Philip S. Wells

Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND This article addresses the treatment of VTE disease. METHODS We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence. RESULTS For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C). CONCLUSION Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences.

A COMPARISON OF THREE MONTHS OF ANTICOAGULATION WITH EXTENDED ANTICOAGULATION FOR A FIRST EPISODE OF IDIOPATHIC VENOUS THROMBOEMBOLISM

BACKGROUND Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. METHODS In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. RESULTS A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months. Of 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of venous thromboembolism (27.4 percent per patient-year), as compared with 1 of 79 patients assigned to receive warfarin (1.3 percent per patient-year, P<0.001). Warfarin resulted in a 95 percent reduction in the risk of recurrent venous thromboembolism (95 percent confidence interval, 63 to 99 percent). Three patients assigned to the warfarin group had nonfatal major bleeding (two had gastrointestinal bleeding and one genitourinary bleeding), as compared with none of those assigned to the placebo group (3.8 vs. 0 percent per patient-year, P=0.09). CONCLUSIONS Patients with a first episode of idiopathic venous thromboembolism should be treated with anticoagulant agents for longer than three months.

Excluding Pulmonary Embolism at the Bedside without Diagnostic Imaging: Management of Patients with Suspected Pulmonary Embolism Presenting to the Emergency Department by Using a Simple Clinical Model and D-Dimer

