I.C.M. Mos

Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis.

RATIONALE The potential role of elevated brain-type natriuretic peptides (BNP) in the differentiation of patients suffering from acute pulmonary embolism at risk for adverse clinical outcome has not been fully established. OBJECTIVES We evaluated the relation between elevated BNP or N-terminal-pro-BNP (NT-pro-BNP) levels and clinical outcome in patients with pulmonary embolism. METHODS Articles reporting on studies that evaluated the risk of adverse outcome in patients with pulmonary embolism and elevated BNP or NT-pro-BNP levels were abstracted from Medline and EMBASE. Information on study design, patient and assay characteristics, and clinical outcome was extracted. Primary endpoints were overall mortality and predefined composite outcome of adverse clinical events. MEASUREMENTS AND MAIN RESULTS Data from 13 studies were included. In 51% (576/1,132) of the patients, BNP or NT-pro-BNP levels were increased. The different analyses were performed in subpopulations. Elevated levels of BNP or NT-pro-BNP were significantly associated with right ventricular dysfunction (P < 0.001). Patients with high BNP or NT-pro-BNP concentration were at higher risk of complicated in-hospital course (odds ratio [OR], 6.8; 95% confidence interval [CI], 4.4-10) and 30-day mortality (OR, 7.6; 95% CI, 3.4-17). Patients with a high NT-pro-BNP had a 10% risk of dying (68/671; 95% CI, 8.0-13%), whereas 23% (209/909; 95% CI, 20-26%) had an adverse clinical outcome. CONCLUSIONS High concentrations of BNP distinguish patients with pulmonary embolism at higher risk of complicated in-hospital course and death from those with low BNP levels. Increased BNP or NT-pro-BNP concentrations alone, however, do not justify more invasive treatment regimens.

Performance of 4 Clinical Decision Rules in the Diagnostic Management of Acute Pulmonary Embolism: A Prospective Cohort Study

BACKGROUND Several clinical decision rules (CDRs) are available to exclude acute pulmonary embolism (PE), but they have not been directly compared. OBJECTIVE To directly compare the performance of 4 CDRs (Wells rule, revised Geneva score, simplified Wells rule, and simplified revised Geneva score) in combination with d-dimer testing to exclude PE. DESIGN Prospective cohort study. SETTING 7 hospitals in the Netherlands. PATIENTS 807 consecutive patients with suspected acute PE. INTERVENTION The clinical probability of PE was assessed by using a computer program that calculated all CDRs and indicated the next diagnostic step. Results of the CDRs and d-dimer tests guided clinical care. MEASUREMENTS Results of the CDRs were compared with the prevalence of PE identified by computed tomography or venous thromboembolism at 3-month follow-up. RESULTS Prevalence of PE was 23%. The proportion of patients categorized as PE-unlikely ranged from 62% (simplified Wells rule) to 72% (Wells rule). Combined with a normal d-dimer result, the CDRs excluded PE in 22% to 24% of patients. The total failure rates of the CDR and d-dimer combinations were similar (1 failure, 0.5% to 0.6% [upper-limit 95% CI, 2.9% to 3.1%]). Even though 30% of patients had discordant CDR outcomes, PE was not detected in any patient with discordant CDRs and a normal d-dimer result. LIMITATION Management was based on a combination of decision rules and d-dimer testing rather than only 1 CDR combined with d-dimer testing. CONCLUSION All 4 CDRs show similar performance for exclusion of acute PE in combination with a normal d-dimer result. This prospective validation indicates that the simplified scores may be used in clinical practice. PRIMARY FUNDING SOURCE Academic Medical Center, VU University Medical Center, Rijnstate Hospital, Leiden University Medical Center, Maastricht University Medical Center, Erasmus Medical Center, and Maasstad Hospital.

Safety of ruling out acute pulmonary embolism by normal computed tomography pulmonary angiography in patients with an indication for computed tomography: systematic review and meta-analysis.

Introduction: Several outcome studies have ruled out acute pulmonary embolism (PE) by normal computed tomography pulmonary angiography (CTPA). We performed a meta‐analysis in order to determine the safety of this strategy in a specific group of patients with a strict indication for CTPA, that is, ‘likely’ or ‘high’ clinical probability for PE, an elevated D‐dimer concentration, or both. Methods: Studies that ruled out PE by normal CTPA, with or without subsequent normal bilateral compression ultrasonography (CUS), in patients with a strict indication for CTPA, were searched for in Medline, EMBASE, Web of Science and the Cochrane dataset. The primary endpoint was the occurrence of (fatal) venous thromboembolism (VTE) in a 3‐month follow‐up period. Results: Three studies were identified that excluded PE by CTPA alone (2020 patients), and three studies that performed additional CUS of the legs after normal CTPA (1069 patients). The pooled incidence of VTE at 3 months was 1.2% [95% confidence interval (CI) 0.8–1.8] based on a normal CTPA result as a sole test, and 1.1% (95% CI 0.6–2.0) based on normal CTPA and negative CUS findings, resulting in negative predictive values of 98.8% (95% CI 98.2–99.2) and 98.9% (95% CI 98.0–99.4), respectively. This compares favorably with the VTE failure rate after normal pulmonary angiography (1.7%, 95% CI 1.0–2.7). The risk of fatal PE did not differ between the diagnostic strategies (0.6% vs. 0.5%). Conclusion: A normal CTPA result alone can safely exclude PE in all patients in whom CTPA is required to rule out this disease. There is no need for additional ultrasonography to rule out VTE in these patients.

