Diagnostic efficacy of ECG-derived ventricular gradient for the detection of chronic thromboembolic pulmonary hypertension in patients with acute pulmonary embolism.

INTRODUCTION: Application of the chronic thromboembolic pulmonary hypertension (CTEPH) rule out criteria (manual electrocardiogram [ECG] reading and N-terminal pro-brain natriuretic peptide [NTproBNP] test) can rule out CTEPH in pulmonary embolism (PE) patients with persistent dyspnea (InShape II algorithm). Increased pulmonary pressure may also be identified using automated ECG-derived ventricular gradient optimized for right ventricular pressure overload (VG-RVPO). METHOD: A predefined analysis of the InShape II study was performed. The diagnostic performance of the VG-RVPO for the detection of CTEPH and the incremental diagnostic value of the VG-RVPO as new rule-out criteria in the InShape II algorithm were evaluated. RESULTS: 60 patients were included; 5 (8.3%) were ultimately diagnosed with CTEPH. The mean baseline VG-RVPO (at time of PE diagnosis) was -18.12 mV·ms for CTEPH patients and - 21.57 mV·ms for non-CTEPH patients (mean difference 3.46 mV·ms [95%CI -29.03 to 35.94]). The VG-RVPO (after 3-6 months follow-up) normalized in patients with and without CTEPH, without a clear between-group difference (mean Δ VG-RVPO of -8.68 and - 8.42 mV·ms respectively; mean difference of -0.25 mV·ms, [95%CI -12.94 to 12.44]). The overall predictive accuracy of baseline VG-RVPO, follow-up RVPO and Δ VG-RVPO for CTEPH was moderate to poor (ROC AUC 0.611, 0.514 and 0.539, respectively). Up to 76% of the required echocardiograms could have been avoided with VG-RVPO criteria replacing the InShape II rule-out criteria, however at cost of missing up to 80% of the CTEPH diagnoses. CONCLUSION: We could not demonstrate (additional) diagnostic value of VG-RVPO as standalone test or as on top of the InShape II algorithm.

Prediction of chronic thromboembolic pulmonary hypertension with standardised evaluation of initial computed tomography pulmonary angiography performed for suspected acute pulmonary embolism.

OBJECTIVES: Closer reading of computed tomography pulmonary angiography (CTPA) scans of patients presenting with acute pulmonary embolism (PE) may identify those at high risk of developing chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to validate the predictive value of six radiological predictors that were previously proposed. METHODS: Three hundred forty-one patients with acute PE were prospectively followed for development of CTEPH in six European hospitals. Index CTPAs were analysed post hoc by expert chest radiologists blinded to the final diagnosis. The accuracy of the predictors using a predefined threshold for 'high risk' (≥ 3 predictors) and the expert overall judgment on the presence of CTEPH were assessed. RESULTS: CTEPH was confirmed in nine patients (2.6%) during 2-year follow-up. Any sign of chronic thrombi was already present in 74/341 patients (22%) on the index CTPA, which was associated with CTEPH (OR 7.8, 95%CI 1.9-32); 37 patients (11%) had ≥ 3 of 6 radiological predictors, of whom 4 (11%) were diagnosed with CTEPH (sensitivity 44%, 95%CI 14-79; specificity 90%, 95%CI 86-93). Expert judgment raised suspicion of CTEPH in 27 patients, which was confirmed in 8 (30%; sensitivity 89%, 95%CI 52-100; specificity 94%, 95%CI 91-97). CONCLUSIONS: The presence of ≥ 3 of 6 predefined radiological predictors was highly specific for a future CTEPH diagnosis, comparable to overall expert judgment, while the latter was associated with higher sensitivity. Dedicated CTPA reading for signs of CTEPH may therefore help in early detection of CTEPH after PE, although in our cohort this strategy would not have detected all cases. KEY POINTS: • Three expert chest radiologists re-assessed CTPA scans performed at the moment of acute pulmonary embolism diagnosis and observed a high prevalence of chronic thrombi and signs of pulmonary hypertension. • On these index scans, the presence of ≥ 3 of 6 predefined radiological predictors was highly specific for a future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), comparable to overall expert judgment. • Dedicated CTPA reading for signs of CTEPH may help in early detection of CTEPH after acute pulmonary embolism.

Identification of chronic thromboembolic pulmonary hypertension on CTPAs performed for diagnosing acute pulmonary embolism depending on level of expertise.