Pulmonary embolism is a relatively common disease, with an estimated annual incidence in the United States of 23 cases diagnosed per 100 000 persons (1). More than 50% of cases are undiagnosed. Untreated pulmonary embolism has a high mortality, although risk for death is reduced significantly with anticoagulation (2). Because the clinical signs and symptoms of pulmonary embolism are not specific, timely diagnostic testing must be done to confirm the diagnosis. Ventilation-perfusion lung scanning is the most common imaging procedure for suspected pulmonary embolism. However, the result is frequently nondiagnostic, and additional testing is needed to confirm a diagnosis. Patients presenting to the emergency department with suspected pulmonary embolism present a challenge, particularly if diagnostic testing is not immediately available. We recently validated a simple model (3), which we incorporated into a diagnostic algorithm, to classify pretest probability of pulmonary embolism by using clinical findings along with results on electrocardiography and chest radiography. We had not tested our model or the diagnostic algorithm in an emergency department setting. Another diagnostic test, d-dimer assay, may be useful in patients with suspected pulmonary embolism, but experience with this test to exclude pulmonary embolism diagnoses in an emergency department has been limited [4]. In the current study, we used a diagnostic algorithm based on our clinical model and a non-enzyme-linked immunosorbent d-dimer assay in patients presenting to emergency departments with suspected pulmonary embolism. We sought to 1) demonstrate the safety of excluding the diagnosis of pulmonary embolism in an emergency department using diagnostic algorithms that were based on pretest probability and d-dimer assay results and 2) confirm the reliability of the pretest probability clinical model and d-dimer testing for pulmonary embolism in an emergency department. Methods Patients Data for this study were collected from September 1998 to September 1999 at four participating medical centers in Canada: The Ottawa Civic Hospital, Ottawa, Ontario; the London Health Sciences Centre, London, Ontario; the Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia; and St. Pauls Hospital, Vancouver, British Columbia. The study was approved by the ethics review committees at each of the institutions. Consecutive patients presenting to the emergency departments of the participating centers were eligible if they had suspicion of pulmonary embolism with symptoms for less than 30 days and were experiencing acute onset of new or worsening shortness of breath or chest pain. Exclusion criteria were 1) suspected deep venous thrombosis of the upper extremity as a likely source of pulmonary embolism, 2) no symptoms of pulmonary embolism within 3 days of presentation, 3) anticoagulant therapy for more than 24 hours, 4) expected survival time less than 3 months, 5) contraindication to contrast media, 6) pregnancy, 7) geographic inaccessibility precluding follow-up, or 8) age younger than 18 years. Interventions After giving informed consent, patients were evaluated by 1 of 43 emergency department physicians, who used a simple clinical model to determine the clinical probability of pulmonary embolism (5). The physician assigned points for the following: clinical signs and symptoms of deep venous thrombosis (objectively measured leg swelling and pain with palpation in the deep-vein region), 3.0 points; heart rate higher than 100 beats/min, 1.5 points; immobilization (bedrest, except to access the bathroom, for 3 consecutive days) or surgery in the previous 4 weeks, 1.5 points; previous objectively diagnosed deep venous thrombosis or pulmonary embolism, 1.5 points; hemoptysis, 1.0 point; malignancy (patients with cancer who were receiving treatment, those in whom treatment had been stopped within the past 6 months, or those who were receiving palliative care), 1.0 point; and pulmonary embolism as likely as or more likely than an alternative diagnosis, 3.0 points (5). For the final variable, which was not strictly defined, physicians were told to use the clinical information (obtained by history and physical examination), along with results on chest radiography, electrocardiography, and whatever blood tests were considered necessary to diagnose pulmonary embolism. The pretest probability of pulmonary embolism was considered low in patients whose score was less than 2.0, moderate in patients whose score was at least 2.0 but no higher than 6.0, and high in patients whose score was greater than 6.0. The SimpliRED whole-blood agglutination d-dimer test (AGEN Biomedical, Ltd., Brisbane, Australia) was performed on citrated blood samples in a local coagulation laboratory. In all patients, the d-dimer test was performed only after the clinical model had been applied and the resultant probability had been recorded. Patients were to be managed as outlined in Figure 1. Pulmonary embolism was considered excluded if the patient had been assigned a low clinical pertest probability and had a negative result on d-dimer testing; no imaging procedures were performed in these patients. All other patients had ventilation-perfusion lung scanning. For patients who presented outside normal working hours (between 3:30 p.m. and 7:00 a.m.), a therapeutic dose (200 U/kg of body weight) of the low-molecular-weight heparin Dalteparin (Pharmacia-Upjohn, Mississauga, Ontario, Canada) was given subcutaneously, and diagnostic testing was done in the next 18 hours (6). Dalteparin was given to these patients only after the clinical model was applied and d-dimer testing was done. Figure 1. Diagnostic algorithm for initial evaluation of patients with suspected pulmonary embolism. Ventilation-perfusion scans were interpreted by nuclear medicine physicians who had no knowledge of the clinical model outcome or d-dimer result. The scan interpretations were used to determine patient management. Ventilation-perfusion scans were interpreted as 1) normal, if no perfusion defects were found, 2) high probability, if at least one segmental (or larger) perfusion defect with normal ventilation or at least two large subsegmental perfusion defects [>75% of a segment] with normal ventilation were found, or 3) nondiagnostic, if ventilation-perfusion defects were detected but did not meet the criteria for high probability (7). A lung-segment reference chart was used to interpret ventilation-perfusion scans (8). Compression ultrasonography, when indicated, was performed on both lower extremities from the common femoral vein to the trifurcation of the calf veins, but the calf veins were not examined. Lack of vein compressibility was diagnostic of deep venous thrombosis [9]. In patients with a history of deep venous thrombosis, diagnosis of recurrent thrombus required 1) the noncompressibility on ultrasonography to be in the previously uninvolved extremity or in an area previously unaffected by thrombus or 2) the clot diameter to be more than 4 mm greater than on previous measurement (10). In patients with previous pulmonary embolism, only new defects were considered. Patients were considered to have pulmonary embolism if they had abnormal results on ultrasonography or angiography, a high-probability result on ventilation-perfusion scan, or a venous thromboembolic event during the 3-month follow-up. In all other patients, a diagnosis of pulmonary embolism was considered excluded. Treatment and Follow-up Anticoagulant therapy was withheld in patients in whom a diagnosis of pulmonary embolism was excluded. These patients were given instruction cards and were directed to return at once if they developed new or worsening symptoms or signs suggesting pulmonary embolism or deep venous thrombosis. If at any time venous thromboembolism (deep venous thrombosis or pulmonary embolism) was suspected, patients were studied by using a standardized approach (3). Diagnoses of deep venous thrombosis and pulmonary embolism were excluded if results on ultrasonography and ventilation-perfusion scanning, respectively, were normal. Pulmonary embolism was diagnosed if a new ventilation-perfusion scan showed high probability, and deep venous thrombosis was diagnosed if results on ultrasonography were abnormal. Patients with nondiagnostic scans and equivocal ultrasonography results had gold-standard testing-pulmonary angiography and venography, respectively; the results were evaluated according to previously defined criteria (3). After 3 months, patients were followed up for development of thromboembolic events at a return appointment or by telephone contact. A committee blinded to all patient variables adjudicated suspected outcome events during follow-up. Statistical Analysis Our primary outcome was the proportion of patients who had a venous thromboembolic event during 3-month follow-up among patients in whom the diagnosis of pulmonary embolism had been excluded before follow-up (Figure 1). We and other authors have used this type of outcome in previous studies (3, 11, 12). Our primary analysis was an intention-to-treat analysis of all enrolled patients. We also planned a secondary analysis to evaluate the safety of our strategy in patients in whom the diagnostic algorithm was followed correctly. Because the SimpliRED test can rule out thromboembolism by yielding a negative result, we could also determine the negative predictive values of the d-dimer results in the three pretest-probability groups by determining thromboembolic event rates during the entire study period in those with negative d-dimer results. Before calculating the negative predictive values, we computed the total number of venous thromboembolic events diagnosed during the initial study period (the study period from presentation to follow-up) or follow-up to determine the overall event rates. Then, we determined the negative predictive value by dividing the number of patie

