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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.

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 …

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.

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 (

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.

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.

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.

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

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.

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.

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.

Pulmonary embolism remains a major cause of death in high-risk medical and surgical patients. This is unfor tunate as effective measures for prevention of venous throm boembolism in such patients are now available. Based on Level 1 evidence from clincial trials and systematic reviews, recom mendations can be made for the prevention of venous throm boembolism in most situations. If such information is not avail able, recommendations based on extrapolation from similar risk situations or from consensus opinions must be used. Additional clinical trials are required to fill in such gaps in our knowledge and permit adequate protection against fatal pulmonary embo lism in most if not all medical and surgical patients. Key Words: Heparin—Low molecular weight heparin—Oral anti coagulants—Intermittent pneumatic compression—Graduated compression stockings—Deep vein thrombosis—Pulmonary embolism.

Summary Background D-dimer concentrations have not been evaluated extensively as a predictor of increased venous thromboembolism (VTE) risk in acutely ill, hospitalized medical patients. Objectives To analyze the relationships between D-dimer concentration, VTE and bleeding in the MAGELLAN trial (NCT00571649). Patients/methods This was a multicenter, randomized, controlled trial. Patients aged ≥ 40 years, hospitalized for acute medical illnesses with risk factors for VTE received subcutaneous enoxaparin 40 mg once daily for 10 ± 4 days then placebo up to day 35, or oral rivaroxaban 10 mg once daily for 35 ± 4 days. Patients (n = 7581) were grouped by baseline D−dimer ≤ 2 × or > 2 × the upper limit of normal. VTE and major plus non-major clinically relevant bleeding were recorded at day 10, day 35, and between days 11 and 35. Results The frequency of VTE was 3.5-fold greater in patients with high D-dimer concentrations. Multivariate analysis showed that D-dimer was an independent predictor of the risk of VTE (odds ratio 2.29 [95% confidence interval 1.75–2.98]), and had a similar association to established risk factors for VTE, for example cancer and advanced age. In the high D-dimer group, rivaroxaban was non-inferior to enoxaparin at day 10 and, unlike the low D-dimer group, superior to placebo at day 35 (P

Randomized clinical trials have identified a population of acute medically ill patients who remain at risk for venous thromboembolism (VTE) beyond the standard duration of therapy and hospital discharge. The aim of the APEX study is to determine whether extended administration of oral betrixaban (35–42 days) is superior to a standard short course of prophylaxis with subcutaneous enoxaparin (10 ± 4 days followed by placebo) in patients with known risk factors for post-discharge VTE. Patients initially are randomized to receive either betrixaban or enoxaparin (and matching placebo) in a double dummy design. Following a standard duration period of enoxaparin treatment (with placebo tablets) or betrixaban (with placebo injections), patients receive only betrixaban (or alternative matching placebo). Patients are considered for enrollment if they are older than 40 years, have a specified medical illness, and restricted mobility. They must also meet the APEX criteria for increased VTE risk (aged ≥75 years, baseline D-Dimer ≥2× upper the limit of “normal”, or 2 additional ancillary risk factors for VTE). The primary efficacy end point is the composite of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, non-fatal (pulmonary embolus) pulmonary embolism, or VTE-related death through day 35. The primary safety outcome is the occurrence of major bleeding. We hypothesize that extended duration betrixaban VTE prophylaxis will be safe and more effective than standard short duration enoxaparin in preventing VTE in acute medically ill patients with known risk factors for post hospital discharge VTE.

Venous thromboembolism (VTE) causes significant morbidity and mortality in hospitalized medical populations; however, medical patients do not currently receive thromboprophylaxis beyond their hospital stay. We reviewed the real-life occurrence of VTE-related care for 100 days post-hospitalization in Calgary, Canada. Using medical visit records with a unique patient identifier number applied throughout the city’s hospitals, 989 high-risk patients were selected for review. Almost three-quarters of the elderly patients received appropriate prophylaxis while in hospital, and only 2% received prophylaxis on discharge. Over the 100-day follow-up, 21% of the patients presented with clinically suspected VTE, of which 3.8% had confirmed VTE. Patients with multiple risk factors (≥3) had the highest frequency of confirmed VTE (≥6.1%). This study suggests that the actual rate of VTE-related follow-up care in patients post-hospitalization is high in the first 100 days, particularly among those who have multiple risk factors, warranting consideration of extended thromboprophylaxis in this population.

