Paul L. den Exter

Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study.

IMPORTANCE D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. INTERVENTIONS All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01134068.

Risk of Recurrent Venous Thromboembolism and Mortality in Patients With Cancer Incidentally Diagnosed With Pulmonary Embolism: A Comparison With Symptomatic Patients

PURPOSE The routine use of modern computed tomography scanners has led to an increased detection of incidental pulmonary embolism (PE), in particular in patients with cancer. The clinical relevance of these incidental findings is unknown. PATIENTS AND METHODS In this retrospective cohort study, oncology patients in whom PE was objectively proven between 2004 and 2010 and anticoagulant treatment was started, were included. Fifty-one patients with incidental PE and 144 with symptomatic PE were observed for 1 year to compare the risks of recurrent venous thromboembolism (VTE), bleeding complications, and mortality. Kaplan-Meier and Cox survival analyses were performed. RESULTS Incidental and symptomatic patients did not differ with respect to mean age, sex, cancer type and stage, and risk factors for VTE. As a result from evolving treatment guidelines, approximately half of the patients in both groups received long-term treatment with vitamin K antagonists in stead of currently recommended low-molecular-weight heparin. The 12-month cumulative incidence of recurrent VTE was 13.3% in the incidental group versus 16.9% in the symptomatic group (P = .77). Notably, 20% VTE events recurred after premature termination of anticoagulant therapy. The risk of major bleeding complications was also comparable in the two groups (12.5% for incidental patients and 8.6% for symptomatic patients; P = .5). The respective 12-month mortality risks were 52.9% and 53.3% (P = .7). CONCLUSION Our findings suggest that oncology patients diagnosed with and treated for incidental PE, have similar high rates of recurrent VTE, bleeding complications, and mortality, as compared with oncology patients who develop symptomatic PE.

Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism

The clinical significance of subsegmental pulmonary embolism (SSPE) remains to be determined. This study aimed to investigate whether SSPE forms a distinct subset of thromboembolic disease compared with more proximally located pulmonary embolism (PE). We analyzed 3728 consecutive patients with clinically suspected PE. SSPE patients were contrasted to patients with more proximal PE and to patients in whom suspected PE was ruled out, in regards of the prevalence of thromboembolic risk factors and the 3-month risks of recurrent venous thromboembolism (VTE) and mortality. PE was confirmed in 748 patients, of whom 116 (16%) had SSPE; PE was ruled out in 2980 patients. No differences were seen in the prevalence of VTE risk factors, the 3-month risk of recurrent VTE (3.6% vs 2.5%; P = .42), and mortality (10.7% vs 6.5%; P = .17) between patients with SSPE and those with more proximal PE. When compared with patients without PE, aged >60 years, recent surgery, estrogen use, and male gender were found to be independent predictors for SSPE, and patients with SSPE were at an increased risk of VTE during follow-up (hazard ratio: 3.8; 95% CI: 1.3-11.1). This study indicates that patients with SSPE mimic those with more proximally located PE in regards to their risk profile and clinical outcome.

Wells Rule and D-Dimer Testing to Rule Out Pulmonary Embolism A Systematic Review and Individual-Patient Data Meta-analysis

