Maaike Sohne

Brain Natriuretic Peptide as a Predictor of Adverse Outcome in Patients With Pulmonary Embolism

Background—Despite effective treatment with anticoagulants, 2% to 7% of patients with pulmonary embolism will die as a result of their disease. Methods and Results—We examined in 110 consecutive patients with pulmonary embolism whether plasma brain natriuretic peptide (BNP), a novel marker of (right) ventricular dysfunction, is a predictor of fatal pulmonary embolism. The relationship between BNP concentration measured at presentation and clinical outcome was assessed by comparing the proportion of outcome events among tertiles. Positive and negative predictive values of BNP levels in the highest and lowest tertiles were calculated. The risk of death related to pulmonary embolism if the BNP level is >21.7 pmol/L is 17% (95% CI, 6% to 33%). The negative predictive value for uneventful outcome of a BNP value <21.7 pmol/L is 99% (95% CI, 93% to 100%). Conclusion—This is the first study to show that plasma BNP levels seem to predict adverse outcome in patients with acute pulmonary embolism.

Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.

Objectives In older patients, the the D-dimer test for pulmonary embolism has reduced specificity and is therefore less useful. In this study a new, age dependent cut-off value for the test was devised and its usefulness with older patients assessed. Design Retrospective multicentre cohort study. Setting General and teaching hospitals in Belgium, France, the Netherlands, and Switzerland. Patients 5132 consecutive patients with clinically suspected pulmonary embolism. Intervention Development of a new D-dimer cut-off point in patients aged >50 years in a derivation set (data from two multicentre cohort studies), based on receiver operating characteristics (ROC) curves. This cut-off value was then validated with two independent validation datasets. Main outcome measures The proportion of patients in the validation cohorts with a negative D-dimer test, the proportion in whom pulmonary embolism could be excluded, and the false negative rates. Results The new D-dimer cut-off value was defined as (patient’s age×10) μg/l in patients aged >50. In 1331 patients in the derivation set with an “unlikely” score from clinical probability assessment, pulmonary embolism could be excluded in 42% with the new cut-off value versus 36% with the old cut-off value (<500 μg/l). In the two validation sets, the increase in the proportion of patients with a D-dimer below the new cut-off value compared with the old value was 5% and 6%. This absolute increase was largest among patients aged >70 years, ranging from 13% to 16% in the three datasets. The failure rates (all ages) were 0.2% (95% CI 0% to 1.0%) in the derivation set and 0.6% (0.3% to 1.3%) and 0.3% (0.1% to 1.1%) in the two validation sets. Conclusions The age adjusted D-dimer cut-off point, combined with clinical probability, greatly increased the proportion of older patients in whom pulmonary embolism could be safely excluded.

Further validation and simplification of the Wells clinical decision rule in pulmonary embolism

The Wells rule is a widely applied clinical decision rule in the diagnostic work-up of patients with suspected pulmonary embolism (PE). The objective of this study was to replicate, validate and possibly simplify this rule. We used data collected in 3,306 consecutive patients with clinically suspected PE to recalculate the odds ratios for the variables in the rule, to calculate the proportion of patients with PE in the probability categories, the area under the ROC curve and the incidence of venous thromboembolism during follow-up. We compared these measures with those for a modified and a simplified version of the decision rule. In the replication, the odds ratios in the logistic regression model were found to be lower for each of the seven individual variables (p = 0.02) but the proportion of patients with PE in the probability categories in our study group were comparable to those in the original derivation and validation groups. The area under the ROC of the original, modified and simplified decision rule was similar: 0.74 (p = 0.99; p = 0.07). The venous thromboembolism incidence at three months in the group of patients with a Wells score < or = 4 and a normal D-dimer was 0.5%, versus 0.3% with a modified rule and 0.5% with a simplified rule. The proportion of patients safely excluded for PE was 32%, versus 31% and 30%, respectively. This study further validates the diagnostic utility of the Wells rule and indicates that the scoring system can be simplified to one point for each variable.

Accuracy of clinical decision rule, D‐dimer and spiral computed tomography in patients with malignancy, previous venous thromboembolism, COPD or heart failure and in older patients with suspected pulmonary embolism