Patients with iliac deep vein thrombosis (DVT) have a poor prognosis and high incidence of postthrombotic syndrome (PTS). We evaluated the effect of low-molecular-weight heparin (LMWH; tinzaparin) versus usual care (tinzaparin plus warfarin for ≥12 weeks at home) in the development of PTS according to DVT location (iliac/noniliac) by retrospective analysis of the Home-LITE cohort (480 patients with proximal DVT). Patients with iliac DVT had an overall odds ratio of 0.53 (95% confidence interval [CI] 0.33, 0.83; P = .0079) for PTS (including ulcer data) in favor of tinzaparin. Patients with noniliac DVT had a similar odds ratio (0.79 [95% CI 0.67, 0.93], P = .0046) to that reported in the overall Home-LITE population (0.76 [95% CI 0.66, 0.89], P = .0004; including ulcer data), both in favor of tinzaparin. Long-term LMWH may be a suitable alternative for the prevention of PTS in patients with iliac DVT who are unlikely to undergo invasive thrombolysis.

Background and Purpose— The optimal duration of venous thromboembolism prophylaxis in acute stroke patients is unknown. This subanalysis of the Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization (EXCLAIM) study investigated extended-duration thromboprophylaxis with enoxaparin, compared with placebo following standard-duration enoxaparin, in ischemic stroke patients. Methods— Acutely ill medical patients with recently reduced mobility received open-label enoxaparin 40 mg for 10±4 days, and they were then randomized to double-blind enoxaparin 40 mg daily or placebo for further 28±4 days. Venous thromboembolism incidence (symptomatic/asymptomatic deep-vein thrombosis, symptomatic/fatal pulmonary embolism) up to day 28 after randomization and major bleeding rates up to 48 h after the last dose of study treatment were reported. Results— In total, 389 of 5963 (6.5%) randomized patients had ischemic stroke: 198 received extended-duration prophylaxis and 191 placebo. Extended-duration prophylaxis reduced venous thromboembolism incidence versus placebo (2.4% versus 8.0%; absolute risk difference, −5.6%; 95% CI, −10.5% to −0.7%), but it was associated with an increase in major bleeding (1.5% versus 0% in enoxaparin and placebo groups; absolute risk difference, +1.5%; 95% CI, −0.2% to 3.2%). Conclusion— Extended-duration thromboprophylaxis with enoxaparin was associated with reduced venous thromboembolism risk and increased major bleeding in the subgroup of patients with ischemic stroke in the EXCLAIM study. Clinical Trial Registration Information— URL: http://clinicaltrials.gov . Unique Identifier: NCT00077753.

Background: The exposure of all the currently licenced DOACs is increased in renal impairment and by certain drug interactions. The Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among acutely ill medical patients. The full 80 mg dose of betrixaban was halved to 40 mg among subjects with severe renal insufficiency (calculated creatinine clearance Objectives and Methods: The goal of this analysis is to assess the efficacy and safety of full (80 mg) and reduced dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. Subjects were stratified into the two dose groups prior to randomization according to the pre-specified dosing criteria. The primary efficacy outcome was the composite of asymptomatic proximal and symptomatic venous thromboembolism (proximal or distal deep-vein thrombosis, symptomatic nonfatal pulmonary embolism, or death from venous thromboembolism). The principal safety outcome was major bleeding. Results: The median concentration of betrixaban among subjects administered the 80 mg dose was higher than that of the 40 mg dose (19 ng/ml vs 11 ng/ml, p Conclusion: For extended duration prophylaxis against VTE in hospitalized medically ill patients, the full 80 mg dose of extended duration betrixaban achieves higher serum concentrations than the 40 mg dose and is associated with improved efficacy across all cohorts relative to standard dose enoxaparin, without an excess risk of major bleeding. Based upon the approximate halving of plasma concentrations in this analysis and the lack of improvement in clinical outcomes, the reduced 40 mg dose may have been excessively downwardly adjusted. Conversely, the 80 mg dose was efficacious in all cohorts, including cohort 1. The inclusion of the 40 mg dose in the primary analysis may explain at least in part the marginal statistical result in the original report. Disclosures Cohen: Takeda: Consultancy; Medscape: Speakers Bureau; XO1: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; NHS: Membership on an entity's Board of Directors or advisory committees; Lifeblood: Membership on an entity's Board of Directors or advisory committees; Department of Health: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Janssen: Consultancy; Aspen: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; Colation to Prevent Venous Thromboembolism: Other: Founder; Leo Pharma: Consultancy; UK Government Health Select Committee: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria. Goldhaber:Portola: Consultancy. Hull:Portola: Consultancy. Hernandez:Portola: Consultancy. Gold:Portola Pharmaceuticals: Employment. Wiens:Portola: Employment, Equity Ownership. Harrington:Portola: Consultancy. Gibson:Portola: Consultancy.