The diagnosis of pulmonary embolism (PE) cannot be based on clinical features alone because the signs and symptoms of PE are not specific (1). Objective imaging tests, including computed tomography pulmonary angiography (CTPA), are therefore warranted to confirm or refute the presence of PE (2). Only 15% to 25% of presenting patients have PE (3), so CTPA is not an appropriate first-line test because of radiation exposure, costs, and risk for contrast-induced nephropathy. To guide decisions about who should be referred for imaging, various diagnostic algorithms have been developed over the past 2 decades. They aim to identify patients at low risk for PE in whom imaging and anticoagulant treatment can be safely withheld. One frequently used algorithm consists of the sequential application of the dichotomized Wells rule (4), which estimates the clinical probability of PE, and d-dimer testing. Pulmonary embolism can be considered ruled out in patients with a Wells score of 4 or less and a negative d-dimer test result (conventionally 500 g/L) (5). This combination is present in approximately 30% to 40% of those with suspected PE (3). The latter proportion is commonly called the efficiency of the algorithm. The proportion of these patients with symptomatic venous thromboembolism (VTE) during 3-month follow-up (the failure rate) is less than 1% (3). It has recently been shown that the efficiency can be safely increased by applying an age-adjusted d-dimer positivity threshold, which is defined as the age of patients multiplied by 10 g/L in those older than 50 years (6). Although many studies have validated the clinical utility and safety of the dichotomized Wells rule combined with d-dimer testing in excluding PE, an individual-patient data (IPD) meta-analysis can address important questions with greater precision and power. First, what is the overall efficiency and safety of the Wells rule and fixed d-dimer testing? Second, what is the performance of this strategy in clinically important subgroups? Third and most important, how do the efficiency and safety of age-adjusted d-dimer testing compare with fixed d-dimer testing? To answer these questions, we did a systematic review and IPD meta-analysis combining patient-level data from 6 large, prospective outcome studies in which diagnostic management of clinically suspected PE had been guided by the Wells rule and d-dimer testing. Using the fixed and age-adjusted d-dimer thresholds, we estimated the efficiency and failure rate of this diagnostic algorithm overall; in inpatients; and in persons with cancer, chronic obstructive pulmonary disease (COPD), age 75 years or older, previous VTE, and delayed presentation. Methods We developed a protocol (Supplement) and followed the guidance of the PRISMA-IPD (Preferred Reporting Items for Systematic reviews and Meta-Analyses of individual participant data) Statement (7). Supplement. Supplementary Material Supplement. Statistical Code Data Sources and Searches We searched MEDLINE and EMBASE from 1 January 1998 (the year in which the Wells score was introduced) (8) to 13 February 2016. The search was based on a previously published search strategy (3), which included terms for pulmonary embolism and d-dimer, and an adapted search filter for diagnostic and prognostic studies (9). We restricted the search to original studies in adults. No language restrictions were applied. The full search strategy is provided in Appendix Table 1. Two authors (N.E. and T.H.) independently screened the titles and abstracts of the identified articles and independently assessed the full-text articles for eligibility. Conflicts were resolved by discussion. Appendix Table 1. Full Electronic Search Strategy Study Selection Eligible studies included those that had prospectively enrolled, consecutive, hemodynamically stable adults presenting in a secondary care setting (emergency department or inpatient ward) with signs and symptoms suggestive of acute PE. At the individual level, the clinical probability of PE had to be assessed by the Wells rule and followed by quantitative d-dimer testing in patients with a Wells score of 4 or less (indicating PE unlikely). According to the study protocol, patients with a PE-unlikely Wells score and a negative d-dimer test result were to be managed without imaging and anticoagulant therapy but prospectively followed for 3 months to document the occurrence of VTE (Appendix Figure). By applying these criteria, we aimed to identify all studies that prospectively evaluated the current diagnostic management of patients with suspected PE in a secondary care setting. Appendix Figure. Diagnostic management of pulmonary embolism in the present IPD meta-analysis. IPD= individual-patient data; PE= pulmonary embolism. * The Wells score is a sum score of the following 7 variables: alternative diagnosis less likely than PE (3 points), clinical signs and symptoms of deep venous thrombosis (3 points), previous deep venous