Risk of arterial cardiovascular events in patients after pulmonary embolism

Studies have reported inconsistent evidence for an association between venous thrombosis and arterial cardiovascular events. We further studied the association between both diseases by comparing the occurrence of cardiovascular events in patients diagnosed with acute pulmonary embolism (PE) contrasted to patients with comparable baseline risk characteristics (patients in whom PE was clinically suspected but ruled out). Included were 259 patients with provoked PE, 95 patients with unprovoked PE, and 334 control patients without PE. Patients diagnosed with PE were treated with vitamin K antagonists for 6 months. Median follow-up was 4.2 years. Sixty-three arterial cardiovascular events were registered (incidence, 5.1/100 patient-years). Adjusted hazard ratio was not different between patients with all-cause PE and control patients (1.39, 95% confidence interval [CI], 0.83-2.3) but increased for patients with unprovoked PE versus both patients with provoked PE and control patients without PE (2.18; 95% CI, 1.1-4.5; and 2.62; 95% CI, 1.4-4.9, respectively). This effect was confirmed after redefining the study start date to the moment the vitamin K antagonists were discontinued. Our study underlines the association between unprovoked venous thrombosis and arterial cardiovascular events; however, risk differences between patients with provoked PE and patients in whom PE was clinically suspected but ruled out could not be demonstrated.

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.

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.

Diagnostic outcome management study in patients with clinically suspected recurrent acute pulmonary embolism with a structured algorithm

INTRODUCTION The value of diagnostic strategies in patients with clinically suspected recurrent pulmonary embolism (PE) has not been established. The aim was to determine the safety of a simple diagnostic strategy using the Wells clinical decision rule (CDR), quantitative D-dimer testing and computed tomography pulmonary angiography (CTPA) in patients with clinically suspected acute recurrent PE. MATERIALS AND METHODS Multicenter clinical outcome study in 516 consecutive patients with clinically suspected acute recurrent PE without using anticoagulants. RESULTS An unlikely clinical probability (Wells rule 4 points or less) was found in 182 of 516 patients (35%), and the combination of an unlikely CDR-score and normal D-dimer result excluded PE in 88 of 516 patients (17%), without recurrent venous thromboembolism (VTE) during 3month follow-up (0%; 95% CI 0.0-3.4%). CTPA was performed in all other patients and confirmed recurrent PE in 172 patients (overall prevalence of PE 33%) and excluded PE in the remaining 253 patients (49%). During follow-up, seven of these 253 patients returned with recurrent VTE (2.8%; 95% CI 1.2-5.5%), of which in one was fatal (0.4 %; 95 % CI 0.02-1.9%). The diagnostic algorithm was feasible in 98% of patients. CONCLUSIONS A diagnostic algorithm consisting of a clinical decision rule, D-dimer test and CTPA is effective in the management of patients with clinically suspected acute recurrent PE. CTPA provides reasonable safety in excluding acute recurrent PE in patients with a likely clinical probability or an elevated D-dimer test for recurrent PE, with a low risk for fatal PE at follow-up.

Computed tomography pulmonary angiography as a single imaging test to rule out pulmonary embolism.

Purpose of review The aim is to review the evidence on the diagnostic value of computed tomography pulmonary angiography (CTPA) as a single test to rule out acute pulmonary embolism by focussing on the most recent literature and potential alternative and additional imaging modalities or diagnostic strategies. Recent findings Clinical outcome studies have demonstrated that, using algorithms with sequential diagnostic tests, pulmonary embolism can be safely ruled out in patients with a clinical probability indicating pulmonary embolism to be unlikely and a normal D-dimer test result. This obviates the need for additional radiological imaging tests in around one-third of patients. CTPA has been shown to have a high sensitivity and specificity for the diagnosis of pulmonary embolism. Several emerging tests with potential diagnostic or other advantages over CTPA need further validation before they can be implemented in routine clinical care. Summary CTPA is the imaging test of first choice. The presence or absence of pulmonary embolism can be determined with sufficient certainty without the need for additional imaging tests after a negative CTPA. Compression ultrasonography and ventilation-perfusion scintigraphy is reserved for patients with concomitant symptomatic deep vein thrombosis or a stringent contraindication for CTPA, respectively. Currently, magnetic resonance pulmonary angiography is not a suitable alternative for CTPA.

A simple decision rule including D-dimer to reduce the need for computed tomography scanning in patients with suspected pulmonary embolism.

An ‘unlikely’ clinical decision rule with a negative D‐dimer result safely excludes pulmonary embolism (PE) in 30% of presenting patients. We aimed to simplify this diagnostic approach and to increase its efficiency.