Wells Rule and d-Dimer Testing to Rule Out Pulmonary Embolism

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