Aims: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria.... Show moreAims: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria. Methods and results: A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI. Conclusion: In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care. Show less
Pulmonary embolism is a serious and potentially life-threatening disease in the acute phase, and may also have a major impact on a patient’s daily life in the long run. The overall aim of this... Show morePulmonary embolism is a serious and potentially life-threatening disease in the acute phase, and may also have a major impact on a patient’s daily life in the long run. The overall aim of this thesis was evaluating important aspects of the post-pulmonary embolism syndrome with an emphasis on early diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) and the associated consequence for patients’ prognosis. Show less
Pulmonary hypertension (PH) is a condition of increased blood pressure within the arteries of the lung (mPAP > 20mmHg) which affects approximately 1% of the global population. Chronic... Show morePulmonary hypertension (PH) is a condition of increased blood pressure within the arteries of the lung (mPAP > 20mmHg) which affects approximately 1% of the global population. Chronic thromboembolic pulmonary hypertension (CTEPH), group 4 PH, is characterized by unresolved pulmonary emboli and pulmonary vascular remodeling of both occluded and non-occluded vessels. The general aim of this thesis was to improve the understanding of CTEPH pathophysiology by focusing on patient endothelial cell (EC) behaviour and function. For this purpose, we isolated ECs from vascular material collected at pulmonary endarterectomy in patients with CTEPH (referred to as CTEPH-EC) and validated them as an in vitro model for studying endothelial pathology in CTEPH. In conclusion, we identified several abnormalities in CTEPH-EC that could play a role in pathological mechanisms driving CTEPH-specific vascular changes. We described alterations in key processes such as angiogenesis and migration, oxidative stress, metabolism and inflammation. Each of these processes may represent targets for novel therapies or biomarkers. Show less
Introduction: We recently proposed a scale for assessment of patient-relevant functional limitations following an episode of venous thromboembolism (VTE). Further development of this post-VTE... Show moreIntroduction: We recently proposed a scale for assessment of patient-relevant functional limitations following an episode of venous thromboembolism (VTE). Further development of this post-VTE functional status (PVFS) scale is still needed.Methods: Guided by the input of VTE experts and patients, we refined the PVFS scale and its accompanying manual, and attempted to acquire broad consensus on its use.Results: A Delphi analysis was performed involving 53 international VTE experts with diverse scientific and clinical backgrounds. In this process, the number of scale grades of the originally proposed PVFS scale was reduced and descriptions of the grades were improved. After these changes, a consensus was reached on the number/definitions of the grades, and method/timing of the scale assessment. The relevance and potential impact of the scale was confirmed in three focus groups totaling 18 VTE patients, who suggested additional changes to the manual, but not to the scale itself. Using the improved manual, the.-statistics between PVFS scale self-reporting and its assessment via the structured interview was 0.75 (95%CI 0.58-1.0), and 1.0 (95%CI 0.83-1.0) between independent raters of the recorded interview of 16 focus groups members.Conclusion: We improved the PVFS scale and demonstrated broad consensus on its relevance, optimal grades, and methods of assessing among international VTE experts and patients. The interobserver agreement of scale grade assignment was shown to be good-to-excellent. The PVFS scale may become an important outcome measure of functional impairment for quality of patient care and in future VTE trials. Show less
The post-thromotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) are the most feared long term complication of a deep venous thrombosis (DVT) and pulmonary embolism (PE)... Show moreThe post-thromotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) are the most feared long term complication of a deep venous thrombosis (DVT) and pulmonary embolism (PE) respectively. We have reviewed the literature on arguments for and against routine screening of CTEPH in patients after an episode of an acute PE. The incidence of CTEPH is relevant in this evaluation. In a systematic review and meta-analysis we showed a CTEPH incidence of 0.56% in all comers and of ~3% in the survivors. We showed that a very recent developed screening algorithm, the InShape II algorithm, is sensitive and reproducible for detecting early CTEPH in the course of an acute PE. Beside this, most patient who were diagnosed with CTEPH in the course of an acute PE already showed signs of CTEPH on the initial CT scan made for PE diagnosis.In the last chapter we focus on PTS in the course of a DVT. In patients included in the MEGA database the 0-1 year incidence was 21.8%, after 8 years of follow-up an additional 7% developed PTS. During follow-up PTS symptoms improves in almost 70% of patients. Show less