Value of assessment of pretest probability of deep-vein thrombosis in clinical management

BACKGROUND When ultrasonography is used to investigate deep-vein thrombosis, serial testing is recommended for those who test negative initially. Serial testing is inconvenient for patients and costly. We aimed to assess whether the calculation of pretest probability of deep-vein thrombosis, with a simple clinical model, could be used to improve the management of patients who present with suspected deep-vein thrombosis. METHODS Consecutive outpatients with suspected deep-vein thrombosis had their pretest probability calculated with a clinical model. They then underwent compression ultrasound imaging of proximal veins of the legs. Patients at low pretest probability underwent a single ultrasound test. A negative ultrasound excluded the diagnosis of deep-vein thrombosis whereas a positive ultrasound was confirmed by venography. Patients at moderate pretest probability with a positive ultrasound were treated for deep-vein thrombosis whereas patients with an initial negative ultrasound underwent a single follow-up ultrasound 1 week later. Patients at high pretest probability with a positive ultrasound were treated whereas those with negative ultrasound underwent venography. All patients were followed up for 3 months for thromboembolic complications. FINDINGS 95 (16.0%) of all 593 patients had deep-vein thrombosis; 3%, 17%, and 75% of the patients with low, moderate, and high pretest probability, respectively, had deep-vein thrombosis. Ten of 329 patients with low pretest probability had the diagnosis confirmed, nine at initial testing and one at follow-up. 32 of 193 patients with moderate pretest probability had deep-vein thrombosis, three diagnosed by the serial (1 week) test, and two during follow-up. 53 of 71 patients with high pretest probability had deep-vein thrombosis (49 by the initial ultrasound and four by venography). Only three (0.6%) of all 501 (95% CI 0.1-1.8) patients diagnosed as not having deep-vein thrombosis had events during the 3-month follow-up. Overall only 33 (5.6%) of 593 patients required venography and serial testing was limited to 166 (28%) of 593 patients. INTERPRETATION Management of patients with suspected deep-vein thrombosis based on clinical probability and ultrasound of the proximal deep veins is safe and feasible. Our strategy reduced the need for serial ultrasound testing and reduced the rate of false-negative or false-positive ultrasound studies.

Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy

Background: Whether to continue oral anticoagulant therapy beyond 6 months after an “unprovoked” venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants. Methods: In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5–7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p < 0.10) with high interobserver reliability to derive a clinical decision rule. Results: We identified 91 confirmed episodes of recurrent venous thromboembolism during follow-up after discontinuing oral anticoagulation therapy (annual risk 9.3%, 95% CI 7.7%–11.3%). Men had a 13.7% (95% CI 10.8%–17.0%) annual risk. There was no combination of clinical predictors that satisfied our criteria for identifying a low-risk subgroup of men. Fifty-two percent of women had 0 or 1 of the following characteristics: hyperpigmentation, edema or redness of either leg; D-dimer ≥ 250 μg/L while taking warfarin; body mass index ≥ 30 kg/m2; or age ≥ 65 years. These women had an annual risk of 1.6% (95% CI 0.3%–4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%–17.3%). Interpretation: Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men. (http://Clinicaltrials.gov trial register number NCT00261014)

