CT venography is recommended, but the choice of diagnostic tests depends on the clinical situation.The reliability of multislice CT angiography is enhanced by clinical assessment and CT venography used with it. Clinical assessment and D-dimer are recommended before imaging.

SummaryThe accuracy of computed tomography (CT) imaging for the diagnosis of acute pulmonary embolism (PE) was reviewed. Single detector CT, based on pooled data, showed a sensitivity of 73% and multidetector CT, mostly 4-slice, showed a sensitivity of 83%. Respective specificities were 87% and 96%. Among patients with suspected PE evaluated with single slice CT,20% of patients found to have venous thromboembolic disease were diagnosed on the basis of a positive CT venous phase venogram. With multislice CT, 14% were diagnosed on the basis of a positive CT venogram.The positive likelihood ratio with single detector CT was 5.7 and with multidetector CT it was 19.6. Respective negative likelihood ratios were 0.31 and 0.18. Calculations of post-test probability using pretest probability and likelihood ratios according to Bayes’ theorem showed that even with multidetector CT, false positive and false negative images are not uncommon when clinical assessment is discordant with the CT interpretation. Outcome studies showed recurrent PE in only 1.7% or fewer untreated patients with negative CT pulmonary angiograms.

Clot-burden change in patients receiving anticoagulant therapy, by predicting subsequent recurrent venous thromboembolism, may provide a clinically relevant surrogate endpoint of prognostic importance. The validity of this objective measure is yet to be established.A PubMed search was performed to retrieve articles published up to December 2003. We identified 11 randomized trials reported from 1990 to 2003 that met our study identification and selection criteria. Anticoagulant therapy subsequently approved by regulatory affairs was assessed by clot-burden change and the validated outcome measure, long-term venous thromboembolism. Two additional randomized trials, partly meeting the inclusion criteria, were included in the sensitivity analysis.Individual studies suggested a predictive relationship between clot-burden change and likelihood of recurrent venous thromboembolism irrespective of the particular anticoagulant. The summary treatment effects strongly favored the therapy under evaluation and were in harmony for improved clot-burden (relative risk 0.82; 95% CI, 0.76-0.88; P0.001) and for recurrent venous thromboembolism (relative risk 0.56; 95% CI, 0.42-0.76; P0.001). The aggregate data show a striking predictive correlation for clot-burden change and subsequent recurrent venous thromboembolism using meta-regression analysis; (correlation = 0.81, P = 0.005) validating quantitative clot-burden assessment.Clot-burden change predicts long-term outcome, providing clinically relevant, patient-specific prognostic findings that may guide duration of anticoagulant therapy as well as provide a valid surrogate endpoint for clinical trials of innovative antithrombotic therapy, allowing more efficient trials exposing far fewer patients to the hazards of ineffective therapy than is required for outcome studies. Noninvasive assessment (duplex ultrasonography) of clot-burden change is currently being deployed for use in clinical trials.

Warfarin and related compounds are efficacious and safe in a variety of clinical thrombotic disorders; however, these drugs have a narrow therapeutic window, whereby inadequate therapy is associated with an increased thrombotic risk and overanticoagulation is associated with bleeding. Therefore, attempts have been made to develop alternatives to warfarin. Ximelagatran, an oral direct thrombin inhibitor, has been shown to be as efficacious and safe as warfarin for the prevention and treatment of different thrombotic disorders. This article reviews the pharmacology of the coumarins, the most commonly used vitamin K antagonists, and the practical aspects regarding their use in the management of thrombotic disorders. The future role of the oral direct thrombin inhibitor ximelagatran also is reviewed.

Venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) is a common problem in the elderly population. Indeed, increasing age is a significant risk factor for venous thromboembolism. The treatment of venous thromboembolism in the elderly population presents certain unique problems related to aging, such as decreasing body weight, increasing renal insufficiency and numerous comorbid conditions, which complicate therapy. Treatment of venous thromboembolism in the elderly has been complicated by an increased incidence of bleeding, particularly with the use of warfarin. The risk of bleeding may be substantially reduced by carefully adjusting the warfarin dose to maintain a therapeutic INR and for this purpose anticoagulant management clinics have been shown to be useful. The low-molecular-weight heparins have been shown to be efficacious and safe for the treatment of venous thromboembolism in several clinical trials, including many patients in the older age brackets. Furthermore, these agents can safely be used in the out-of-hospital setting. Long-term use of low-molecular-weight heparin is an alternative to the use of oral anticoagulant therapy, particularly in patients with cancer or recurrent venous thromboembolism.

Objective. Study of the uptake of new medical technologies provides useful information on the transfer of published evidence into usual practice. We conducted an audit of selected hospitals in three countries (Canada, France, and Switzerland) to identify clinical predictors of low-molecular-weight (LMW) heparin use and outpatient treatment, and to compare the pace of uptake of these new therapeutic approaches across hospitals. Design. Historical review of medical records. Setting and participants. We reviewed the medical records of 3043 patients diagnosed with deep vein thrombosis (DVT) in five Canadian, two French, and two Swiss teaching hospitals from 1994 to 1998. Measures. We explored independent clinical variables associated with LMW heparin use and outpatient treatment, and determined crude and adjusted rates of LMW heparin use and outpatient treatment across hospitals. Results. For the years studied, the overall rates of LMW heparin use and outpatient treatment in the study sample were 34.1 and 15.8%, respectively, with higher rates of use in later years. Many comorbidities were negatively associated with outpatient treatment, and risk-adjusted rates of use of these new approaches varied significantly across hospitals. Conclusion. There has been a relatively rapid uptake of LMW heparins and outpatient treatment for DVT in their early years of availability, but the pace of uptake has varied considerably across hospitals and countries.