Thromboprophylaxis in lower limb immobilisation after injury (TiLLI).

Venous thromboembolic disease is a major global cause of morbidity and mortality. An estimated 10 million episodes are diagnosed yearly; over half of these episodes are provoked by hospital admission/procedures and result in significant loss of disability adjusted life years. Temporary lower limb immobilisation after injury is a significant contributor to the overall burden of venous thromboembolism (VTE). Existing evidence suggests that pharmacological prophylaxis could reduce overall VTE event rates in these patients, but the proportional reduction of symptomatic events remains unclear. Recent studies have used different pharmacological agents, dosing regimens and outcome measures. Consequently, there is wide variation in thromboprophylaxis strategies, and international guidelines continue to offer conflicting advice for clinicians. In this review, we provide a summary of recent evidence assessing both the clinical and cost effectiveness of thromboprophylaxis in patients with temporary immobilisation after injury. We also examine the evidence supporting stratified thromboprophylaxis and the validity of widely used risk assessment methods.

Obstacle course runs: review of acquired injuries and illnesses at a series of Canadian events (RACE).

BACKGROUND: The growing popularity of obstacle course runs (OCRs) has led to significant concerns regarding their safety. The influx of injuries and illnesses in rural areas where OCRs are often held can impose a large burden on emergency medical services (EMS) and local EDs. Literature concerning the safety of these events is minimal and mostly consists of media reports. We sought to characterise the injury and illness profile of OCRs and the level of medical care required. METHODS: This study analysed OCR events occurring in eight locations across Canada from May to August 2015 (total 45 285 participants). Data were extracted from event medical charts of patients presenting to the onsite medical team, including injury or illness type, onsite treatment and disposition. RESULTS: There were 557 race participants treated at eight OCR events (1.2% of all participants). There were 609 medical complaints in total. Three quarters of injuries were musculoskeletal in nature. Eighty-nine per cent returned to the event with no need for further medical care. The majority of treatments were completed with first aid and basic medical equipment. Eleven patients (2% of patients) required transfer to hospital by EMS for presentations including fracture, dislocation, head injury, chest pain, fall from height, and abdominal pain. CONCLUSIONS: We found that 1.2% of race participants presented to onsite medical services. The majority of complaints were minor and musculoskeletal in nature. Only 2% of those treated were transferred to hospital through EMS. This is consistent with other types of mass gathering events.

BET 2: Acupuncture and fibromyalgia.

A shortcut review was carried out to see if acupuncture is an effective pain treatment in fibromyalgia. One Cochrane review and five subsequent papers and conference abstracts were identified. There are no large studies addressing this question and acupuncture has been compared with many different treatment modalities. Acupuncture may be a valid treatment for pain in fibromyalgia, but more research is required to validate this.

Direct oral anticoagulants: a practical guide for the emergency physician.

The direct oral anticoagulants (DOACs) are the mainstay for stroke prophylaxis in nonvalvular atrial fibrillation and treatment of acute venous thrombosis. They are attractive alternatives to warfarin because of their efficacy, ease of prescription and safety profile. The emergency department has gained expertise in the management of DOAC bleeding complications, but has been slower to adopt prescription decisions. Emergency clinicians are in a unique position to identify patients who are prescribed DOACs and are at high risk of impending bleeding. This is a practical guide for the emergency clinician on how to prescribe DOACs, the red flags for DOAC patients in the emergency department and advances in the treatment of bleeding.

Should we be looking for and treating isolated calf vein thrombosis?