Accuracy of Ultrasound for the Diagnosis of Deep Venous Thrombosis in Asymptomatic Patients after Orthopedic Surgery: A Meta-Analysis

Patients who have major orthopedic operations have an increased risk for deep venous thrombosis; without prophylaxis, the incidence of deep venous thrombosis is about 50% after hip replacement and about 65% after major knee surgery [1]. In both of these groups, the incidence of the more dangerous proximal venous thrombosis (thrombosis in the popliteal or more proximal veins) is approximately 20%. Most of these thrombi are asymptomatic. Nevertheless, the risk for pulmonary embolism from asymptomatic proximal venous thrombosis is substantial, about 25%, and fatal pulmonary embolism occurs in 1% to 2% of this group [2]. Several effective prophylactic methods are available. However, even with the most effective methods, the incidence of postoperative thrombosis is 15% to 20% for elective hip surgery and the incidence of thrombosis is 20% to 30% for major knee surgery detected by routine venography done at the time of discharge from hospital [1]. Because of this relatively high incidence of thrombosis despite primary prophylaxis, some authorities [3] advocate routine venography before hospital discharge in addition to primary prophylaxis to detect silent deep venous thrombosis in patients who have major orthopedic procedures. Thrombi that are detected are usually treated with anticoagulant agents. Venography is expensive, can be painful, and can produce other side effects [4]; it is therefore not an ideal screening test. Radioactive fibrinogen leg scanning and impedance plethysmography have been used as screening tests but are much less sensitive than venography [5-7]. More recently, venous ultrasound imaging has been evaluated as a screening test after hip surgery and has been recommended as a substitute for venography [8]. The initial studies with venous ultrasound used real-time B-mode imaging and lack of venous compressibility with gentle probe pressure as the diagnostic criterion for venous thrombosis [9-11]. Subsequently, a Doppler component (duplex) and then a color Doppler component were added as adjuncts to the original B-mode imaging. These modifications facilitate the identification of veins, but the definitive diagnostic criterion with both of these newer techniques is generally considered to be noncompressibility of the vein under gentle probe pressure. Studies [9-17] in symptomatic patients have consistently shown a high sensitivity and specificity (97% and 97%, respectively) for all three methods of ultrasound imaging. In contrast, studies evaluating the sensitivity of venous ultrasound imaging for detecting thrombi in asymptomatic patients after surgery have produced inconsistent results, with reported sensitivities ranging from 38% to 100%. The reason for the marked differences in the sensitivity among studies evaluating venous ultrasound imaging for asymptomatic proximal venous thrombosis is uncertain. Possible explanations for the observed differences in sensitivity among studies include 1) falsely high estimates of sensitivity because of bias resulting from shortcomings in the study design, 2) falsely low estimates of accuracy because of background noise caused by inadequate technique, 3) dependence of accuracy on the type of ultrasound method used, and 4) chance. In a previous study [5] addressing the variation in the sensitivity of radioactive fibrinogen leg scanning as a screening test for postoperative deep venous thrombosis, we provided evidence that wide differences were probably caused by bias in study design. Bias can result either from inappropriate patient selection or from diagnostic suspicion bias. To avoid a biased selection of patients, a study should include consecutive patients. To avoid diagnostic suspicion bias, the diagnostic tests should be done and their results interpreted by blinded observers using validated and explicit diagnostic criteria to ensure that the results can be reproduced by other investigators [18]. To critically evaluate the accuracy of ultrasound screening for deep venous thrombosis, we did a systematic overview of the literature. Studies in which the potential for bias was minimized were evaluated separately from those in which bias was not minimized. We determined the accuracy for detecting asymptomatic proximal venous thrombosis of each of the three ultrasound imaging methods (real-time B-mode, duplex, and color Doppler ultrasonography) by doing a meta-analysis (combining the results of studies regardless of the modality used and then analyzing the results separately for each of the three modalities). We also examined the accuracy of ultrasound as a screening test for isolated calf venous thrombosis. Methods The review was initiated by a computer search of the English-language medical literature using the MEDLINE database from January 1982 to October 1993. We used combinations of the medical subject headings ultrasound, orthopedics, postoperative period, and thrombophlebitis to identify