Screening For Chronic Thromboembolic Pulmonary Hypertension Research Articles

Preexisting Chronic Thromboembolic Pulmonary Hypertension in Acute Pulmonary Embolism

Chronic thromboembolic pulmonary hypertension (CTEPH) is considered a complication of pulmonary embolism (PE). However, signs of CTEPH may exist in patients with a first symptomatic PE. Which radiologic findings on CT pulmonary angiography (CTPA) at the time of acute PE could indicate the presence of preexisting CTEPH? This study included unselected patients with acute PE who were prospectively followed up for 2 years with a structured visit schedule. Two expert radiologists independently assessed patients' baseline CTPAs for preexisting CTEPH; in case of disagreement, a decision was reached by a 2:1 majority with a third expert radiologist. In addition, the radiologists checked for predefined individual parameters suggesting chronic PE and pulmonary hypertension. Signs of chronic PE or CTEPH at baseline were identified in 46 of 303 included patients (15%). Intravascular webs, arterial narrowing or retraction, dilated bronchial arteries, and right ventricular hypertrophy were the main drivers of the assessment. Five (1.7%) patients were diagnosed with CTEPH during follow-up. All four patients diagnosed with CTEPH early (83-108days following acute PE) were found in enriched subgroups based on the experts' overall assessment or fulfilling a minimum number of the predefined radiologic criteria at baseline. The specificity of preexisting CTEPH diagnosis and the level of radiologists' agreement improved as the number of required criteria increased. Searching for predefined radiologic parameters suggesting preexisting CTEPH at the time of acute PE diagnosis may allow for targeted follow-up strategies and risk-adapted CTEPH screening, thus facilitating earlier CTEPH diagnosis.

Keep minds opening for chronic thromboembolic pulmonary hypertension: More data, less clarity

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare sequelae of pulmonary embolism (PE), resulting from persistent obstruction of pulmonary arteries with non‐resolving thromboemboli and consecutive pulmonary small‐vessel remodeling.1,2 From the landmark research by Pengo et al.3 reporting that the cumulative incidence of CTEPH after acute episode of PE was 3.8% (95% confidence interval [CI] 1.1–6.5) at 2 years, subsequent studies reported a notable wide range of incidences, ranging from 0.1% to 11.8%,4,5 which keep the rationale of routine screening for CTEPH after an episode of PE in intense debate.

Quantification of the pulmonary vascular obstruction index on ventilation/perfusion lung scintigraphy: Comparison of a segmental visual scoring to the Meyer score.

Quantifying the pulmonary vascular obstruction index (PVOI) is essential for the management of patients with pulmonary embolism or chronic thromboembolic pulmonary hypertension (CTEPH). The reference method for quantifying the PVOI with planar lung ventilation/perfusion (V/Q) scintigraphy is the Meyer score, which was validated using pulmonary angiography as a reference standard. However, it is complex to use in daily practice. In contrast, a rapid and fast quantification method consists in estimating the PVOI based on the number of segmental perfusion defects. However, the accuracy of this method has never been evaluated. In this study, we aimed to compare PVOI quantification on planar V/Q scintigraphy assessed by a segmental visual scoring (SVS) to the Meyer score. The eligible study population consisted of consecutive patients who underwent planar V/Q scan for CTEPH screening. A central review was performed by three nuclear medicine physicians. PVOI was assessed by summing the number of segmental perfusion defects or equivalent (2 sub-segments = 1 segment = 5%) and by Meyer's method. The two interpretations were performed 6 months apart. A Spearman rank correlation coefficient was calculated to evaluate correlation between the two measurement methods. An intra-class correlation (ICC) was calculated to assess agreement. A Bland et Altman plot analysis was used to evaluate agreement between the two measurements. A total of 226 V/Q scans were interpreted. Spearman rank correlation coefficient between SVS and Meyer was 0.963 (95%CI 0.952-0.971) for mismatched perfusion defects and 0.963 (95%CI 0.953-0.972) for perfusion defects regardless of ventilation. Intra-class correlation (ICC) for agreement was 0.978 (95%CI 0.972-0.983) for mismatched perfusion defects and 0.968 (95%CI 0.959-0.976) for perfusion defects regardless of ventilation. In Bland & Altmann analysis, the mean difference between the SVS method and the Meyer score was 0.42 and 0.61 for the mismatched or matched evaluation, respectively. Our study shows a high correlation, and low differences in PVOI quantification when using a segmental visual scoring (SVS) as compared to the Meyer score. The SVS has the great advantage to be easy and rapid to apply in daily practice.