Summary.  Background: The diagnostic work‐up of patients with suspected pulmonary embolism (PE) has been optimized and simplified by the use of clinical decision rules (CDR), D‐dimer (DD) testing and spiral computed tomography (s‐CT). Whether this strategy is equally safe and efficient in specific subgroups of patients is evaluated in this study. Methods: A diagnostic strategy including a CDR, DD test and s‐CT was evaluated in patients with malignancy, previous venous thromboembolism (VTE), chronic obstructive pulmonary disease or heart failure and in older patients. PE was ruled out by either an unlikely CDR and a normal DD or a s‐CT negative for PE. The safety of these tests was assessed by the 3‐month incidence rate of symptomatic VTE in those without PE at baseline. The efficiency was evaluated by calculating the numbers needed to test for the different subgroups. Results: The venous thromboembolic incidence rate after the combination of an unlikely CDR and a normal DD varied from 0% (95% CI: 0–7.9%) in the 482 patients older than 75 years of age to 2% (95% CI: 0.05–10.9%) in the 474 patients with a malignancy. For s‐CT these incidences varied from 0.3% to 1.8%. The number needed to test in order to rule out one patient from PE with the studied strategy was highest in cancer patients and in the elderly patients (approximately 10). Conclusion: It appears to be safe to rule out PE by either the combination of an unlikely CDR and a normal DD or by a negative s‐CT in various subgroups of patients with suspected PE. However, the clinical usefulness of the CDR in combination with the DD as the initial step in the diagnostic process varied among these patient groups.

The incidence and prognostic significance of elevated cardiac troponins in patients with submassive pulmonary embolism.

Summary.  Although the incidence and prognostic significance of elevated cardiac troponins are known in patients with massive pulmonary embolism (PE), few studies have addressed this issue in patients with hemodynamically stable, submassive PE, who comprise the majority of patients presenting with PE. This prospective cohort study was, therefore, designed to determine the incidence and prognostic significance of elevated cardiac troponins in patients with submassive PE. Consecutive patients with acute, symptomatic, submassive PE that was confirmed by objective diagnostic testing were studied. All patients received treatment with either unfractionated heparin or fondaparinux followed by a coumarin derivative and underwent clinical follow‐up for 3 months. Cardiac troponin I (cTnI) levels were measured within 24 h of clinical presentation. An elevated cTnI was defined as > 0.5 μg L−1 and indicated myocardial injury. Major myocardial injury, that is associated with myocardial infarction, was defined by a cTnI > 2.3 μg L−1. The clinical outcomes were recurrent venous thromboembolism and all‐cause death. In 458 patients with submassive PE, the incidence of cTnI > 0.5 μg L−1 was 13.5%[95% confidence interval (CI): 10.4–16.7], and the incidence of cTnI > 2.3 μg L−1 was 3.5% (95% CI: 2.0–5.6). An elevated cTnI > 0.5 μg L−1 was associated with an increased risk of all‐cause death [odds ratio (OR) = 3.5; 95% CI: 1.0–11.9], but did not appear to confer an increased risk of recurrent venous thromboembolism (OR = 1.1; 95% CI: 0.2–4.9). In patients who present with submassive PE, an elevated cTnI occurs in about one in seven patients and is associated with a 3.5‐fold increased risk of all‐cause death.

Diagnostic strategy using a modified clinical decision rule and D-dimer test to rule out pulmonary embolism in elderly in- and outpatients

Excluding or confirming pulmonary embolism remains a diagnostic challenge. In elderly patients pulmonary embolism is associated with substantial co-morbidity and mortality, and many elderly patients with suspected pulmonary embolism are inpatients. The safety and efficacy of the combination of a clinical probability (CDR) and d-dimer test in excluding pulmonary embolism in this group is unclear. We retrospectively analysed data of two prospective studies of consecutive in-and outpatients with suspected pulmonary embolism. The patients were categorized into three age groups: <65 years, 65-75 years and >75 years. The sensitivity, negative predictive value and the proportion of patients with the combination of a non-high CDR score according to Wells (< or = 4) and a normal d-dimer result were calculated for each group. In 747 consecutive patients with suspected pulmonary embolism, sensitivity and negative predictive value of a non-high CDR and a normal d-dimer result in outpatients (n=538) of all age categories (<65 years, 65-75 years and >75 years) were both 100%. These tests were, however, less reliable for inpatients(n=209), irrespective of their age (sensitivity 91% [ CI: 79-98%], negative predictive value 88 % [CI: 74-96%]. The proportion of both in-and outpatients >75 years with a non-high CDR and a normal d-dimer concentration was only 14%, whereas this was 22% in patients 65-75 years and 41% among in-and outpatients <65 years, respectively. In elderly outpatients the combination of a non-high CDR and a normal d-dimer result is a safe strategy to rule out pulmonary embolism. However, in inpatients this algorithm is not reliable to safely exclude pulmonary embolism. In addition, the proportion of patients >65 years in which this strategy excludes pulmonary embolism is markedly lower compared to younger patients.