BACKGROUND: Expert reading often reveals radiological signs of chronic thromboembolic pulmonary hypertension (CTEPH) or chronic PE on computed tomography pulmonary angiography (CTPA) performed at the time of acute pulmonary embolism (PE) presentation preceding CTEPH. Little is known about the accuracy and reproducibility of CTPA reading by radiologists in training in this setting. OBJECTIVES: To evaluate 1) whether signs of CTEPH or chronic PE are routinely reported on CTPA for suspected PE; and 2) whether CTEPH-non-expert readers achieve comparable predictive accuracy to CTEPH-expert radiologists after dedicated instruction. METHODS: Original reports of CTPAs demonstrating acute PE in 50 patients whom ultimately developed CTEPH, and those of 50 PE who did not, were screened for documented signs of CTEPH. All scans were re-assessed by three CTEPH-expert readers and two CTEPH-non-expert readers (blinded and independently) for predefined signs and overall presence of CTEPH. RESULTS: Signs of chronic PE were mentioned in the original reports of 14/50 cases (28%), while CTEPH-expert radiologists had recognized 44/50 (88%). Using a standardized definition (≥3 predefined radiological signs), moderate-to-good agreement was reached between CTEPH-non-expert readers and the experts' consensus (k-statistics 0.46; 0.61) at slightly lower sensitivities. The CTEPH-non-expert readers had moderate agreement on the presence of CTEPH (κ-statistic 0.38), but both correctly identified most cases (80% and 88%, respectively). CONCLUSIONS: Concomitant signs of CTEPH were poorly documented in daily practice, while most CTEPH patients were identified by CTEPH-non-expert readers after dedicated instruction. These findings underline the feasibility of achieving earlier CTEPH diagnosis by assessing CTPAs more attentively.

Non-invasive early exclusion of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: the InShape II study.

BACKGROUND: The current diagnostic delay of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE) is unacceptably long, causing loss of quality-adjusted life years and excess mortality. Validated screening strategies for early CTEPH diagnosis are lacking. Echocardiographic screening among all PE survivors is associated with overdiagnosis and cost-ineffectiveness. We aimed to validate a simple screening strategy for excluding CTEPH early after acute PE, limiting the number of performed echocardiograms. METHODS: In this prospective, international, multicentre management study, consecutive patients were managed according to a screening algorithm starting 3 months after acute PE to determine whether echocardiographic evaluation of pulmonary hypertension (PH) was indicated. If the 'CTEPH prediction score' indicated high pretest probability or matching symptoms were present, the 'CTEPH rule-out criteria' were applied, consisting of ECG reading and N-terminalpro-brain natriuretic peptide. Only if these results could not rule out possible PH, the patients were referred for echocardiography. RESULTS: 424 patients were included. Based on the algorithm, CTEPH was considered absent in 343 (81%) patients, leaving 81 patients (19%) referred for echocardiography. During 2-year follow-up, one patient in whom echocardiography was deemed unnecessary by the algorithm was diagnosed with CTEPH, reflecting an algorithm failure rate of 0.29% (95% CI 0% to 1.6%). Overall CTEPH incidence was 3.1% (13/424), of whom 10 patients were diagnosed within 4 months after the PE presentation. CONCLUSIONS: The InShape II algorithm accurately excluded CTEPH, without the need for echocardiography in the overall majority of patients. CTEPH was identified early after acute PE, resulting in a substantially shorter diagnostic delay than in current practice.

Correction: Quality of initial anticoagulant treatment and risk of CTEPH after acute pulmonary embolism.

[This corrects the article DOI: 10.1371/journal.pone.0232354.].

Quality of initial anticoagulant treatment and risk of CTEPH after acute pulmonary embolism.

BACKGROUND: The pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is not fully understood. Poor-quality anticoagulation may contribute to a higher risk of CTEPH after acute pulmonary embolism (PE), partly explaining the transition from acute PE to CTEPH. We assessed the association between the time in therapeutic range (TTR) of vitamin-K antagonist (VKA) treatment and incidence of CTEPH after a PE diagnosis. METHODS: Case-control study in which the time spent in, under and above therapeutic range was calculated in 44 PE patients who were subsequently diagnosed with CTEPH (cases). Controls comprised 150 consecutive PE patients in whom echocardiograms two years later did not show pulmonary hypertension. All patients were treated with VKA for at least 6 months after the PE diagnosis. Time in (TTR), under and above range were calculated. Mean differences between cases and controls were estimated by linear regression. RESULTS: Mean TTR during the initial 6-month treatment period was 72% in cases versus 78% in controls (mean difference -6%, 95%CI -12 to -0.1), mainly explained by more time above the therapeutic range in the cases. Mean difference of time under range was 0% (95%CI -6 to 7) and 2% (95CI% -3 to 7) during the first 3 and 6 months, respectively. In a multivariable model, adjusted odds ratios (ORs) for CTEPH were around unity considering different thresholds for 'poor anticoagulation', i.e. TTR <50%, <60% and <70%. CONCLUSION: Subtherapeutic initial anticoagulation was not more prevalent among PE patients diagnosed with CTEPH than in those who did not develop CTEPH.

