Tom van der Hulle

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

The influence of clan structure on the genetic variation in a single Ghanaian village.

Socioeconomic and cultural factors are thought to have an important role in influencing human population genetic structure. To explain such population structure differences, most studies analyse genetic differences among widely dispersed human populations. In contrast, we have studied the genetic structure of an ethnic group occupying a single village in north-eastern Ghana. We found a markedly skewed male population substructure because of an almost complete lack of male gene flow among Bimoba clans in this village. We also observed a deep male substructure within one of the clans in this village. Among all males, we observed only three Y-single-nucleotide polymorphism (SNP) haplogroups: E1b1a*-M2, E1b1a7a*-U174 and E1b1a8a*-U209, P277, P278. In contrast to the marked Y-chromosomal substructure, mitochondrial DNA HVS-1 sequence variation and autosomal short-tandem repeats variation patterns indicate high genetic diversities and a virtually random female-mediated gene flow among clans. On the extreme micro-geographical scale of this single Bimoba village, correspondence between the Y-chromosome lineages and clan membership could be due to the combined effects of the strict patrilocal and patrilineal structure. If translated to larger geographic scales, our results would imply that the extent of variation in uniparentally inherited genetic markers, which are typically associated with historical migration on a continental scale, could equally likely be the result of many small and different cumulative effects of social factors such as clan membership that act at a local scale. Such local scale effects should therefore be considered in genetic studies, especially those that use uniparental markers, before making inferences about human history at large.

Reliability of diagnosing incidental pulmonary embolism in cancer patients

BACKGROUND With the routine use of advanced multi-slice CT scanners, pulmonary embolism (PE) is increasingly detected as an incidental finding among cancer patients. Although this generally leads to therapeutic interventions, the accuracy of diagnosing PE on routinely performed contrast enhanced CT scans is unknown. METHODS Consecutive cancer patients diagnosed with incidental PE were eligible for inclusion. Their CT images were reassessed in a blinded fashion by two thoracic radiologists. To ensure blindness, a total of 19 cancer staging CT images without PE were included. The inter-observer reliability for the presence of PE was calculated with use of Kappa statistics. RESULTS A total of 62 incidental PE patients (mean age 64years, 60% male) were included. All patients received anticoagulant treatment upon diagnosis. Level of agreement between the two expert readers was high: they disagreed on the presence of PE in only two patients (3.2%), resulting in a Kappa statistic of 0.93. After final consensus reading, it was concluded that the CT images of all 62 patients initially diagnosed with incidental PE were indeed positive for PE. CONCLUSIONS This study indicates that an incidental PE diagnosis is reliable and highly reproducible, despite the suboptimal reading conditions of a non-dedicated scan protocol.

Advances in the diagnosis and management of acute pulmonary embolism

The diagnostic management of acute pulmonary embolism (PE) is complicated by its heterogeneous clinical presentation. Current diagnostic algorithms, combining clinical probability estimation with D-dimer testing and imaging tests, are very safe to exclude PE, although at costs of high numbers of CT-examinations. In view of cost- and time-saving as well as safety issues, several attempts have recently been undertaken to reduce the number of required imaging tests. Especially the age-adjusted D-dimer threshold has greatly improved the potential for non-invasive exclusion of PE. Once the diagnosis of PE is established, immediate initiation of anticoagulant therapy is of vital importance. A new generation of direct oral anticoagulants, which overcomes the main disadvantages of conventional vitamin-K antagonists, has recently emerged. Risk stratification of hemodynamically stable PE patients with use of clinical decision rules, cardiac biomarkers or imaging tests, aids physicians in determining the most appropriate treatment approach for the individual patient. This is essential to differentiate patients at low risk of adverse outcome, who may be safely treated at home, from intermediate-risk patients, who require closer monitoring and for whom recent studies have evaluated the efficacy and safety of systemic thrombolytic therapy. This article reviews recent advances and challenges that remain in the diagnostic work-up and initial management of acute, clinically stable PE.

The Newer Anticoagulants in Thrombosis Control in Cancer Patients

Cancer and hemostasis are strongly correlated and the development of venous thromboembolism (VTE) has a major adverse impact on the outcome of cancer patients. Treatment of cancer-associated VTE is far more challenging than treating VTE in the non-cancer population, as the clinical course of cancer patients is characterized by increased rates of both recurrent thromboembolic episodes and bleeding complications. This has led to the development of a distinct management approach towards VTE in patients with active cancer. Low-molecular-weight heparins (LMWHs) currently represent the therapeutic agent of choice, as a result of a proven higher efficacy compared to vitamin K antagonists (VKAs). However, as LMWHs require daily subcutaneous injections, weight-adjusted doses, and still confers high risks of recurrent VTE and bleeding complications, management of cancer-associated VTE warrants further optimization. In recent years several novel, target-specific oral anticoagulants have been introduced and evaluated in clinical trials. These new anticoagulants display several advantages compared to conventional anticoagulants. This review will evaluate their trial results up-to-date with a particular focus on the cancer patients included in these trials. The potential of these agents in the setting of cancer-associated VTE will be discussed and directions for future research will be provided.