Management of isolated calf deep vein thrombosis is an area of significant international debate and variable clinical practice. Both therapeutic anticoagulation and conservative management carry risk. As clinical care of suspected and confirmed venous thromboembolic disease increasingly becomes the remit of emergency medicine, complex decisions are left to practising clinicians at the front door. We aim to provide a contemporary overview of recent evidence on this topic and associated challenges facing clinicians. Given the lack of high-level evidence, we present this work as a narrative review, based on structured literature review and expert opinion. A decision to manage calf thrombosis is principally dependent on the risk of complications without treatment balanced against the risks of therapeutic anticoagulation. Estimates of the former risks taken from systematic review, meta-analysis, observational cohort and recent pilot trial evidence include proximal propagation 7%-10%, pulmonary embolism 2%-3% and death <1%. Fatal bleeding with therapeutic anticoagulation stands at <0.5%, and major bleeding at approximately 2%. Estimates of haemorrhagic risk are based on robust data from large prospective management studies of venous thromboembolic disease; the risks of untreated calf deep vein thrombosis are based on small cohorts and therefore less exact. Pending further trial evidence, these risks should be discussed with patients openly, in the context of personal preference and shared decision-making. Anticoagulation may maximally benefit those patients with extensive and/or symptomatic disease or those with higher risk for complication (unprovoked, cancer-associated or pregnancy).

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Which form of aspirin is the fastest to inhibit platelet aggregation in emergency department patients with non-ST segment elevation myocardial infarction?

A short cut review was carried out to establish whether, in patients with suspected acute coronary syndromes presenting to the emergency department, what form of aspirin has the most rapid onset of action. Papers comparing the speed of onset of chewable aspirin, or soluble aspirin or solid aspirin were included. This summarises all three parts of a combined best evidence topic report (BET). The clinical bottom line is that chewable aspirin may be faster than soluble aspirin at decreasing the amount of time to achieve platelet inhibition in a patient. Soluble aspirin is faster than whole solid aspirin, which is faster than enteric-coated aspirin.

Overview of the new oral anticoagulants: opportunities and challenges.

The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges.

Time trends in intracranial bleeding associated with direct oral anticoagulants: a 5-year cohort study.

BACKGROUND: Over the past 5 years, dabigatran, rivaroxaban and apixaban were approved for stroke prevention. Phase III studies have shown a lower risk of intracranial bleeding with these direct oral anticoagulants than with warfarin; however, there is a lack of real-life data to validate this. We analyzed time trends in atraumatic intracranial bleeding from 2009 to 2013 among patients prescribed oral anticoagulants and those not prescribed oral anticoagulants. METHODS: We used ICD-10-CA (enhanced Canadian version of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems) codes to identify all patients with atraumatic intracranial bleeding who presented to our neurosurgical centre (serving a population of more than 1.2 million). Trained researchers extracted data on anticoagulant medications used in the week before diagnosis of the intracranial bleed. Provincial prescription data for oral anticoagulants were obtained from IMS Brogan CompuScript Market Dynamics. The primary outcome was the time trend in incident intracranial bleeds associated with oral anticoagulation during the period 2009-2013. The secondary outcomes were the time trend in intracranial bleeds not associated with oral anticoagulation and the provincial prescribing patterns for oral anticoagulants during the same period. RESULTS: A total of 2050 patients presented with atraumatic intracranial bleeds during the study period. Of the 371 (18%) prescribed an anticoagulant in the week before presentation, 335 were prescribed an oral anticoagulant. There was an increasing time trend in intracranial bleeding associated with oral anticoagulants (p = 0.009; 6 additional events per year) and in intracranial bleeding not associated with oral anticoagulation (p = 0.06). During 2013, prescriptions for warfarin decreased to 70% of all oral anticoagulant prescriptions in the province, whereas those for dabigatran and rivaroxaban increased to 17% and 12%, respectively. INTERPRETATION: We observed increasing time trends in intracranial bleeding, both associated with and not associated with oral anticoagulants, over the study period. Although aggregate provincial data showed increased prescribing of oral anticoagulants, other more likely explanations for our findings include an aging population or increasing frailty.

Validity of standard gamble estimated quality of life in acute venous thrombosis.