Usefulness of standard computed tomography pulmonary angiography performed for acute pulmonary embolism for identification of chronic thromboembolic pulmonary hypertension: results of the InShape III study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is often diagnosed after a long delay, even though signs may already be present on the computed tomography pulmonary angiogram (CTPA) used to diagnose a preceding acute pulmonary embolism (PE). In this setting of suspected acute PE, we evaluated the diagnostic accuracy of dedicated CTPA reading for the diagnosis of already existing CTEPH. METHODS: Three blinded expert radiologists scored radiologic signs of CTEPH on initial CTPA scans with confirmed acute PE in 50 patients who were subsequently diagnosed with CTEPH during follow-up (cases), and in 50 patients in whom sequential echocardiograms performed >2 years after the acute PE diagnosis did not show any signs of pulmonary hypertension (controls). All 50 control index CTPA scans had signs of right ventricular (RV) overload. Sensitivity and specificity of expert CTPA reading was calculated, and best-predicting radiologic parameters were identified. RESULTS: The overall expert reading yielded a sensitivity of 72% (95% confidence interval [CI] 58%-84%) and a specificity of 94% (95% CI 83%-99%) for CTEPH diagnosis. Multivariate analysis identified 6 radiologic parameters as independent predictors: intravascular webs; pulmonary artery retraction or dilatation; bronchial artery dilatation; right ventricular (RV) hypertrophy; and interventricular septum flattening. The presence of 3 or more these parameters was associated with a sensitivity of 70% (95% CI 55%-82%), a specificity of 96% (95% CI 86%-100%), and a c-statistic of 0.92. CONCLUSIONS: Standardized reading of CTPA scans performed for acute PE can be useful for the diagnosis of CTEPH when structured identification of 6 characteristics is employed during interpretation. The use of this strategy may help reduce diagnostic delay of CTEPH.

Post-thrombotic syndrome: Short and long-term incidence and risk factors.

BACKGROUND: The reported incidences of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT) vary. Further, PTS symptom development over time and its long-term incidence are unknown. METHODS: Patients included in the MEGA study were interviewed at 1 year and completed a questionnaire at 8 years of follow-up regarding symptoms and signs of PTS based on the Villalta score after a first DVT diagnosis. The cumulative incidence of PTS at 0-1 and 1-8 year, changes in PTS classification and the effect of possible clinical and laboratory risk factors were determined. RESULTS: After 1 year, 361 out of 1657 patients diagnosed with DVT were classified as having PTS, for a 0-1 year cumulative incidence of 21.8% (95%CI 19.9-23.8), out of whom 92 (5.6%) had severe PTS. After 8 years 633 patients without previous PTS completed the second questionnaire, of whom 44 were classified as having PTS, for a 1-8 year cumulative incidence of 7% (95%CI 5.2-9.2); of these 13 (2.1%) were classified as severe PTS. During follow-up PTS complaints improved in 69% and worsened in 7% of patients. At 1 year, risk factors were female sex (RR 1.5; 95%CI 1.2-1.9) and obesity (RR 1.5; 95%CI 1.2-7.9), with the same effect sizes at 8 years. Provoked/unprovoked DVT, thrombus location, pregnancy, hormone use and several laboratory parameters did not affect risk of PTS, either at 1 or 8 years. CONCLUSION: The incidence of PTS remained substantial up to 8 years after a first DVT. Symptoms improved in a large proportion of the cases. The short and long term risks were highest in women and obese patients.

Fatal recurrent VTE after anticoagulant treatment for unprovoked VTE: a systematic review.

Current guidelines recommend long-term anticoagulant therapy in patients with unprovoked venous thromboembolism (VTE). The risk of fatal recurrent VTE after treatment discontinuation (versus that of fatal bleeding during anticoagulation) is of particular relevance in the decision to continue or stop anticoagulation after the first 3 months. Our primary aim was to provide a point-estimate of the yearly rate of fatal recurrent VTE and VTE case-fatality rate in patients with unprovoked VTE after anticoagulation cessation. Data were extracted from both randomised controlled trials and observational studies published before May 1, 2017. The pooled fatality rates were calculated using a random-effects model. 18 studies with low-to-moderate bias were included in the primary analysis, totalling 6758 patients with a median (range) follow-up duration of 2.2 (1-5) years. After anticoagulation cessation, the weighted pooled rate of VTE recurrence was 6.3 (95% CI 5.4-7.3) per 100 patient-years and the weighted pooled rate of fatal recurrent VTE was 0.17 (95% CI 0.047-0.33) per 100 patient-years, for a case-fatality rate of 2.6% (95% CI 0.86-5.0). These numbers are a solid benchmark for comparison to the risks associated with long-term anticoagulation treatment for the decision on the optimal duration of treatment of patients with unprovoked VTE.

