Mareike Lankeit

Fibrinolysis for patients with intermediate-risk pulmonary embolism

BACKGROUND The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism

AIMS To assess the role of cardiac troponin T (cTnT) levels on admission using a new, highly sensitive assay (hsTnT) in the risk assessment of normotensive patients with acute pulmonary embolism (PE). METHODS AND RESULTS We prospectively studied 156 consecutive normotensive patients with confirmed PE. The prognostic value of hsTnT at baseline was compared with the conventional cTnT troponin assay and with N-terminal pro-brain natriuretic peptide concentrations. Long-term follow-up was available for 153 patients (98.1%). Highly sensitive troponin T values ranged from 0.001 to 357.2 pg/mL [median 27.2 (25th-75th percentile 9.4-69.4) pg/mL]. Overall, 100 patients (64%) had hsTnT > or =14 pg/mL. Baseline hsTnT was higher in patients with an adverse 30-day outcome (> or =1: death, need for catecholamines, endotracheal intubation, or cardiopulmonary resuscitation) compared with an uncomplicated course [71.7 (35.5-117.9) vs. 26.4 (9.2-68.2) pg/mL; P = 0.027]. The cut-off value of 14 pg/mL showed an excellent prognostic sensitivity and negative predictive value (both 100%). In comparison, as many as 50% of the patients with an adverse early outcome would have been misclassified as low risk by cTnT (cut-off 0.03 ng/mL). Logistic regression indicated a two-fold increase in the risk of an adverse outcome for each increase of hsTnT by 1SD of the natural logarithm (P = 0.037). Patients with elevated hsTnT levels had a reduced probability of long-term survival (P = 0.029 by log-rank); by Coxs regression analysis, hsTnT was the only laboratory biomarker predicting an elevated risk of death over the long term. CONCLUSION Highly sensitive troponin T assays may be capable of improving risk stratification of non-high-risk PE.

Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test

AIMS In patients with acute pulmonary embolism (PE), right ventricular dysfunction at echocardiography is associated with increased in-hospital mortality. The aims of this study in patients with acute PE were to identify a sensitive and simple criterion for right ventricular dysfunction at multidetector computed tomography (MDCT) using echocardiography as the reference standard and to evaluate the predictive value of the identified MDCT criterion for in-hospital death or clinical deterioration. METHODS AND RESULTS Right ventricular dysfunction at MDCT was defined as the right-to-left ventricular dimensional ratio and was centrally assessed by a panel unaware of clinical and echocardiographic data. A right-to-left ventricular dimensional ratio ≥0.9 at MDCT had a 92% sensitivity for right ventricular dysfunction [95% confidence interval (CI) 88-96]. Overall, 457 patients were included in the outcome study: 303 had right ventricular dysfunction at MDCT. In-hospital death or clinical deterioration occurred in 44 patients with and in 8 patients without right ventricular dysfunction at MDCT (14.5 vs. 5.2%; P< 0.004). The negative predictive value of right ventricular dysfunction for death due to PE was 100% (95% CI 98-100). Right ventricular dysfunction at MDCT was an independent predictor for in-hospital death or clinical deterioration in the overall population [hazard ratio (HR) 3.5, 95% CI 1.6-7.7; P= 0.002] and in haemodynamically stable patients (HR 3.8, 95% CI 1.3-10.9; P= 0.007). CONCLUSION In patients with acute PE, MDCT might be used as a single procedure for diagnosis and risk stratification. Patients without right ventricular dysfunction at MDCT have a low risk of in-hospital adverse outcome.

Predictive Value of the High-Sensitivity Troponin T Assay and the Simplified Pulmonary Embolism Severity Index in Hemodynamically Stable Patients With Acute Pulmonary Embolism A Prospective Validation Study

Background— The new, high-sensitivity troponin T (hsTnT) assay may improve risk stratification of normotensive patients with acute pulmonary embolism (PE). We externally validated the prognostic value of hsTnT, and of the simplified Pulmonary Embolism Severity Index (sPESI), in a large multicenter cohort. Methods and Results— We prospectively examined 526 normotensive patients with acute PE; of those, 31 (5.9%) had an adverse 30-day outcome. The predefined hsTnT cutoff value of 14 pg/mL was associated with a high prognostic sensitivity and negative predictive value, comparable to those of the sPESI. Both hsTnT ≥14 pg/mL (OR, 4.97 [95% CI, 1.71–14.43]; P=0.003) and sPESI ≥1 point(s) (OR, 9.51 [2.24–40.29]; P=0.002) emerged, besides renal insufficiency (OR, 2.97 [1.42–6.22]; P=0.004), as predictors of early death or complications; in a multivariable model, they remained independent predictors of outcome (P=0.044 and 0.012, respectively). A total of 127 patients (24.1%) were identified as low risk by a sPESI of 0 and hsTnT <14 pg/mL; none of them had an adverse 30-day outcome. During 6-month follow-up, 52 patients (9.9%) died. Kaplan-Meier analysis illustrated that patients with hsTnT ≥14 pg/mL (P=0.001) and those with sPESI ≥1 (P<0.001) had a decreased probability of 6-month survival. Patients with sPESI of 0 and hsTnT <14 pg/mL at baseline had a 42% reduction in the risk of dying (hazard ratio, 0.58 [0.01–0.42]; P=0.005). Conclusions— The hsTnT assay and the sPESI improve risk stratification of acute PE. Combination of both modalities may yield additive prognostic information and particularly identify possible candidates for out-of-hospital treatment.