all articles that evaluated screening with venous ultrasound imaging. Bibliographies of retrieved articles were checked for any additional studies. Recent journals were searched independently and using Current Contents to find new reports that were not identified in the computer search. Early reports of data that were later published in full were excluded from the analysis. Abstracts were also excluded because it is usually not possible to completely evaluate the methods and data. Remaining articles were then critically reviewed for the presence of three key methodologic criteria for the evaluation of the accuracy of diagnostic tests. Two of the authors independently checked the articles for the following methodologic standards: 1) previous establishment of objective criteria for normal and abnormal venographic and ultrasonographic results, 2) an independent comparison of the ultrasound result with contrast venography [the reference standard for diagnosis of venous thrombosis] by investigators blinded to the other test result, and 3) the prospective evaluation of consecutive eligible patients. A study was considered to have included consecutive patients if this was explicitly mentioned in the article or if the article stated that patients were excluded only if they refused consent or were allergic to contrast medium. Reports satisfying all three methodologic standards were classified as level 1 studies; otherwise, reports were classified as level 2 studies. Sensitivity, specificity, and positive predictive values for proximal and isolated calf venous thrombosis were calculated for the studies individually and were then calculated for the results of the pooled level 1 and pooled level 2 studies. Separate analyses were done for each of the three different ultrasound modalities (real-time B-mode, duplex, or color Doppler ultrasonography). A statistical test of homogeneity was calculated for the sensitivity and specificity of the three modalities in the pooled level 1 analysis. The 95% CIs for sensitivity and specificity were calculated according to the binomial distribution, adjusting for heterogeneity among studies using a random-effects model. The calculation of the 95% CIs for positive predictive value took into account sampling error in the sensitivities and specificities [19]. Likelihood ratios, and their 95% CIs, for abnormal ultrasound results were calculated for each study using the modification of adding 0.5 to each cell when zero entries occurred in the 2 2 table [20, 21]. Accuracy data were compared between level 1 and level 2 studies by using the normal approximation to the binomial distribution and by adjusting for between-study heterogeneity with a random-effects model [22]. Two-tailed P values are reported, and values of less than 0.05 were considered to be statistically significant. Results We identified 30 studies, all in patients who had had orthopedic surgery. Thirteen of these studies were excluded from analysis: Two studies were excluded because venography was not done or was done only in patients with abnormal ultrasound results [23, 24], 4 studies were excluded because it was impossible to distinguish the data on asymptomatic patients from those on symptomatic patients [25-28], and 7 studies were excluded because they were abstracts or early reports of studies later reported in full [29-35]. Sixteen of the remaining 17 reports evaluated proximal venous thrombi; real-time B-mode ultrasonography was evaluated in 7 reports [7, 36-41], duplex ultrasonography was evaluated in 7 reports [42-48], and color Doppler ultrasonography was evaluated in 2 reports [49, 50]. The last eligible report evaluated color Doppler ultrasonography only for the detection of isolated calf venous thrombosis, and, consequently, this report is included only in that analysis [51]. When level 1 and level 2 studies were combined, 2001 patients were studied. Two hundred seventeen proximal deep venous thrombi were detected by venography for an overall prevalence of no more than 10.8%. (Some studies reported deep venous thromboses by limbs only.) Table 1 shows the characteristics of the 16 analyzed studies, including documentation of the presence or absence of the three criteria necessary to minimize bias when evaluating the accuracy of diagnostic tests. In general, the timing of the ultrasound assessment, mean patient age, and prevalence of proximal venous thrombosis were similar. Studies with the highest rates of deep venous thrombosis did not provide information about whether or not prophylaxis was used or about the method of prophylaxis. Table 1. Summary of Trials Included in the Meta-Analysis* Accuracy of Ultrasonography for Proximal Venous Thrombosis In the level 1 studies Table 2, ultrasonography detected 95 of 153 proximal thrombi, for a sensitivity of 62% (95% CI, 54% to 70%). A falsely abnormal ultrasonographic result was found for 49 of 1463 venograms, for a specificity of 97% (CI, 96% to 98%). Accordingly, the positive predictive value was 66% (95 of 144; CI, 58% to 74%). Th