INTRODUCTION: The standard gamble is considered the 'gold standard' technique for measuring quality of life. We recently used the standard gamble to estimate quality of life in acute venous thrombosis, and found unexpected variability in the responses. The current study aimed to explore the reasons for variability by comparing the standard gamble technique in patients with acute venous thrombosis to other quality of life measurement tools. MATERIALS AND METHODS: Thrombosis clinic patients treated for venous thrombosis were eligible to participate. Patients evaluated their current health state by performing a standard gamble interview, reporting on a visual analogue scale, completing the SF-36 and disease specific questionnaires (PEmb-Qol and VEINES-QOL/Sym). Validity was assessed by correlating the standard gamble utilities with the other methods. Test-retest reliability, responsiveness and acceptability were also assessed. RESULTS: Forty-four patients were interviewed, with 16 attending for a repeat interview. The median standard gamble utility was 0.97 (0.84-1.0), SF-6D 0.64 (0.59 - 0.80) and visual analogue score 70 (60 - 80). Participants with pulmonary embolism had lower standard gamble estimates than those with deep vein thrombosis. There was good discriminant validity in that the standard gamble estimates were not associated with risk taking behavior, negative outlook, sex or education. Test-retest reliability with the standard gamble was moderate and there was evidence of a ceiling effect. CONCLUSIONS: Standard gamble utilities are higher than other methods of measuring quality of life in venous thrombosis. The choice of utility values adopted in studies will impact on future economic studies.

The anticoagulation of calf thrombosis (ACT) project: results from the randomized controlled external pilot trial.

BACKGROUND: There is currently little evidence defining the clinical importance of detecting and treating isolated distal DVT (IDDVT). International guidelines vary regarding diagnostic and therapeutic advice. The potential benefits of anticoagulation are unquantified. We sought to evaluate the feasibility of a randomized controlled study within a modern framework and provide a primary outcome point estimate. METHODS: In this open-label, external pilot randomized controlled trial, consecutive, symptomatic, ambulatory patients with IDDVT were approached for inclusion. Participants were allocated to receive either therapeutic anticoagulation or conservative management. Patients underwent blinded color-duplex imaging at 7 and 21 days and follow-up at 3 months. Principal feasibility outcomes included recruitment rate and attrition. The principal clinical outcome was a composite including proximal propagation, pulmonary embolism, death attributable to VTE disease, or major bleeding. Analysis was by intention to treat. RESULTS: In total, 93 patients with IDDVT were screened, and 70 of those eligible (88.6%) were recruited. All patients but one were followed-up by direct contact after 90 days. Allocation crossover occurred in 15 patients (21.4%). The principal clinical outcome occurred in four of 35 of those conservatively treated (11.4%) and zero of 35 in the anticoagulated group (absolute risk reduction, 11.4%; 95% CI, -1.5 to 26.7, P = .11, number needed to treat of nine). There were no major bleeding episodes. CONCLUSIONS: We have established the feasibility of definitive study regarding the value of therapeutic anticoagulation in IDDVT and provide an approximate point estimate for serious complications with a contemporary conservative strategy. TRIAL REGISTRY: Current Controlled Trials; No.: ISRCTN75175695; URL: www.controlled-trials.com.

Single whole-leg compression ultrasound for exclusion of deep vein thrombosis in symptomatic ambulatory patients: a prospective observational cohort study.

International guidance has recently recommended serial proximal compression ultrasound (CUS) as first line imaging for suspected deep vein thrombosis (DVT). Single whole-leg CUS is a routine alternative diagnostic strategy that can reduce repeated attendances and identify alternative pathology. We conducted a prospective observational cohort study. Consecutive ambulatory, adult patients with suspected DVT and negative or inconclusive whole-leg CUS had anticoagulation withheld and were followed for 3 months. The primary outcome was a predefined clinically relevant adverse event rate. Secondary outcomes included technical failure, alternative diagnoses and all cause mortality. 212 patients agreed to participate and completed follow up. One patient was subsequently diagnosed with an isolated distal DVT. The adverse event rate was thus 1/212, 0·47% (95% confidence interval [CI] 0·08-2·62). Technical imaging failure occurred in 11·3% of cases (95% CI 7·7-16·3). Several potential predictors of an inconclusive result were identified on multivariate analysis. 150 (70·8%) patients were provided with a documented alternative diagnosis. Patients who have anticoagulation withheld following a negative or inconclusive whole-leg CUS for suspected DVT have a low rate of adverse events. Technical failure remains an issue: several factors were significantly associated with inconclusive results and may warrant an alternative diagnostic approach.