thrombosis or PE (1.5 points), tachycardia (1.5 points), immobilization or surgery within the past 4 wk (1.5 points), active cancer (treatment in the past 6 mo, current treatment, or palliative care; 1 point), and hemoptysis (1 point). Fixed d-dimer testing (500 g/L) or age-adjusted d-dimer testing (age10 g/L in patients aged >50 years), according to study protocol. Data Extraction and Quality Assessment Authors of studies fulfilling the inclusion criteria were invited to provide IPD, and all agreed. We sought study-level information on d-dimer assays used; imaging tests done to confirm PE; and definitions of the outcomes, regardless of whether outcome measures were adjudicated by an independent committee. Patient-level data collected at baseline included information on demographics, risk factors for VTE, Wells score items, d-dimer levels (converted to g/L), and results of imaging tests. We also collected follow-up data about anticoagulant treatment for reasons other than VTE, symptomatic VTE, mortality, or loss to follow-up. We followed the subgroup definitions used in each study without any adjustments and ascertained these definitions by the case report forms of the studies and variable labels in the study databases. Two authors who were not involved in the original studies independently assessed each study for potential sources of bias and applicability concerns using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool (10). Data Synthesis and Analysis Our analysis focused on the efficiency and failure rate of the diagnostic strategy. Efficiency was defined as the number of patients with a Wells score of 4 or less and a negative d-dimer test result relative to the total number of patients. We evaluated the efficiency of 2 d-dimer positivity thresholds: the conventional, fixed threshold of 500 g/L and an age-adjusted threshold, which was defined as the age of patients multiplied by 10 g/L in patients older than 50 years. For example, the age-adjusted strategy in a patient aged 75 years would lead to a d-dimer positivity threshold of 750 g/L. To evaluate age-adjusted d-dimer testing in our study, we reclassified patients enrolled in studies that evaluated fixed d-dimer testing according to the age-adjusted d-dimer threshold post hoc. The failure rate was defined as the proportion of patients with symptomatic deep venous thrombosis, nonfatal PE, or fatal PE during 3-month follow-up or objectively confirmed PE at baseline that was previously ruled out on the basis of a Wells score of 4 or less and a negative d-dimer test result. Death was considered to be caused by PE if it was confirmed by autopsy, if an imaging test for PE yielded positive results just before death, or in the case of sudden death due to unknown reasons. The efficiency and failure rates were calculated overall and in clinically important high-risk subgroups, including inpatients and patients with cancer, COPD, age 51 to 74 years, age 75 years or older, previous VTE, and symptoms lasting more than 7 days. Statistical Analysis To avoid bias associated with excluding missing data (11), we used multiple imputation separately within each study (10 times). The proportion of missing values is reported in Appendix Table 2. Results across the multiply imputed data sets were combined by using the Rubin rule (12) (Appendix). Appendix Table 2. Proportion of Missing Values in Each Study* A single-stage meta-analytic approach was used (13, 14) to analyze the efficiency and failure rates. The overall efficiency (the proportion of patients in whom imaging could be withheld) was estimated using a multilevel logistic regression model (also called a generalized linear mixed-effects model), with the combination of a Wells score of 4 or less and a negative d-dimer test result as the outcome variable. To account for the clustering of observations within studies, we specified a random effect for the intercept. For the analysis in subgroups, we used a full random-effects model (13) by adding the subgroup indicator as a covariate and allowing a study-specific random effect. From these models, we calculated the marginal probabilities (with 95% CIs) of having a PE-unlikely Wells score and a negative d-dimer test result, both overall and in the different subgroups (Appendix). Differences in efficiency between subgroups were tested by using the Wald test statistic with the significance level set at 0.05. The absolute difference in the efficiency of the fixed and age-adjusted d-dimer testing strategies was calculated by subtracting the point estimates of the marginal probabilities from the 2 models. The 95% CIs around these estimates were obtained by repeating the analyses in 500 bootstrap samples (Appendix). Using similar methods, we estimated the failure ratethe proportion of patients with symptomatic VTE during 3-month follow-up in whom the Wells score and d-dimer test result had ruled out PE at baseline. The outcome variable in this multilevel logistic re