Imaging Advances in Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is an under recognized complication of pulmonary embolism with significant morbidity and mortality when left untreated. There have been ongoing advances in the treatment of CTEPH with potentially excellent outcomes for patients when diagnosed and treated in a timely fashion. Although ventilation-perfusion scintigraphy remains critical in screening for CTEPH, the radiologic diagnosis involves multiple modalities from digital subtraction angiography to high quality computed tomography pulmonary angiography. State of the art imaging in CTEPH now also includes dual energy computed tomography, lung subtraction iodine mapping, and magnetic resonance imaging.

Chronic thromboembolic pulmonary hypertension: diagnosis, operability assessment and patient selection for pulmonary endarterectomy

Healthcare providers outside pulmonary hypertension (PH) centers having misinformation or insufficient education, and a general lack of treatment awareness contribute to a massive underdiagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), diagnostic delay and refusal of surgery by patients. Together with the subjective operability assessment, this leads to too few patients undergoing pulmonary endarterectomy (PEA); even though this surgery results in improved survival and exercise capacity. Acute pulmonary embolism (PE) survivors should undergo a CTEPH screening strategy. Patients screened positive and those with CTEPH symptoms (with or without history of PE), should undergo transthoracic echocardiography (TTE) to determine the probability of PH. High PH probability patients should undergo a ventilation/perfusion (V/Q) scan. A negative scan rules out CTEPH. Patients with a positive V/Q scan, but also patients with findings suggestive for CTEPH on computed tomography pulmonary angiography (CTPA) to diagnose acute PE, should be referred to a CTEPH center. Further diagnostic work-up currently consists of catheter based pulmonary angiography, CTPA and right heart catheterization. However, new imaging technologies might replace them in the near future, with one single imaging tool to screen, diagnose and assess operability as the ultimate goal. Operability assessment should be performed by a multidisciplinary CTEPH team. PEA surgery should be organized in a single center per country or for each forty to fifty million inhabitants in order to offer the highest level of expertise. Informing patients about PEA should preferably be done by the treating surgeon. Based on the estimated incidence of CTEPH and with a better education of patients and healthcare providers, despite the advent of new interventional and medical therapies for CTEPH, the number of PEA surgeries performed should still have the potential to grow significantly.

Development and validation of a claims-based model to identify patients at risk of chronic thromboembolic pulmonary hypertension following acute pulmonary embolism

Objective Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease that often follows pulmonary embolism (PE). Screening for CTEPH is challenging, often delaying diagnosis and worsening prognosis. Predictive risk models for CTEPH could help identify at-risk patients, but existing models require multiple clinical inputs. We developed and validated a predictive risk model for CTEPH using health insurance claims that can be used by payers/quality-of-care organizations to screen patients post-PE. Methods Adult patients newly diagnosed with acute PE (index date) were identified from the Optum De-identified Clinformatics Extended DataMart (January 2007–March 2018; development set) and IBM MarketScan (January 2008–June 2019; validation set) databases. Predictors were identified 12 months before or on the index PE. Risk of “likely CTEPH” was assessed post-PE based on CTEPH-related diagnoses and procedures since the CTEPH diagnosis code (ICD-10-CM: I27.24) was not available until 1 October 2017. Stepwise variable selection was used to build the model using the development set; model validation was subsequently conducted using the validation set. Results The development set included 93,428 patients, of whom 11,878 (12.7%) developed likely CTEPH. Older age (odds ratios [OR] = 1.16–1.49), female (OR = 1.09), unprovoked PE (i.e. without thrombotic factors; OR = 1.14), hypertension (OR = 1.07), osteoarthritis (OR = 1.08), diabetes (OR = 1.07), chronic obstructive pulmonary disease (OR = 1.11), obesity (OR = 1.21) were associated with higher odds of likely CTEPH, and oral anticoagulants with lower odds (OR= 0.50, all p < .01). C-statistic was 0.77 in the development and validation sets. Conclusion A claims-based risk model reliably predicted the risk of CTEPH post-PE and could be used to identify high-risk patients who may benefit from focused monitoring.