Estimating quality of life in acute venous thrombosis.

IMPORTANCE: Future funding for new treatments in venous thromboembolism will be guided by cost-utility analyses. There is little available information on the utility of acute venous thromboembolism, limiting the validity of economic analyses. OBJECTIVE: To measure the quality of life in the health states relating to thromboembolism cost-utility analyses. DESIGN: A prospective cohort study. SETTING: A single-center, university-affiliated thrombosis clinic. PARTICIPANTS: Two hundred sixteen thrombosis clinic patients with a history of lower limb deep vein thrombosis (DVT) or pulmonary embolism (PE). EXPOSURES: Participants consented to take a standard gamble interview. Each participant rated the quality of life in acute DVT, acute PE, and bleeding complication health states. MAIN OUTCOMES AND MEASURES: The standard gamble measured quality of life (utility value) for acute DVT, acute PE, major intracranial bleeding event, minor intracranial bleeding event, and gastrointestinal bleeding event. RESULTS: Two hundred fifteen responses were included in the analysis. Twenty-six percent had experienced both PE and DVT; 54%, DVT alone; and 20%, PE alone. Forty-two percent had experienced more than 1 episode of thrombosis, and 23% had had cancer-associated thrombosis. We found the median utility for acute DVT was 0.81 (interquartile range [IQR], 0.55-0.94); acute PE, 0.75 (IQR, 0.45-0.91); major intracranial bleeding event, 0.15 (IQR, 0.00-0.65); minor intracranial bleeding event, 0.75 (IQR, 0.55-0.92); and gastrointestinal bleeding event, 0.65 (IQR, 0.15-0.86). The median length of symptoms for DVT or PE was 1 week (IQR, <1-3 weeks). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest published study on utilities in which the participants had personal experience of venous thromboembolism. We present unique information for economic analyses but have also identified future challenges for research in this area. Our summary results differ from those previously published, and we found wide variation in individual responses.

Predicting short term mortality after investigation for venous thromboembolism.

INTRODUCTION: Deaths following diagnosis of venous thromboembolism (VTE) often result from another concurrent illness. The specificity of mortality markers predicting death from pulmonary embolism is unknown. The aim of this analysis was to compare blood predictors of death in patients with confirmed VTE to patients with negative investigations for VTE. MATERIALS AND METHODS: Consecutive patients investigated for VTE were prospectively consented from a single hospital over 9months. VTE was diagnosed and excluded with a standard diagnostic algorithm. Blood was drawn for biomarker analysis and analyzed in batches for NT-proBNP, high sensitivity troponin T, C-reactive protein (CRP), fatty acid binding protein (FABP) and ischemia modified albumin (IMA). Participants were followed for 3months. The cohort was analyzed in two groups: those diagnosed with VTE and those who had thrombosis excluded. Regression analysis for 3-month mortality was performed for each group. RESULTS: 16/153 patients diagnosed with VTE died within three months (10.5%) as did 23/606 patients who had negative investigations for VTE (3.8%). Predictors for death following VTE included cancer, NT-proBNP, troponin T, FABP, and Hb<95g/L. NT-proBNP>500pg/ml in acute cancer associated VTE predicted death with C-statistic of 0.89 (0.80-0.99). Cancer, NT-proBNP and troponin T also predicted death in patients with negative investigations for VTE. CONCLUSION: Several blood markers are not specific for death from PE and may be surrogate markers of global declining health.

The diagnosis of venous thromboembolism.

Venous thromboembolism (VTE) is a serious and potentially fatal medical condition. Correct diagnosis and early treatment of VTE with anticoagulant drugs are critical steps in preventing further complications and recurrence. Evidence suggests that patients with suspected deep vein thrombosis (DVT) or pulmonary embolism (PE) should be managed with a diagnostic strategy that includes clinical pretest probability assessment, D-dimer test, and imaging. Clinical probability scoring, complemented by selective D-dimer testing, has become the recommended strategy for diagnosis. The reason is that overwhelming evidence suggests that patients with suspected VTE are better managed with a diagnostic strategy. If diagnostic algorithms are followed correctly, the chances of adverse events are extremely low (< 1%) in patients in whom VTE has been ruled out, whereas incomplete strategies leads to an increased risk of recurrent VTE or death. This review focuses on the application of diagnostic strategies with suspected DVT or PE into daily clinical practice while discussing the benefits and disadvantages of different approaches.