Differential impact of syncope on the prognosis of patients with acute pulmonary embolism: a systematic review and meta-analysis.

Aims: Controversial reports exist in the literature regarding the prognostic role and therapeutic implications of syncope in patients with acute pulmonary embolism (PE). We conducted a systematic review and meta-analysis to investigate the association between syncope and short-term adverse outcomes, taking into account the presence or absence of haemodynamic compromise at acute PE presentation. Methods and results: The literature search identified 1664 studies, 29 of which were included for a total of 21 956 patients with PE (n = 3706 with syncope). Syncope was associated with higher prevalence of haemodynamic instability [odds ratio (OR) 3.50; 95% confidence interval (CI) 2.67-4.58], as well as with echocardiographic signs of right ventricular (RV) dysfunction (OR 2.10; CI 1.60-2.77) at presentation. Patients with syncope had a higher risks of all-cause early (either in-hospital or within 30 days) death (OR 1.73; CI 1.22-2.47) and PE-related 30-day adverse outcomes (OR 2.00; CI 1.11-3.60). The absolute risk difference (95% CI) for all-cause death was +6% (+1% to +10%) in studies including unselected patients, but it was -1% (-2% to +1%) in studies restricted to normotensive patients. We observed no prognostic impact of syncope in studies with a lower score at formal quality assessment and in those conducted retrospectively. Conclusion: Syncope as a manifestation of acute PE was associated with a higher prevalence of haemodynamic instability and RV dysfunction at presentation, and an elevated risk for early PE-related adverse outcomes. The association with an increased risk of early death appeared more prominent in studies including unselected patients, when compared with those focusing on normotensive patients only.

Sensitivity of a Simple Noninvasive Screening Algorithm for Chronic Thromboembolic Pulmonary Hypertension after Acute Pulmonary Embolism.

Background Recently, we constructed a noninvasive screening algorithm aiming at earlier chronic thromboembolic pulmonary hypertension (CTEPH) detection after acute pulmonary embolism (PE), consisting of a prediction score and combined electrocardiography (ECG)/N-terminal pro-brain natriuretic peptide (NT-proBNP) assessment. The aim of this study was to confirm the algorithm's sensitivity for CTEPH detection and to evaluate the reproducibility of its individual items. Methods Two independent researchers calculated the prediction score in 54 consecutive patients with a history of acute PE and proven CTEPH based on clinical characteristics at PE diagnosis, and evaluated the ECG and NT-proBNP level assessed at the moment of CTEPH diagnosis. Interobserver agreement for the assessment of the prediction score, right-to-left ventricle (RV/LV) ratio measurement on computed tomography pulmonary angiography, as well as ECG reading was evaluated by calculating Cohen's kappa statistics. Results Median time between PE diagnosis and presentation with CTEPH was 9 months (interquartile range: 5-15). The sensitivity of the algorithm was found to be 91% (95% confidence interval [CI]: 79-97%), indicating that 27 of 30 cases of CTEPH would have been detected when applying the screening algorithm to 1,000 random PE survivors with a 3% CTEPH incidence (projected negative predictive value: 99.7%; 95% CI: 99.1-99.9%). The interobserver agreement for calculating the prediction score, RV/LV ratio measurement, and ECG reading was excellent with a kappa of 0.96, 0.95, and 0.89, respectively. Conclusion The algorithm had a high sensitivity of 91% and was highly reproducible. Prospective validation of the algorithm in consecutive PE patients is required before it can be used in clinical practice.

Accuracy and reproducibility of CT right-to-left ventricular diameter measurement in patients with acute pulmonary embolism.