Systematic Review: Case-Fatality Rates of Recurrent Venous Thromboembolism and Major Bleeding Events Among Patients Treated for Venous Thromboembolism

BACKGROUND Case-fatality rates are important for assessing the risks and benefits of anticoagulation in patients with venous thromboembolism (VTE). PURPOSE To summarize case-fatality rates of recurrent VTE and major bleeding events during anticoagulation and recurrent VTE after anticoagulation. DATA SOURCES MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and all evidence-based medicine reviews in the Ovid interface through the second quarter of 2008. STUDY SELECTION 69 articles (13 prospective cohort studies and 56 randomized, controlled trials) that reported on patients with symptomatic VTE who received anticoagulation therapy for at least 3 months and on the rate of fatal recurrent VTE and fatal major bleeding. DATA EXTRACTION Two reviewers independently extracted data onto standardized forms. DATA SYNTHESIS During the initial 3 months of anticoagulation, the rate of recurrent fatal VTE was 0.4% (95% CI, 0.3% to 0.6%), with a case-fatality rate of 11.3% (CI, 8.0% to 15.2%). The rate of fatal major bleeding events was 0.2% (CI, 0.1% to 0.3%), with a case-fatality rate of 11.3% (CI, 7.5% to 15.9%). After anticoagulation, the rate of fatal recurrent VTE was 0.3 per 100 patient-years (CI, 0.1% to 0.4%), with a case-fatality rate of 3.6% (CI, 1.9% to 5.7%). LIMITATIONS Estimates come from heterogeneous trial and cohort populations and are not derived from patient-level longitudinal data. Differences in case-fatality rates during and after anticoagulation may be attributable to unmeasured patient characteristics. CONCLUSION The case-fatality rates of recurrent VTE and major bleeding events are similar during the initial period of VTE treatment. The case-fatality rate of recurrent VTE decreases after completion of the initial period of anticoagulation. When combined with absolute rates of recurrent VTE and major bleeding events, case-fatality rates provide clinicians with a surrogate measure of mortality to balance the risks and benefits of anticoagulant therapy in patients with VTE. PRIMARY FUNDING SOURCE Canadian Institute for Health Research and Heart and Stroke Foundation of Ontario.

Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND Objective testing for DVT is crucial because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious. This guideline focuses on the identification of optimal strategies for the diagnosis of DVT in ambulatory adults. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. RESULTS We suggest that clinical assessment of pretest probability of DVT, rather than performing the same tests in all patients, should guide the diagnostic process for a first lower extremity DVT (Grade 2B). In patients with a low pretest probability of first lower extremity DVT, we recommend initial testing with D-dimer or ultrasound (US) of the proximal veins over no diagnostic testing (Grade 1B), venography (Grade 1B), or whole-leg US (Grade 2B). In patients with moderate pretest probability, we recommend initial testing with a highly sensitive D-dimer, proximal compression US, or whole-leg US rather than no testing (Grade 1B) or venography (Grade 1B). In patients with a high pretest probability, we recommend proximal compression or whole-leg US over no testing (Grade 1B) or venography (Grade 1B). CONCLUSIONS Favored strategies for diagnosis of first DVT combine use of pretest probability assessment, D-dimer, and US. There is lower-quality evidence available to guide diagnosis of recurrent DVT, upper extremity DVT, and DVT during pregnancy.

A systematic review of perceived risks, psychological and behavioral impacts of genetic testing

Genetic testing may enable early disease detection, targeted surveillance, and result in effective prevention strategies. Knowledge of genetic risk may also enable behavioral change. However, the impact of carrier status from the psychological, behavior, and perceived risk perspectives is not well understood. We conducted a systematic review to summarize the available literature on these elements. An extensive literature review was performed to identify studies that measured the perceived risk, psychological, and/or behavioral impacts of genetic testing on individuals. The search was not limited to specific diseases but excluded the impacts of testing for single gene disorders. A total of 35 articles and 30 studies were included. The studies evaluated hereditary nonpolyposis colorectal carcinoma, hereditary breast and ovarian cancer, and Alzheimer disease. For affective outcomes, the majority of the studies reported negative effects on carriers but these were short-lived. For behavioral outcomes, an increase in screening behavior of varying rates was demonstrated in carriers but the change in behaviors was less than expected. With respect to perceived risk, there were generally no differences between carriers and noncarriers by 12 months after genetic testing and over time risk perception decreased. Overall, predispositional genetic testing has no significant impact on psychological outcomes, little effect on behavior, and did not change perceived risk. It seems as though better patient education strategies are required. Our data would suggest better knowledge among carriers would not have significant psychological impacts and therefore, it is worth pursuing improved educational strategies.