The Anticoagulation of Calf Thrombosis (ACT) project: study protocol for a randomized controlled trial.

BACKGROUND: Half of all lower limb deep vein thrombi (DVT) in symptomatic ambulatory patients are located in the distal (calf) veins. While proximal disease warrants therapeutic anticoagulation to reduce the associated risks, distal DVT often goes untreated. However, a proportion of untreated distal disease will undoubtedly propagate or embolize. Concern also exists that untreated disease could lead to long-term post thrombotic changes. Currently, it is not possible to predict which distal thrombi will develop such complications. Whether these potential risks outweigh those associated with unrestricted anticoagulation remains unclear. The Anticoagulation of Calf Thrombosis (ACT) trial aims to compare therapeutic anticoagulation against conservative management for patients with acute symptomatic distal deep vein thrombosis. METHODS: ACT is a pragmatic, open-label, randomized controlled trial. Adult patients diagnosed with acute distal DVT will be allocated to either therapeutic anticoagulation or conservative management. All patients will undergo 3 months of clinical and assessor blinded sonographic follow-up, followed by 2-year final review. The project will commence initially as an external pilot study, recruiting over a 16-month period at a single center to assess feasibility measures and clinical event rates. Primary outcome measures will assess feasibility endpoints. Secondary clinical outcomes will be collected to gather accurate data for the design of a definitive clinical trial and will include: (1) a composite endpoint combining thrombus propagation to the popliteal vein or above, development of symptomatic pulmonary embolism or sudden death attributable to venous thromboembolic disease; (2) the incidence of major and minor bleeding episodes; (3) the incidence of post-thrombotic leg syndrome at 2 years using a validated screening tool; and (4) the incidence of venous thromboembolism (VTE) recurrence at 2 years. DISCUSSION: The ACT trial will explore the feasibility of comparing therapeutic anticoagulation to conservative management in acute distal DVT, within a modern cohort. We also aim to provide contemporary data on clot propagation, bleeding rates and long-term outcomes within both groups. These results will inform the conduct of a definitive study if feasibility is established.

Prevention and treatment of venous thromboembolism in patients with cancer.

Venous thromboembolism (VTE) is the second leading cause of death and a major cause of morbidity in patients with cancer. Pharmacologic thromboprophylaxis is recommended in all hospitalized cancer patients without contraindications to anticoagulants. The role of thromboprophylaxis in outpatients undergoing chemotherapy is less certain because of the diversity of the tumor types and their associated risks of VTE and bleeding. Thromboprophylaxis should only be considered in patients at high risk for VTE. Cancer patients with a newly diagnosed VTE should be preferably treated with low-molecular-weight heparin for a minimum of 3-6 months. Treatment duration should be individualized based on the clinical status and stage of the cancer, the risk of recurrent VTE, the risk of bleeding, and personal preference of the patient. Further research is required to assess the role of the new oral anticoagulants (direct Xa and thrombin inhibitors) for this high-risk population.

Is ischaemia-modified albumin a test for venous thromboembolism?