Quality of life after pulmonary embolism as assessed with SF-36 and PEmb-QoL

INTRODUCTION Although quality of life (QoL) is recognized as an important indicator of the course of a disease, it has rarely been addressed in studies evaluating the outcome of care for patients with pulmonary embolism (PE). This study primarily aimed to evaluate the QoL of patients with acute PE in comparison to population norms and to patients with other cardiopulmonary diseases, using a generic QoL questionnaire. Secondary, the impact of time period from diagnosis and clinical patient characteristics on QoL was assessed, using a disease-specific questionnaire. METHODS QoL was assessed in 109 consecutive out-patients with a history of objectively confirmed acute PE (mean age 60.4 ± 15.0 years, 56 females), using the generic Short Form-36 (SF-36) and the disease specific Pulmonary Embolism Quality of Life questionnaire (PEmb-QoL). The score of the SF-36 were compared with scores of the general Dutch population and reference populations with chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), a history of acute myocardial infarction (AMI), derived from the literature. Scores on the SF-35 and PEmb-QoL were used to evaluate QoL in the short-term and long-term clinical course of patients with acute PE. In addition, we examined correlations between PEmb-QoL scores and clinical patient characteristics. RESULTS Compared to scores of the general Dutch population, scores of PE patients were worse on several subscales of the SF-36 (social functioning, role emotional, general health (P<0.001), role physical and vitality (P<0.05)). Compared to patients with COPD and CHF, patients with PE scored higher (=better) on all subscales of the SF-36 (P ≤ 0.004) and had scores comparable with patients with AMI the previous year. Comparing intermediately assessed QoL with QoL assessed in long-term follow-up, PE patients scored worse on SF-36 subscales: physical functioning, social functioning, vitality (P<0.05), and on the PEmb-QoL subscales: emotional complaints and limitations in ADL (P ≤ 0.03). Clinical characteristics did not correlate with QoL as measured by PEmb-QoL. CONCLUSION Our study demonstrated an impaired QoL in patients after treatment of PE. The results of this study provided more knowledge about QoL in patients treated for PE.

A clinical prognostic model for the identification of low-risk patients with acute symptomatic pulmonary embolism and active cancer.

BACKGROUND Physicians need a specific risk-stratification tool to facilitate safe and cost-effective approaches to the management of patients with cancer and acute pulmonary embolism (PE). The objective of this study was to develop a simple risk score for predicting 30-day mortality in patients with PE and cancer by using measures readily obtained at the time of PE diagnosis. METHODS Investigators randomly allocated 1,556 consecutive patients with cancer and acute PE from the international multicenter Registro Informatizado de la Enfermedad TromboEmbólica to derivation (67%) and internal validation (33%) samples. The external validation cohort for this study consisted of 261 patients with cancer and acute PE. Investigators compared 30-day all-cause mortality and nonfatal adverse medical outcomes across the derivation and two validation samples. RESULTS In the derivation sample, multivariable analyses produced the risk score, which contained six variables: age > 80 years, heart rate ≥ 110/min, systolic BP < 100 mm Hg, body weight < 60 kg, recent immobility, and presence of metastases. In the internal validation cohort (n = 508), the 22.2% of patients (113 of 508) classified as low risk by the prognostic model had a 30-day mortality of 4.4% (95% CI, 0.6%-8.2%) compared with 29.9% (95% CI, 25.4%-34.4%) in the high-risk group. In the external validation cohort, the 18% of patients (47 of 261) classified as low risk by the prognostic model had a 30-day mortality of 0%, compared with 19.6% (95% CI, 14.3%-25.0%) in the high-risk group. CONCLUSIONS The developed clinical prediction rule accurately identifies low-risk patients with cancer and acute PE.

Thromboembolic resolution assessed by CT pulmonary angiography after treatment for acute pulmonary embolism

The systematic assessment of residual thromboembolic obstruction after treatment for acute pulmonary embolism (PE) has been understudied. This assessment is of potential clinical importance, should clinically suspected recurrent PE occur, or as tool for risk stratification of cardiopulmonary complications or recurrent venous thromboembolism (VTE). This study aimed to assess the rate of PE resolution and its implications for clinical outcome. In this prospective, multi-center cohort study, 157 patients with acute PE diagnosed by CT pulmonary angiography (CTPA) underwent follow-up CTPA-imaging after six months of anticoagulant treatment. Two expert thoracic radiologists independently assessed the presence of residual thromboembolic obstruction. The degree of obstruction at baseline and follow-up was calculated using the Qanadli obstruction index. All patients were followed-up for 2.5 years. At baseline, the median obstruction index was 27.5 %. After six months of treatment, complete PE resolution had occurred in 84.1 % of the patients (95 % confidence interval (CI): 77.4-89.4 %). The median obstruction index of the 25 patients with residual thrombotic obstruction was 5.0 %. During follow-up, 16 (10.2 %) patients experienced recurrent VTE. The presence of residual thromboembolic obstruction was not associated with recurrent VTE (adjusted hazard ratio: 0.92; 95 % CI: 0.2-4.1).This study indicates that the incidence of residual thrombotic obstruction following treatment for PE is considerably lower than currently anticipated. These findings, combined with the absence of a correlation between residual thrombotic obstruction and recurrent VTE, do not support the routine use of follow-up CTPA-imaging in patients treated for acute PE.