Low-molecular-weight heparin, compared with unfractionated heparin, has a higher bioavailability and a more prolonged half-life. There are limited data comparing the use of low-molecular-weight heparin with unfractionated heparin for the treatment of deep vein thrombosis. We have compared fixed-dose, subcutaneous low-molecular-weight heparin given once daily with adjusted-dose intravenous heparin given by continuous infusion in a multicenter double-blind clinical trial for the initial treatment of patients with proximal vein thrombosis. Clinical outcomes were objectively documented. Six of 213 patients receiving low-molecular-weight heparin (2.8%) and 15 of 219 patients receiving intravenous heparin (6.9%) developed new episodes of venous thromboembolism (p = 0.07; 95% confidence interval for the difference, 0.02%-8.1%). During initial therapy, major bleeding occurred in one patient receiving low-molecular-weight heparin (0.5%) and in 11 patients receiving intravenous heparin (5.0%), a risk reduction of 91% (p = 0.006). This apparent protection against major bleeding was lost during long-term therapy. Minor bleeding complications were rare. During the period of the study, 10 patients receiving low-molecular-weight heparin (4.7%) died, as compared with 21 patients receiving intravenous heparin (9.6%), a risk reduction of 51%(p = 0.049). This study shows that low-molecular-weight heparin is at least as effective as classic intravenous heparin therapy and that there was a reduction in deaths and bleeding complications. Furthermore, low-molecular-weight heparin was more convenient to administer. The simplified therapy with low-molecular-weight heparin given by once-daily subcutaneous injection without monitoring may allow patients with uncomplicated proximal deep vein thrombosis to be cared for as outpatients. Key Words: Low-molecular-weight heparin—Unfractionated heparin—Deep vein thrombosis—Deaths—Bleeding complications.

Recent or continued immobility is a significant risk factor for venous thromboembolism (VTE) in acutely ill medical patients. Patients may benefit from thromboprophylaxis; however, its optimal duration remains unclear. The Extended Clinical Prophylaxis in Acutely Ill Medical Patients (EXCLAIM) study was the first trial to systematically investigate how the degree of immobilization relates to the risk of developing VTE. EXCLAIM offers insights into the duration of VTE risk associated with reduced mobility and helps identify which patients would benefit most from extended-duration thromboprophylaxis. Further recent studies suggest that extended-duration thromboprophylaxis may be in order in certain high-risk patients to protect the patients from the risk of VTE events occurring, particularly in the posthospitalization period. Baseline d-dimer data and level of mobility could be included in risk assessment. Physicians are recommended to consider the use of extended-duration thromboprophylaxis based on individual risk assessment management (RAM) and balance of benefit and harm.

The post-thrombotic syndrome (PTS) is a frequent and burdensome disease, but no gold standard test exists to diagnose it. The value of patient-reported outcomes (PROs) in recording transient signs/symptoms, thereby possibly improving diagnosis/monitoring and subsequent clinical care in some diseases, is increasingly being recognized. For example, PROs have been successfully used in cancer, rheumatoid arthritis, and endometriosis. In this context, we describe a patient-reported questionnaire (the Patient-Tracked Symptoms questionnaire) that contains questions on the presence of signs/symptoms of PTS. This questionnaire has face validity and was successfully used in the Home-LITE trial. It could prove valuable in monitoring patient symptoms, especially in home-based patients who do not have regular contact with hospital clinicians. Patients who report symptoms can then undergo follow-up assessment by health care professionals at their next clinic visit. The Patient-Tracked Symptoms questionnaire could help clinicians to recognize the PTS early, enabling them to initiate treatment promptly.