BACKGROUND: Right ventricular (RV) dysfunction caused by acute pulmonary embolism (PE) is associated with poor short- and long-term prognosis. RV dilatation as a proxy for RV dysfunction can be assessed by calculating the right-to-left ventricle diameter (RV/LV) ratio on standard computed tomography pulmonary angiography (CTPA) images. It is unknown whether dedicated training is required to accurately and reproducibly measure RV/LV ratio therefore we aimed to assess these parameters in residents in internal medicine without experience in CTPA reading. METHODS: CTPA images of 100 patients with PE were assessed by three residents after single instruction, and one experienced thoracic radiologist. Maximum diameters were evaluated in the axial view by measuring the distance between the ventricular endocardium and the interventricular septum, perpendicular to the long axis of the heart. RV dilatation was defined as a ratio of ≥1.0. Interobserver accuracy and reproducibility was determined using Kappa statistics, Bland-Altman analysis and Spearman's rank correlation. RESULTS: The kappa statistic for the presence of RV dilatation of the residents compared to the experienced radiologist ranged from 0.83-0.94. The average interobserver difference in calculated RV/LV ratio's (±SD) between the three residents was: -0.01 (SD0.11), 0.07 (SD0.14) and 0.06 (SD0.18) with an overall mean RV/LV diameter ratio of 1.04. In line with this, Spearman's rank correlation coefficients were 0.92, 0.88 and 0.85 respectively indicating very good correlation (p<0.01 for all). CONCLUSION: After simple instruction, RV/LV diameter ratio assessment on CTPA images by clinical residents is accurate and reproducible, which is of help in identifying PE patients at risk.

Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature.

The incidence of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE) is relevant for management decisions but is currently unknown.We performed a meta-analysis of studies including consecutive PE patients followed for CTEPH. Study cohorts were predefined as "all comers", "survivors" or "survivors without major comorbidities". CTEPH incidences were calculated using random effects models.We selected 16 studies totalling 4047 PE patients who were mostly followed up for >2-years. In 1186 all comers (two studies), the pooled CTEPH incidence was 0.56% (95% CI 0.1-1.0). In 999 survivors (four studies) CTEPH incidence was 3.2% (95% CI 2.0-4.4). In 1775 survivors without major comorbidities (nine studies), CTEPH incidence was 2.8% (95% CI 1.5-4.1). Both recurrent venous thromboembolism and unprovoked PE were significantly associated with a higher risk of CTEPH, with odds ratios of 3.2 (95% CI 1.7-5.9) and 4.1 (95% CI 2.1-8.2) respectively. The pooled CTEPH incidence in 12 studies that did not use right heart catheterisation as the diagnostic standard was 6.3% (95% CI 4.1-8.4).The 0.56% incidence in the all-comer group probably provides the best reflection of the incidence of CTEPH after PE on the population level. The ∼3% incidences in the survivor categories may be more relevant for daily clinical practice. Studies that assessed CTEPH diagnosis by tests other than right heart catheterisation provide overestimated CTEPH incidences.

To screen or not to screen for chronic thromboembolic pulmonary hypertension after acute pulmonary embolism.

Chronic thromboembolic pulmonary hypertension (CTEPH) is the most severe long term complication of acute pulmonary embolism (PE). Untreated, CTEPH is associated with a very poor prognosis and high risk of mortality, although curation can be achieved by surgical removal of the obstructive endothelialised thromboemboli from the pulmonary arteries. Early CTEPH diagnosis may improve surgical possibilities and patients outcome. Currently, early diagnosis of CTEPH is a major challenge as demonstrated by an unacceptable median diagnostic delay of over a year and as a result, surgery is impossible in 40% of patients. Most important reasons for this delay are the non-specific clinical presentation of CTEPH and lack of guideline recommendations with regard to the optimal follow-up of patients with acute PE. Despite compelling reasons to diagnose CTEPH earlier, acute PE is not classified among the conditions that warrant screening for pulmonary hypertension. Meaningful screening programs improve the patients' prognosis, and screening tools should be simple, widely available, non-invasive and acceptable to patients. In this review, we discuss current knowledge of available screening instruments for CTEPH, provide recommendations for clinical practice and expand on future developments of this particular subject.

[Cerebrospinal fluid ascites from a ventriculoperitoneal shunt]. / Liquorascites bij een ventriculoperitoneale drain.

BACKGROUND: In a patient with hydrocephalus, the placement of a ventriculoperitoneal shunt is the first treatment of choice. Cerebrospinal fluid ascites is a rare complication of a ventriculoperitoneal shunt, particularly a late complication which can arise more than two years after the implantation of the shunt. CASE DESCRIPTION: We describe a 29-year-old woman who developed cerebrospinal fluid ascites 15 years after a ventriculoperitoneal shunt had been placed. She was referred due to abdominal pain. Ultrasound showed ascites and a CT scan showed free fluid in all of the abdominal compartments. The ascites disappeared after a ventriculoatrial shunt was placed. CONCLUSION: This case demonstrates that cerebrospinal fluid ascites can occur as a late complication, years after the placement of a ventriculoperitoneal shunt.