New anticoagulants in the treatment of patients with cancer-associated venous thromboembolism

Venous thromboembolism (VTE) represents a common source of morbidity and mortality among patients with malignant disease. In this specific setting, the treatment of VTE is challenging as cancer patients display a high tendency to develop recurrent VTE, as well as anticoagulant-related bleeding complications. Low-molecular-weight heparins have been demonstrated to be more effective in the long-term prevention of recurrent VTE in cancer patients compared with conventional treatment with vitamin K antagonists. A limitation of this therapeutic approach includes the long-term requirement of daily subcutaneous injections, which may be burdensome to patients. Over the past decade, several novel oral anticoagulants have emerged, which can be administered in fixed doses without the need for monitoring. Clinical trials evaluating these agents for treatment in the general VTE population yielded promising results. This review summarizes the current management of cancer-associated VTE, overviews the trials that investigated the novel anticoagulant drugs for the treatment of acute VTE and discusses the potential of these novel agents for use in cancer patients.

Recurrence risk after anticoagulant treatment of limited duration for late, second venous thromboembolism

Patients with a second venous thromboembolism generally receive anticoagulant treatment indefinitely, although it is known that the recurrence risk diminishes over time while the risk of hemorrhage persists with continued anticoagulation and increases with age. Based on these arguments and limited evidence for indefinitely prolonged treatment, the Dutch guidelines recommend considering treatment of a limited duration (i.e. 12 months) for a ‘late’ second venous thromboembolism, defined by a second venous thromboembolism diagnosed more than 1 year after discontinuing treatment for a first event. It is hypothesized that the risk of continued anticoagulation might outweigh the benefits in such circumstances. We evaluated this management in daily practice. Since 2003, limited duration of treatment was systematically considered at our hospital in consecutive patients, in whom we determined the recurrence risk. Of 131 patients with late second venous thromboembolism, 77 were treated for a limited duration, of whom 26 developed a symptomatic third venous thromboembolism thereafter during a cumulative follow-up of 277 years, resulting in an incidence rate of 9.4/100 patient-years (95% confidence interval: 6.1–14). The incidence rates in patients with unprovoked and provoked venous thromboembolism were 12/100 patient-years (95% confidence interval: 7.4–19) and 5.6/100 patient-years (95% confidence interval: 2.2–12), respectively [adjusted hazard ratio 2.8 (95% confidence interval: 1.1–7.2)]. The recurrence risk after treatment of limited duration for ‘late’ second venous thromboembolism exceeded the risk of hemorrhage associated with extended anticoagulation. Most patients may, therefore, be better served by treatment of indefinite duration, although the risk-benefit ratio of extended anticoagulation should be weighed for every patient.

Ancestral Stories of Ghanaian Bimoba Reflect Millennia-Old Genetic Lineages

Oral history and oral genealogies are mechanisms of collective memory and a main cultural heritage of many populations without a writing system. In the effort to analytically address the correspondence between genetic data and historical genealogies, anthropologists hypothesised that genealogies evolve through time, ultimately containing three parts: literal – where the most recent ancestry is truthfully represented; intended – where ancestry is inferred and reflects political relations among groups; and mythical – that does not represent current social reality. While numerous studies discuss oral genealogies, to our knowledge no genetic studies have been able to investigate to what extent genetic relatedness corresponds to the literal and intended parts of oral genealogies. We report on the correspondence between genetic data and oral genealogies among Bimoba males in a single village in North-Eastern Ghana. We compared the pairwise mismatch distribution of Y chromosome short tandem repeat (Y-STR) haplotypes among all lineages present in this village to the self-reported (oral) relatedness. We found that Bimoba are able to correctly identify unrelated individuals in 92% of the cases. In contrast, they are able to correctly identify related individuals only in 38% of the cases, which can be explained by three processes: (1) the compression of genealogies, leading to increasing inaccuracy with increasing genealogical distance, (2) inclusions into the lineage from intended relations such as clan co-option or adoptions, and (3) false paternities, which in this study were found to have a minor effect on the correspondence between genetic data and oral genealogies. In addition, we observed that 70% of unrelated pairs have from six to eight Y-STR differences, a diversification peak which we attribute to an ancient West African expansion dating around 9454 years ago. We conclude that, despite all caveats, oral genealogies are reflecting ancient lineages more accurately than previously thought.