We assessed the potential safety of withholding treatment of pulmonary embolism (PE) limited to subsegmental branches. Literature review showed that untreated patients with mostly subsegmental PE had no fatal recurrences in 1 to 3 months and no nonfatal recurrences of PE in 3 months. Patients with suspected PE who had nondiagnostic ventilation/perfusion lung scans, adequate cardiorespiratory reserve or low or moderate clinical probability, and negative serial noninvasive leg tests were shown not to require treatment. It appears safe, therefore, to withhold treatment of subsegmental PE providing (1) pulmonary–respiratory reserve is good; (2) no evidence of deep venous thrombosis (DVT) on serial testing; (3) major risk factor for PE was transient and no longer present; (4) no history of central venous catheterization or atrial fibrillation; and (5) willingness to return for serial venous ultrasound. After fully informing patients, some may choose to be treated and some may choose not to be treated.

See related articles by Kelsall at [www.cmaj.ca/cgi/doi/10.1503/cmaj.110255][1], by Frank and colleagues at [www.cmaj.ca/cgi/doi/10.1503/cmaj.110358][2], and by Devereaux and colleagues at [www.cmaj.ca/cgi/doi/10.1503/cmaj.110292][3]. > Russell Hull, the POISE-1 investigators, and Cyril Frank and

In a multi-center trial, gadolinium enhanced magnetic resonance angiography (MRA) for diagnosis of acute pulmonary embolism (PE) had a high rate of technically inadequate images. Accordingly, we evaluated the reasons for poor quality MRA of the pulmonary arteries in these patients. We performed a retrospective analysis of the data collected in the PIOPED III study. We assessed the relationship to the proportion of examinations deemed “uninterpretable” by central readers to the clinical centers, MR equipment platform and vendors, degree of vascular opacification in different orders of pulmonary arteries; type, frequency and severity of image artifacts; patient co-morbidities, symptoms and signs; and reader characteristics. Centers, MR equipment vendor and platform, degree of vascular opacification, and motion artifacts influenced the likelihood of central reader determinations that images were “uninterpretable”. Neither the reader nor patient characteristics (age, body mass index, respiratory rate, heart rate) correlated with the likelihood of determining examinations “uninterpretable”. Vascular opacification and motion artifact are the principal factors influencing MRA interpretability. Some centers obtain better images more consistently, but the reasons for differences between centers are unclear.

During a recent multi-center trial assessing gadolinium (Gd)-enhanced magnetic resonance angiography (MRA) for diagnosis of acute pulmonary embolism (PE), the Food and Drug Administration announced a risk of nephrogenic sclerosing fibrosis in patients with renal insufficiency who had received intravenous Gd-based MR contrast agents. Although no patients in this trial had renal insufficiency, in cautious response to this announcement, the trial protocol was changed from an intravenous administration of 0.2 mmol/Kg of a conventional Gd-based MR contrast agent to 0.1 mmol/Kg of gadobenate dimeglumine. The study described herein compares the signal quality of pulmonary MRA performed with double dose conventional agent to single dose gadob-enate dimeglumine. This study is a retrospective analysis of data from a prospective, multicenter study in men and women ≥18 years with documented presence or absence of PE. The study was approved by the Institutional Review Board at all participating centers, and all patients provided written indication of informed consent. We performed both objective and subjective analysis of pulmonary artery image quality. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in the main pulmonary artery were assessed in single and double dose protocols and compared. SNR and CNR of the main PA were correlated with subjective quality assessment of main/lobar, segmental and subsegmental pulmonary arteries. Although there were individual outliers, both SNR (P = 0.01) and CNR (P = 0.008) were higher in all quartiles for examinations using gadobenate dimeglumine than with gadopentetate dimeglumine. Subjective quality of vascular signal intensity at each vessel order was significantly better for gadobenate dimeglumine (P < 0.0001), and correlated well with SNR and CNR at each order (