Impact of delay in clinical presentation on the diagnostic management and prognosis of patients with suspected pulmonary embolism

RATIONALE The nonspecific clinical presentation of pulmonary embolism (PE) frequently leads to delay in its diagnosis. OBJECTIVES This study aimed to assess the impact of delay in presentation on the diagnostic management and clinical outcome of patients with suspected PE. METHODS In 4,044 consecutive patients with suspected PE, patients presenting more than 7 days from the onset of symptoms were contrasted with those presenting within 7 days as regards the safety of excluding PE on the basis of a clinical decision rule combined with D-dimer testing. Patients were followed for 3 months to assess the rates of recurrent venous thromboembolism and mortality. MEASUREMENTS AND MAIN RESULTS A delayed presentation (presentation >7 d) was present in 754 (18.6%) of the patients. The failure rate of an unlikely clinical probability and normal D-dimer test was 0.5% (95% confidence interval [CI], 0.01-2.7) for patients with and 0.5% (95% CI, 0.2-1.2) for those without diagnostic delay. D-dimer testing yielded a sensitivity of 99% (95% CI, 96-99%) and 98% (95% CI, 97-99%) in these groups, respectively. Patients with PE with diagnostic delay more frequently had centrally located PE (41% vs. 26%; P < 0.001). The cumulative rates of recurrent venous thromboembolism (4.6% vs. 2.7%; P = 0.14) and mortality (7.6% vs. 6.6%; P = 0.31) were not different for patients with and without delayed presentation. CONCLUSIONS PE can be safely excluded based on a clinical decision rule and D-dimer testing in patients with a delayed clinical presentation. A delayed presentation for patients who survived acute PE was associated with a more central PE location, although this did not affect the clinical outcome at 3 months.

Computerised clinical decision support for suspected PE

This study aimed to determine the effect of an evidence-based clinical decision support (CDS) algorithm on the use and yield of CT pulmonary angiography (CTPA) and on outcomes of patients evaluated in the emergency department (ED) for suspected PE. The study included 1363 consecutive patients evaluated for suspected PE in an ED during 12 months before and 12 months after initiation of CDS use. Introduction of CDS was associated with decreased CTPA use (55% vs 49%; absolute difference (AD), 6.3%; 95% CI 1.0% to 11.6%; p=0.02). The use of CDS was associated with fewer symptomatic venous thromboembolic events during follow-up in patients with an initial negative diagnostic evaluation for PE (0.7% vs 3.2%; AD 2.5%; 95% CI 0.9% to 4.6%; p<0.01).

Optimization of the diagnostic management of clinically suspected pulmonary embolism in hospitalized patients.

Identical diagnostic algorithms for suspected pulmonary embolism (PE) are used for hospitalized patients and outpatients, while D‐dimer levels, risk factors and pre‐test probability for PE differ, and the percentage of patients managed without computerized tomography pulmonary angiography (CTPA) is lower in hospitalized patients. We aimed to improve the efficiency of the diagnostic algorithm by increasing the threshold of the D‐dimer, the threshold of the Wells rule and by adjustments of the Wells rule. Six‐hundred and twenty‐four hospitalized patients from two previously performed management studies with a PE prevalence of 26% were studied. Adjustments were considered to be safe when the failure rate remained <2%. By applying standard management, 8% (49/624) were managed without CTPA with a failure rate of 0·0% (0/49; 95% confidence interval [CI] 0·0–7·3), and it was 1·7% (8/465; 95%CI 0·8–3·4) for all patients in whom PE was excluded at baseline. All evaluated adjustments resulted in an increase of the failure rate with very small improvements of the efficiency. Given these potentially small improvements and the increasing complexity of clinical practice if adjusted diagnostic algorithms for specific patient categories were introduced, we do not recommend further evaluation of any of the adjustments; we recommend that the standard diagnostic algorithm should continue to be applied.