The Importance of Clinical Probability Assessment in Interpreting a Normal d-Dimer in Patients With Suspected Pulmonary Embolism

BACKGROUND The d-dimer test is widely applied in the diagnostic workup of patients with suspected pulmonary embolism (PE). The objective of this study was to investigate how often the d-dimer test fails when clinical probability is not taken into account. METHODS We used data collected in 1,722 consecutive patients with clinically suspected PE to analyze the 3-month venous thromboembolism (VTE) rate in all patients with a normal d-dimer concentration and separately for patients who have a normal d-dimer concentration with an unlikely or likely clinical probability for PE, as assessed by the Wells clinical decision rule. RESULTS The 3-month VTE rate in all patients with a normal d-dimer concentration (n = 563) was 2.3% (95% confidence interval [CI], 1.4 to 3.9%). In the patients with an unlikely probability of PE (n = 477), VTE was confirmed in 1.1% of the patients with a normal d-dimer concentration (95% CI, 0.4 to 2.4%). In those patients with a likely clinical probability of PE (n = 86), VTE was confirmed in 9.3% of the patients with a normal d-dimer concentration (95% CI, 4.8 to 17.3%). The difference in VTE incidence between patients with unlikely and likely clinical probabilities of PE was significant (p < 0.001). CONCLUSIONS Our findings indicate that it is of utmost importance to first examine the patient and assess the clinical probability, after which the d-dimer concentration can be taken into account, in order to prevent physicians from being influenced by a normal d-dimer test result when they evaluate the clinical probability of PE. Patients with a likely clinical probability should undergo further testing, regardless of the d-dimer test outcome.

A simple diagnostic strategy in hospitalized patients with clinically suspected pulmonary embolism

Objectives.  Diagnostic strategies in patients with suspected pulmonary embolism have been extensively studied in outpatients; their value in hospitalized patients has not been well established. Our aim was to determine the safety and clinical utility of a simple diagnostic strategy in hospitalized patients with suspected pulmonary embolism.

Brain natriuretic peptide in hemodynamically stable acute pulmonary embolism

Summary.  Background: Controversy exists about the indication of thrombolytic therapy in the subgroup of hemodynamically stable patients with acute pulmonary embolism (PE) and right ventricular dysfunction. Brain natriuretic peptide (BNP) is excreted from the cardiac ventricles in response to cardiomyocyte stretch and can be measured with an easy‐to‐perform blood test. Objective: The objective of this study was to determine the predictive value of elevated BNP levels for early recurrent venous thromboembolism with or without fatal outcome in hemodynamically stable patients with acute PE. In addition, we assessed the potential clinical consequences of initiating thrombolytic therapy based on the BNP levels alone. Methods: A nested case–control study was performed within the framework of a large randomized‐controlled trial totalling 2213 hemodynamically stable patients with confirmed acute, symptomatic PE. Ninety patients experienced a fatal or non‐fatal recurrent venous thromboembolism during the first 3 months of follow‐up (cases); Two hundred and ninety‐seven patients with uneventful follow‐up served as controls. Blood for BNP levels was obtained at referral and assayed in a central laboratory. Results: Cases had significantly higher mean baseline BNP levels (P = 0.0002). The odds ratio (OR) for every logarithmic (log) unit increase in BNP concentration was 2.4 (95% CI: 1.5–3.7). A BNP cut‐off level of 1.25 pmol L−1 [the optimal point on the receiver‐operating characteristic (ROC) curve] was associated with a sensitivity and specificity of 60% and 62%, respectively. In theory, for every patient correctly receiving thrombolytic therapy at this cut‐off, 16 patients will receive this therapy unnecessarily. Conclusions: Brain natriuretic peptide level at presentation is significantly associated with early (fatal) recurrent venous thromboembolism in hemodynamically stable patients with acute PE. However, this relationship appears clinically insufficient to guide the initiation of thrombolytic therapy.

Biomarkers in pulmonary embolism.

Purpose of review Controversy exists about the precise role of thrombolytic therapy in normotensive patients with pulmonary embolism. To resolve this controversy two major questions must be addressed. First, can a subgroup of normotensive pulmonary embolism patients with a high risk for adverse outcomes, such as in-hospital mortality or early recurrent venous thromboembolism, be identified? Second, is there convincing evidence that the benefits of more aggressive therapy counterbalance its risks? Troponin I and T as well as brain natriuretic peptide (BNP) have recently been introduced as promising tools in the risk assessment of patients with pulmonary embolism. Recent findings The studies in series of patients with pulmonary embolism showed prevalences of elevated cardiac biomarkers of 16 to 84%. Positive predictive values for in-hospital mortality varied from 6 to 44%, whereas negative predictive values for uneventful outcome were above 93% in all studies. Summary Although a correlation between elevated biomarkers and in-hospital mortality in pulmonary embolism patients is present in most of the studies, the positive predictive value appears to be insufficient to extend the indication for thrombolytic therapy to all patients with elevated biomarkers. Future research is necessary to show whether combining different biomarkers with echocardiography is more useful.