Haemodynamic instability and right ventricular dysfunction are the key determinants of short-term prognosis in patients with acute pulmonary embolism (PE). Residual thrombi and persistent right... Show moreHaemodynamic instability and right ventricular dysfunction are the key determinants of short-term prognosis in patients with acute pulmonary embolism (PE). Residual thrombi and persistent right ventricular dysfunction may contribute to post-PE functional impairment, and influence the risk of developing chronic thromboembolic pulmonary hypertension. Patients with haemodynamic instability at presentation (high-risk PE) require immediate primary reperfusion to relieve the obstruction in the pulmonary circulation and increase the chances of survival. Surgical removal of the thrombi or catheter-directed reperfusion strategies is alternatives in patients with contraindications to systemic thrombolysis. For haemodynamically stable patients with signs of right ventricular overload or dysfunction (intermediate-risk PE), systemic standard-dose thrombolysis is currently not recommended, because the risk of major bleeding associated with the treatment outweighs its benefits. In such cases, thrombolysis should be considered only as a rescue intervention if haemodynamic decompensation develops. Catheter-directed pharmaco-logical and pharmaco-mechanical techniques ensure swift recovery of echocardiographic and haemodynamic parameters and may be characterized by better safety profile than systemic thrombolysis. For survivors of acute PE, little is known on the effects of reperfusion therapies on the risk of chronic functional and haemodynamic impairment. In intermediate-risk PE patients, available data suggest that systemic thrombolysis may have little impact on long-term symptoms and functional limitation, echocardiographic parameters, and occurrence of chronic thromboembolic pulmonary hypertension. Ongoing and future interventional studies will clarify whether 'safer' reperfusion strategies may improve early clinical outcomes without increasing the risk of bleeding and contribute to reducing the burden of long-term complications after intermediate-risk PE. Show less
IntroductionSymptoms and functional limitation are frequently reported by survivors of acute pulmonary embolism (PE). However, current guidelines provide no specific recommendations on which... Show moreIntroductionSymptoms and functional limitation are frequently reported by survivors of acute pulmonary embolism (PE). However, current guidelines provide no specific recommendations on which patients should be followed after acute PE, when follow-up should be performed, and which tests it should include. Definition and classification of late PE sequelae are evolving, and their predictors remain to be determined.MethodsIn a post hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial, we focused on 219 survivors of acute intermediate-risk PE with clinical and echocardiographic follow-up 6 months after randomisation as well as over the long term (median, 3years after acute PE). The primary outcome was a composite of (1) confirmed chronic thromboembolic pulmonary hypertension (CTEPH) or (2) post-PE impairment' (PPEI), defined by echocardiographic findings indicating an intermediate or high probability of pulmonary hypertension along with New York Heart Association functional class II-IV.ResultsConfirmed CTEPH or PPEI occurred in 29 (13.2%) patients, (6 with CTEPH and 23 with PPEI). A history of chronic heart failure at baseline and incomplete or absent recovery of echocardiographic parameters at 6 months predicted CTEPH or PPEI at long-term follow-up.ConclusionsCTEPH or PPEI occurs in almost one out of seven patients after acute intermediate-risk PE. Six-month echocardiographic follow-up may be useful for timely detection of late sequelae. Show less
This thesis describes the diagnostic management, short term prognosis and long term complications of pulmonary embolism. We have validated a newly derived clinical decision rule, the revised Geneva... Show moreThis thesis describes the diagnostic management, short term prognosis and long term complications of pulmonary embolism. We have validated a newly derived clinical decision rule, the revised Geneva score, for predicting the pre-test probability of having acute pulmonary embolism. This rule can be used in clinical practice to managge patients with suspected pulmonary embolism. We further found that NT-pro-BNp levels are the best predictors of benign clinical course, when compared to troponin and D-dimer levels, and CT derived maesurements of the right ventricular volume and function. Finally, we demonstrate that although the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism is very low, the long term clinical course after pulmonary embolism is complicated frequently by mortalitity, recurrent venous thombosis, newly diagnosed maligancies and arterial cardiovascular events. Show less