Sensitivity and Specificity of a Rapid Whole-Blood Assay for D-Dimer in the Diagnosis of Pulmonary Embolism

Objective testing is necessary to diagnose pulmonary embolism because clinical diagnosis alone is not accurate [1]. Diagnostic algorithms for patients with suspected pulmonary embolism usually involve ventilation-perfusion lung scanning as the initial test. If the scan is normal, pulmonary embolism is excluded; if it shows high probability, pulmonary embolism is diagnosed in most patients; and if it is nondiagnostic (also called non-high-probability, indeterminate, intermediate-probability, or low-probability), further testing is necessary [2-4]. In patients with nondiagnostic scans, who account for more than half of patients with suspected pulmonary embolism, the prevalence of pulmonary embolism is as high as 25%; thus, further investigation is necessary [2, 3]. Pulmonary angiography (the reference standard) or serial compression ultrasonography or impedance plethysmography over 14 days should be done in these patients to identify and treat those who develop proximal deep venous thrombosis [5]. However, these approaches are relatively costly, and pulmonary angiography is invasive. Accordingly, a simple test or combination of tests that could obviate the need to perform further tests in patients with nondiagnostic lung scans would be useful. Recently, high levels of d-dimer, a specific fibrin degradation product, were reported in studies of patients with deep venous thrombosis and pulmonary embolism [6-20]. The SimpliRED assay (Agen Biomedical, Ltd., Brisbane, Australia) is a whole-blood d-dimer assay that is suitable for bedside testing on both capillary and venipuncture samples and provides a result within 5 minutes, obviating the need to centrifuge blood and process plasma. Studies that we recently performed suggested that this assay reliably excludes deep venous thrombosis and pulmonary embolism when results are negative; these findings provided the impetus for the current study [17, 19, 20]. In addition, because our previous study of pulmonary embolism was relatively small [20], the results required confirmation in a larger study. To determine the sensitivity and specificity of the d-dimer assay in patients with suspected pulmonary embolism and to determine whether a negative d-dimer test result could be of value in excluding pulmonary embolism in patients with low pretest clinical probability, nondiagnostic lung scans, or both, we performed a cohort study of more than 1000 patients with suspected pulmonary embolism. Methods The study was performed from September 1993 to May 1996 and was approved by the institutional review boards of each participating hospital. Patients We included most patients from a recent management study that evaluated a standardized clinical model of pretest probability and developed a management strategy involving serial compression ultrasonography in most patients with nondiagnostic lung scans [21]. Thus, our sample comprised consecutive patients 18 years of age or older with clinically suspected acute pulmonary embolism who were referred to thromboembolism consultants at one of the participating tertiary-care hospitals: Chedoke-McMaster Hospitals and Hamilton Civic Hospitals, Hamilton, Ontario, Canada; Ottawa Civic Hospital, Ottawa, Ontario, Canada; and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada. Patients were excluded from the study if they met any of the following criteria: 1) suspected upper-extremity deep venous thrombosis, 2) no symptoms within 48 hours of presentation, 3) treatment with anticoagulants for 72 hours or more, 4) life expectancy less than 3 months, 5) contraindication to contrast media, or 6) geographic inaccessibility. Informed consent was obtained from all patients in the study. Clinical Assessment Patients with clinically suspected pulmonary embolism were seen by a physician or nurse-practitioner (or both) on the health centers thromboembolism service. A history was taken and physical examination was done. Independent of diagnostic testing, all patients had clinical assessment of pretest probability, which was categorized as high, moderate, or low, as described elsewhere [21]. This evaluation involved assessment of 1) presenting symptoms and signs, 2) risk factors for venous thromboembolism, and 3) presence or absence of an alternative diagnosis at least as likely as pulmonary embolism. Objective Testing for Pulmonary Embolism The management approach used in the patient population is summarized in Figure 1. Ventilation-perfusion lung scanning was done in all patients within 24 hours of presentation by using a technique described elsewhere [22]. Scans were classified as normal (that is, the perfusion scan was normal), high probability (segmental or larger perfusion defects with normal ventilation) or nondiagnostic (perfusion defects not meeting criteria for a high-probability scan) [2]. All patients also had bilateral compression ultrasonography from the common femoral vein to the