Performance of the revised Geneva score in patients with a delayed suspicion of pulmonary embolism

To the Editor: Establishing a prompt diagnosis of acute pulmonary embolism is a diagnostic challenge, as the clinical presentation ranges from haemodynamic shock to very subtle symptoms mimicking those of other cardiovascular or pulmonary diseases [1]. This diverse presentation facilitates diagnostic delay and, consequently, also a delay in treatment initiation, which might be an important prognostic indicator for patients with acute pulmonary embolism [1]. The standard diagnostic algorithm for suspected acute pulmonary embolism consists of sequential pre-test probability determination, D-dimer testing and computed tomography pulmonary angiography (CTPA) [2]. The pre-test probability can be estimated using a validated clinical decision rule (CDR), such as the Wells score and the revised Geneva score (RGS) [3, 4]. In addition to an excellent sensitivity and specificity, the main advantage of this diagnostic algorithm is that 20–30% of all patients with a clinical suspicion can be managed without CTPA, since an unlikely clinical probability in combination with a normal high-sensitive D-dimer test result has been shown to accurately rule out acute symptomatic pulmonary embolism [5]. The significance of the appropriate use of this diagnostic management strategy in patients with suspected pulmonary embolism has been highlighted by a prospective cohort study [6]. In patients with inappropriate diagnostic management, the diagnostic failure rate was 7.7%, compared to 1.2% for those patients in whom pulmonary embolism was ruled out according to the strategy (p<0.001). Importantly, symptoms suggestive of pulmonary embolism that could also be ascribed to underlying cardiopulmonary diseases ( e.g. heart failure or chronic lung disease) were identified as an important factor …

Vitamin K Antagonists Compared to Low-Molecular-Weight Heparins for Treatment of Cancer-Associated Venous Thromboembolism: An Observational Study in Routine Clinical Practice

Since several trials have demonstrated that low-molecular-weight-heparin (LMWH) is superior to vitamin K antagonist (VKA) in preventing recurrent venous thromboembolism (VTE) in patients with cancer-associated VTE, guidelines now recommend LMWH monotherapy in this setting. We evaluated whether this shift resulted in improved outcomes in routine clinical practice. We performed a cohort study of consecutive patients with cancer-associated VTE during 2001 and 2010. We compared the risks for recurrent VTE, major bleeding and mortality between patients diagnosed before and after 2008 during a 6-month routine follow-up. A total of 381 patients were included, of which 234 (61.4%) were diagnosed before 2008. Before 2008, 23% of the patients were treated with LMWH; thereafter, this percentage was higher: 67%. The 6-month incidence for recurrent VTE was 8.6% in patients diagnosed before 2008 versus 7.5% for patients diagnosed after 2008 (risk difference [RD]: -1.1%; 95% confidence interval [CI]: -6.3, 5.3). The respective risks for major bleeding were 6.4 versus 4.8% (RD: -1.6%; 95% CI: -3.8 to 5.8), and 39.7 versus 41.5% (RD: 1.8%; 95% CI: -8.8, 12) for overall mortality. The mean time in therapeutic range (TTR) of patients treated with VKA was 61%. Despite a clear shift toward LMWH as agent of choice for cancer-associated VTE, we did not observe a clear improvement in terms of recurrent VTE and bleeding complications.Since several trials have demonstrated that low-molecular-weight-heparin (LMWH) is superior to vitamin K antagonist (VKA) in preventing recurrent venous thromboembolism (VTE) in patients with cancer-associated VTE, guidelines now recommend LMWH monotherapy in this setting. We evaluated whether this shift resulted in improved outcomes in routine clinical practice. We performed a cohort study of consecutive patients with cancer-associated VTE during 2001 and 2010. We compared the risks for recurrent VTE, major bleeding and mortality between patients diagnosed before and after 2008 during a 6-month routine follow-up. A total of 381 patients were included, of which 234 (61.4%) were diagnosed before 2008. Before 2008, 23% of the patients were treated with LMWH; thereafter, this percentage was higher: 67%. The 6-month incidence for recurrent VTE was 8.6% in patients diagnosed before 2008 versus 7.5% for patients diagnosed after 2008 (risk difference [RD]: -1.1%; 95% confidence interval [CI]: -6.3, 5.3). The respective risks for major bleeding were 6.4 versus 4.8% (RD: -1.6%; 95% CI: -3.8 to 5.8), and 39.7 versus 41.5% (RD: 1.8%; 95% CI: -8.8, 12) for overall mortality. The mean time in therapeutic range (TTR) of patients treated with VKA was 61%. Despite a clear shift toward LMWH as agent of choice for cancer-associated VTE, we did not observe a clear improvement in terms of recurrent VTE and bleeding complications.