Growth Differentiation Factor-15 for Prognostic Assessment of Patients with Acute Pulmonary Embolism

RATIONALE Growth differentiation factor (GDF)-15 is a cytokine induced in the heart after ischemia or pressure overload. Circulating levels of GDF-15 provide independent prognostic information in patients with acute coronary syndromes or heart failure. OBJECTIVES We investigated the prognostic value of GDF-15 in acute pulmonary embolism. METHODS In a prospective cohort study, plasma levels of GDF-15 were determined by immunoradiometric assay in 123 consecutive patients with confirmed acute pulmonary embolism. MEASUREMENTS AND MAIN RESULTS GDF-15 concentrations on admission ranged from 553 to 47,274 ng/L; 101 patients (82%) had GDF-15 levels above the upper limit of normal (1,200 ng/L). Patients who experienced pulmonary embolism-related complications during the first 30 days had higher baseline levels of GDF-15 (median, 6,039 [25th to 75th percentiles, 2,778 to 19,772] ng/L) compared with those with an uncomplicated course (median, 2,036 [25th to 75th percentiles, 1,279 to 3,176] ng/L; P < 0.001). By multivariable logistic regression analysis, which included clinical characteristics, cardiac biomarkers (troponin T and NT-proBNP [N-terminal propeptide of B-type natriuretic peptide]), and echocardiographic findings, GDF-15 emerged as an independent predictor of a complicated 30-day outcome (P = 0.033). The c-statistic for GDF-15 was 0.84 (95% confidence interval, 0.76-0.90), as compared with 0.72 for cardiac troponin T, and 0.65 for NT-proBNP. The ability of troponin T, NT-proBNP, and echocardiographic findings of right ventricular dysfunction to predict the risk of a complicated 30-day outcome was enhanced by GDF-15. Furthermore, multivariable Cox regression identified baseline levels of GDF-15 as an independent predictor of long-term mortality (P < 0.001). CONCLUSIONS GDF-15 is a promising new biomarker for risk stratification of pulmonary embolism.

Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis

Aim Thrombolytic therapy induces faster clot dissolution than anticoagulation in patients with acute pulmonary embolism (PE) but is associated with an increased risk of haemorrhage. We reviewed the risks and benefits of thrombolytic therapy in the management of patients with acute PE. Methods and results We systematically reviewed randomized controlled studies comparing systemic thrombolytic therapy plus anticoagulation with anticoagulation alone in patients with acute PE. Fifteen trials involving 2057 patients were included in our meta-analysis. Compared with heparin, thrombolytic therapy was associated with a significant reduction of overall mortality (OR; 0.59, 95% CI: 0.36–0.96). This reduction was not statistically significant after exclusion of studies including high-risk PE (OR; 0.64, 95% CI: 0.35–1.17). Thrombolytic therapy was associated with a significant reduction in the combined endpoint of death or treatment escalation (OR: 0.34, 95% CI: 0.22–0.53), PE-related mortality (OR: 0.29; 95% CI: 0.14–0.60) and PE recurrence (OR: 0.50; 95% CI: 0.27–0.94). Major haemorrhage (OR; 2.91, 95% CI: 1.95–4.36) and fatal or intracranial bleeding (OR: 3.18, 95% CI: 1.25–8.11) were significantly more frequent among patients receiving thrombolysis. Conclusions Thrombolytic therapy reduces total mortality, PE recurrence, and PE-related mortality in patients with acute PE. The decrease in overall mortality is, however, not significant in haemodynamically stable patients with acute PE. Thrombolytic therapy is associated with an increase of major and fatal or intracranial haemorrhage.

Elevated heart-type fatty acid-binding protein levels on admission predict an adverse outcome in normotensive patients with acute pulmonary embolism.