calf trifurcation within 24 hours of presentation, which was performed and interpreted according to a technique described elsewhere [23]. Figure 1. Diagnostic strategy. Patients with nondiagnostic lung scans, low or moderate pretest probability, and a normal initial compression ultrasonogram had repeated compression ultrasonography on days 3 to 5, 6 to 8, and 13 to 15. Anticoagulation was withheld provided that the results of compression ultrasonography remained normal. If the initial or serial ultrasonogram was abnormal, pulmonary embolism was diagnosed. Patients with nondiagnostic scans, high pretest probability, and normal initial compression ultrasonograms underwent venography; if the results of this test were normal, pulmonary angiography was done. If the perfusion lung scan was normal, compression ultrasonography was performed; if ultrasonography results were normal, no further testing was done and pulmonary embolism was considered excluded. If the results were abnormal, pulmonary embolism was diagnosed. Patients with a high-probability lung scan and a high or moderate pretest probability were considered to have pulmonary embolism regardless of compression ultrasonography results. Patients with a high-probability scan, low pretest probability, and normal initial compression ultrasonograms had venography; if venograms were normal, these patients also underwent pulmonary angiography. All patients who did not receive anticoagulants were followed-up for 3 months for the presence or absence of symptomatic venous thromboembolism by clinical evaluation. This consisted of a careful history to elicit symptoms of pulmonary embolism or deep venous thrombosis and appropriate investigation if such symptoms occurred. The final classification of patients as positive or negative for pulmonary embolism was based on a heterogeneous group of outcome measures. Patients were classified as positive if one or more of the following occurred: positive pulmonary angiogram; positive compression ultrasonogram (at any time) or positive contrast venogram; high-probability perfusion lung scan plus moderate or high pretest probability; or symptomatic, objectively confirmed venous thromboembolism during the 3-month follow-up. All other patients were classified as negative. Patients considered positive for pulmonary embolism received full-dose intravenous heparin or subcutaneous low-molecular-weight heparin followed by at least 3 months of oral anticoagulation. Patients who were considered negative for pulmonary embolism did not receive anticoagulant therapy. Measurement of D-Dimer Levels Blood was taken and processed by a research assistant for quantitation of d-dimer by the SimpliRED assay at the time of referral to the thromboembolism consultants. Results were categorized as normal or abnormal on the basis of the absence (normal) or presence (abnormal) of erythrocyte agglutination. This corresponds to the interpretation of d-dimer assay results used in our previous studies [17, 19, 20]. The method for the performance of the assay has been described comprehensively elsewhere [18]. The results of the d-dimer assay were not disclosed to caregivers and were obtained independently of the pretest probability assessment and results of other diagnostic tests. This assay has been shown to have excellent interobserver agreement ( = 0.95 [95% CI, 0.88 to 1.0]), between-assay agreement ( = 0.96 [CI, 0.90 to 1.0]), and reproducibility (97%) [24]. Statistical Analysis Negative predictive values, likelihood ratios, and posterior probabilities and their corresponding exact 95% CIs were calculated by using the binomial distribution [25]. Role of Industry Sponsor Agen Biomedical, Ltd., donated the d-dimer kits but had no role in the design or conduct of the study or the decision to submit this paper for publication. Results During the study, 1881 patients were screened for eligibility. Of these, 484 were excluded because of prolonged anticoagulant therapy (n = 158), expected survival less than 3 months (n = 89), geographic inaccessibility (n = 68), contraindication to contrast medium (n = 60), attending physician refusal (n = 57), pregnancy (n = 23), suspected upper-extremity deep venous thrombosis (n = 17), lack of acute symptoms within 72 hours (n = 7), or age younger than 18 years (n = 5). Of the 1397 eligible patients, 1250 (89%) agreed to enter the study. Of the consenting patients, 2 had inadequate lung scans, 58 could not undergo d-dimer assays because of assay unavailability, and 13 were lost to follow-up and could not be included. Therefore, 1177 patients (59% women; mean age, 53.4 years [range, 20 to 94 years]) were included in the final analysis. Of the 1177 patients, 197 (17%) were classified by the end of the study as positive for pulmonary embolism. None of the 980 patients classified as negative for pulmonary embolism after initial testing died of pulmonary embolism during follow-up. Overall, the d-dimer assay showed a sensitivity of 84.8%, a specificity of 68.4%, a likelihood r