This was a retrospective study of 144 patients with retrievable inferior vena cava (IVC) filters inserted between 2004 and 2008 at a community/teaching hospital. The purpose was to evaluate the incidence of complications and the rate and success of retrieval. Retrieval of IVC filters was attempted in 14 of 144 (10%) patients at an average of 4.6 months. Retrieval was successful in 10 of 14 (71%). Within 6 months of insertion, retrieval was successful in 10 of 12 (83%). Unsuccessful attempts were at 3, 6, 8 and 9 months. Non-bleeding complications of IVC filters occurred in 12 of 144 (8.3%). Half (6 of 12) of the complications occurred after 3 months of insertion. Complications included IVC thrombosis in 3 (2.1%) (1 also had a new deep venous thrombosis [DVT]), a new DVT alone in 6 patients (4.2%), a new DVT with new pulmonary embolism (PE) in 1 patient (0.7%) and filter migration in 2 patients (1.3%). In conclusion, retrieval was attempted in only a small proportion of patients at a community/teaching hospital. Formalized guidelines for follow up may increase the proportion of patients in whom retrieval is attempted. Half of the complications of IVC filters could have been avoided with retrieval within 3 months.

The purpose of this review was to evaluate the accuracy of SPECT in acute pulmonary embolism. Sparse data are available on the accuracy of SPECT based on an objective reference test. Several investigations were reported in which the reference standard for the diagnosis of pulmonary embolism was based in part on the results of SPECT or planar ventilation-perfusion (V/Q) imaging. The sensitivity of SPECT in all but one investigation was at least 90%, and specificity also was generally at least 90%. The sensitivity of SPECT in 4 of 5 investigations was higher than that of planar V/Q imaging. The specificity of SPECT was generally higher, equal, or only somewhat lower than that of planar V/Q imaging. Most investigators reported nondiagnostic SPECT V/Q scans in no more than 3% of cases. Methods of obtaining SPECT images, methods of obtaining planar V/Q images, and the criteria for interpretation varied. The general impression is that SPECT is more advantageous than planar V/Q imaging.

Although heparin is administered to prevent early recurrences of venous thromboembolism (VTE) by preventing new thrombi, allowing old thrombi to attach to venous walls, and covering warfarin until it is therapeutic, heparin largely prevents late recurrences of VTE (after 5 days). The dreaded early occurrence of pulmonary embolism (PE) (on or before day 5) while waiting for the vitamin K antagonist to become antithrombotic did not occur among patients with deep venous thrombosis (DVT), who received acencoumarol alone. Fewer total recurrences resulted if a therapeutic level of heparin was reached within the first 24 hours of treatment of DVT. Fewer total recurrences also resulted if heparin was consistently maintained at therapeutic levels. A recurrent VTE within 5 days, however, occurred infrequently in those in whom heparin was not given, or therapeutic levels were delayed or not maintained. The incidence of early recurrent VTE was not lower in those who received adequate heparin than in those who did not, although the data are sparse. The true incidence of early recurrent VTE is uncertain due to the broad confidence intervals for the observed frequency of early recurrent events. Later recurrences are the norm and may be reduced by early treatment with adequate heparin.

Acutely ill medical patients are at significant risk of developing venous thromboembolic (VTE) complications during or after their hospitalization. Venous thromboembolic events, such as proximal deep vein thrombosis (DVT) or pulmonary embolism (PE), place a high and unacceptable burden on health care resources, up to US$1.5 billion annually in the United States. However, the burden of VTE can be reduced by use of appropriate thromboprophylaxis. Prophylaxis of VTE with either a low-dose unfractionated heparin (UFH) or a low-molecular-weight heparin (LMWH) in medical inpatients is effective, well tolerated and cost-effective, compared with no prophylaxis. Low-molecular-weight heparins have a number of practical benefits over UFH, including once-daily subcutaneous injection and the potential to be used in the outpatient setting. These clinical advantages could translate to improved patient adherence to therapy and provide economic benefits, where LMWHs are more cost-effective compared with UFH.