OBJECTIVES We assessed the predictive value of heart-type fatty acid-binding protein (H-FABP) in normotensive patients with acute pulmonary embolism (PE). BACKGROUND Risk stratification of initially normotensive patients with PE on the basis of right ventricular dysfunction or injury remains controversial. Previous studies investigating biomarkers or imaging modalities included unselected patients, some of whom presented with cardiogenic shock. METHODS We included 126 consecutive normotensive patients with confirmed PE. Complicated 30-day outcome was defined as death, resuscitation, intubation, or use of catecholamines. Long-term survival was assessed by follow-up clinical examination. RESULTS During the first 30 days, 9 (7%) patients suffered complications. These patients had higher baseline H-FABP values (median, 11.2 ng/ml [interquartile range: 8.0 to 36.8 ng/ml]) compared with patients with an uncomplicated course (3.4 ng/ml [2.1 to 4.9 ng/ml]; p < 0.001). H-FABP values were above the calculated (by receiver operating characteristic curve analysis) cutoff value of 6 ng/ml in 29 patients. Eight (28%) of them suffered complications versus 1 of 97 patients with low H-FABP (negative predictive value, 99%; p < 0.001). By logistic regression, elevated (> or =6 ng/ml) H-FABP was associated with a 36.6-fold increase in the death or complication risk. The combination of H-FABP with tachycardia was a particularly useful prognostic indicator. H-FABP also predicted long-term mortality over 499 (interquartile range: 204 to 1,166) days (hazard ratio: 3.6; 95% confidence interval: 1.6 to 8.2; p = 0.003). CONCLUSIONS The H-FABP might be a useful biomarker for risk stratification of normotensive patients with acute PE.

Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk.

Reduced numbers of regulatory T (Treg) cells have been observed in visceral adipose tissue of obese mice and humans. However, it is unknown whether human obesity affects circulating Treg cells and whether their number is associated with markers of systemic inflammation or glucose intolerance.

Identification of intermediate-risk patients with acute symptomatic pulmonary embolism

The identification of normotensive patients with acute pulmonary embolism (PE) at high risk of adverse PE-related clinical events (i.e. intermediate-risk group) is a major challenge. We combined individual patient data from six studies involving 2874 normotensive patients with PE. We developed a prognostic model for intermediate-risk PE based on the clinical presentation and the assessment of right ventricular dysfunction and myocardial injury. We used a composite of PE-related death, haemodynamic collapse or recurrent PE within 30 days of follow-up as the main outcome measure. The primary outcome occurred in 198 (6.9%) patients. Predictors of complications included systolic blood pressure 90–100 mmHg (adjusted odds ratio (aOR) 2.45, 95% CI 1.50–3.99), heart rate ≥110 beats per min (aOR 1.87, 95% CI 1.31–2.69), elevated cardiac troponin (aOR 2.49, 95% CI 1.71–3.69) and right ventricular dysfunction (aOR 2.28, 95% CI 1.58–3.29). We used these variables to construct a multidimensional seven-point risk index; the odds ratio for complications per one-point increase in the score was 1.55 (95% CI 1.43–1.68; p<0.001). The model identified three stages (I, II and III) with 30-day PE-related complication rates of 4.2%, 10.8% and 29.2%, respectively. In conclusion, a simple grading system may assist clinicians in identifying intermediate-risk PE. A simple grading system to identify intermediate-risk pulmonary embolism http://ow.ly/uItnL

Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism

The optimal N-terminal pro-brain natriuretic peptide (NT-proBNP) cut-off value for risk stratification of pulmonary embolism remains controversial. In this study we validated and compared different proposed NT-proBNP cut-off values in 688 normotensive patients with pulmonary embolism. During the first 30 days, 28 (4.1%) patients reached the primary outcome (pulmonary embolism-related death or complications) and 29 (4.2%) patients died. Receiver operating characteristic analysis yielded an area under the curve of 0.70 (0.60–0.80) for NT-proBNP. A cut-off value of 600 pg·mL−1 was associated with the best prognostic performance (sensitivity 86% and specificity 50%) and the highest odds ratio (6.04 (95% CI 2.07–17.59), p=0.001) compared to the cut-off values of 1000, 500 or 300 pg·mL−1. Using multivariable logistic regression analysis, NT-proBNP ≥600 pg·mL−1 had a prognostic impact on top of that of the simplified Pulmonary Embolism Severity Index and right ventricular dysfunction on echocardiography (OR 4.27 (95% CI 1.22–15.01); p=0.024, c-index 0.741). The use of a stepwise approach based on the simplified Pulmonary Embolism Severity Index, NT-proBNP ≥600 pg·mL−1 and echocardiography helped optimise risk assessment. Our findings confirm the prognostic value of NT-proBNP and suggest that a cut-off value of 600 pg·mL−1 is most appropriate for risk stratification of normotensive patients with pulmonary embolism. NT-proBNP should be used in combination with a clinical score and an imaging procedure for detecting right ventricular dysfunction. Stepwise approach based on sPESI, NT-proBNP and echocardiography for pulmonary embolism risk stratification http://ow.ly/tsMud