OBJECTIVE: Patients with symptoms of deep vein thrombosis (DVT) and pulmonary embolism (PE) commonly present to the emergency department (ED). The aim of this study was to assess the role of ischaemia-modified albumin (IMA) testing in the diagnosis of venous thromboembolism (VTE). METHODS: This was a prospective diagnostic cohort study. Inpatients and ED patients >16 years of age investigated for PE or DVT at a single hospital were eligible for study consent. Blinded IMA analysis was performed on the first blood sample taken from each patient. Patients underwent reference standard investigation for PE or DVT, including 3-month follow-up. Receiver operating characteristic (ROC) curves were constructed for IMA and the IMA:albumin ratio in the diagnosis of all VTE, PE and DVT. A sensitivity analysis was performed. RESULTS: 452 patients were consented and investigated for DVT, and 354 patients were consented and investigated for PE (806 in total). 348 patients investigated for PE had IMA testing as did 195 of the first 199 DVT patients. VTE prevalence was 19.7%. The IMA:albumin ratio performed better than IMA alone. The area under the ROC curve (AUC) for IMA:albumin in all VTE was 0.60 (95% CI 0.54 to 0.66), in DVT 0.56 (95% CI 0.46 to 0.65) and in PE 0.63 (95% CI 0.56 to 0.71). In ED patients with symptoms of PE, the AUC for IMA:albumin was 0.69 (95% CI 0.60 to 0.78). CONCLUSIONS: IMA testing cannot be used alone to diagnose DVT or PE, although there is a moderate association with PE in ED patients.

Diagnosing pulmonary embolism: a comparison of clinical probability scores.

Pulmonary embolism (PE) is a major cause of community and in-hospital mortality. This study aimed to compare the performance of the British Thoracic Society (BTS) score to the Wells' score in diagnosing PE. Data from two separate prospective diagnostic PE studies were analysed. All patients underwent gold standard investigation to determine the presence or absence of PE, together with a 3-month follow-up. The posttest prevalence of PE was compared using both scores and the receiver operating characteristic (ROC) curves. Seven hundred and seventy-nine patients were consented and investigated for PE. In patients with pleuritic chest pain, respiratory rate <20 breaths/min and absence of dyspnoea, 4·0% [95% confidence interval (CI) 1·9-7·9%] had PE. The BTS score allocated 463/779 patients as low probability, compared to 565/779 according to the Wells' score. Both scores identified a low risk group in the Manchester Investigation of Pulmonary Embolism Diagnosis cohort, however the BTS low probability group in the Thromboembolism Assessment and Diagnosis study had a prevalence of 9·7% (95% CI 5·8-15·9%). For the BTS score, the areas under the ROC curves were 0·67 (95% CI 0·61-0·72) and 0·71 (95% CI 0·61-0·75). For the Wells' score these were 0·76 (95%CI 0·71-0·81) and 0·68 (95%CI 0·64-0·73). Given the lack of BTS validation studies to date, the Wells' score appears to be the safer assessment option.

Accuracy of very low pretest probability estimates for pulmonary embolism using the method of attribute matching compared with the Wells score.

OBJECTIVES: Attribute matching matches an explicit clinical profile of a patient to a reference database to estimate the numeric value for the pretest probability of an acute disease. The authors tested the accuracy of this method for forecasting a very low probability of venous thromboembolism (VTE) in symptomatic emergency department (ED) patients. METHODS: The authors performed a secondary analysis of five data sets from 15 hospitals in three countries. All patients had data collected at the time of clinical evaluation for suspected pulmonary embolism (PE). The criterion standard to exclude VTE required no evidence of PE or deep venous thrombosis (DVT) within 45 days of enrollment. To estimate pretest probabilities, a computer program selected, from a large reference database of patients previously evaluated for PE, patients who matched 10 predictor variables recorded for each current test patient. The authors compared the outcome frequency of having VTE [VTE(+)] in patients with a pretest probability estimate of <2.5% by attribute matching, compared with a value of 0 from the Wells score. RESULTS: The five data sets included 10,734 patients, and 747 (7.0%, 95% confidence interval [CI] = 6.5% to 7.5%) were VTE(+) within 45 days. The pretest probability estimate for PE was <2.5% in 2,975 of 10,734 (27.7%) patients, and within this subset, the observed frequency of VTE(+) was 48 of 2,975 (1.6%, 95% CI = 1.2% to 2.1%). The lowest possible Wells score (0) was observed in 3,412 (31.7%) patients, and within this subset, the observed frequency of VTE(+) was 79 of 3,412 (2.3%, 95% CI = 1.8% to 2.9%) patients. CONCLUSIONS: Attribute matching categorizes over one-quarter of patients tested for PE as having a pretest probability of <2.5%, and the observed rate of VTE within 45 days in this subset was <2.5%.