Optimizing the diagnosis and assessment of chronic thromboembolic pulmonary hypertension with advancing imaging modalities.

Imaging is key to nearly all aspects of chronic thromboembolic pulmonary hypertension including management for screening, assessing eligibility for pulmonary endarterectomy, and post-operative follow-up. While ventilation/perfusion scintigraphy, the gold standard technique for chronic thromboembolic pulmonary hypertension screening, can have excellent sensitivity, it can be confounded by other etiologies of pulmonary malperfusion, and does not provide structural information to guide operability assessment. Conventional computed tomography pulmonary angiography has high specificity, though findings of chronic thromboembolic pulmonary hypertension can be visually subtle and unrecognized. In addition, computed tomography pulmonary angiography can provide morphologic information to aid in pre-operative workup and assessment of other structural abnormalities. Advances in computed tomography imaging techniques, including dual-energy computed tomography and spectral-detector computed tomography, allow for improved sensitivity and specificity in detecting chronic thromboembolic pulmonary hypertension, comparable to that of ventilation/perfusion scans. Furthermore, these advanced computed tomography techniques, compared with conventional computed tomography, provide additional physiologic data from perfused blood volume maps and improved resolution to better visualize distal chronic thromboembolic pulmonary hypertension, an important consideration for balloon pulmonary angioplasty for inoperable patients. Electrocardiogram-synchronized techniques in electrocardiogram-gated computed tomography can also show further information regarding right ventricular function and structure. While the standard of care in the workup of chronic thromboembolic pulmonary hypertension includes a ventilation/perfusion scan, computed tomography pulmonary angiography, direct catheter angiography, echocardiogram, and coronary angiogram, in the future an electrocardiogram-gated dual-energy computed tomography angiography scan may enable a “one-stop” imaging study to guide diagnosis, operability assessment, and treatment decisions with less radiation exposure and cost than traditional chronic thromboembolic pulmonary hypertension imaging modalities.

Clinical Updates on the Diagnosis and Management of Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a known sequela after acute pulmonary embolism (PE). It is a debilitating disease, and potentially fatal if left untreated. This review provides a clinically relevant overview of the disease and discusses the usefulness and limitations of the various investigational and treatment options. A PubMed search on articles relevant to PE, pulmonary hypertension, CTEPH, pulmonary endarterectomy, and balloon pulmonary angioplasty were performed. A total of 68 articles were found to be relevant and were reviewed. CTEPH occurs as a result of non-resolution of thrombotic material, with subsequent fibrosis and scarring of the pulmonary arteries. Risk factors have been identified, but the underlying mechanisms have yet to be fully elucidated. The cardinal symptom of CTEPH is dyspnoea on exertion, but the diagnosis is often challenging due to lack of awareness. The ventilation/perfusion scan is recommended for screening for CTEPH, with other modalities (eg. dual energy computed tomography pulmonary angiography) also being utilised in expert centres. Conventional pulmonary angiography with right heart catheterisation is important in the final diagnosis of CTEPH. Operability assessment by a multidisciplinary team is crucial for the management of CTEPH, as pulmonary endarterectomy (PEA) remains the guideline recommended treatment and has the best chance of cure. For inoperable patients or those with residual disease post-PEA, medical therapy or balloon pulmonary angioplasty are potential treatment options.

Characteristics and Management of Patients Following Pulmonary Embolism: A Focus on Screening for Chronic Thromboembolic Pulmonary Hypertension

Purpose Chronic thromboembolic pulmonary hypertension (CTEPH) can develop in 1 out of 25 (4%) patients following an acute pulmonary embolism (PE). It is recommended that high risk patients on anticoagulants, who have persistent shortness of breath post-PE, should be screened for CTEPH. Ventilation-perfusion scan is considered a gold standard tool for screening for CTEPH. This retrospective study sought to describe the use of CTEPH-related diagnostic and medical procedures post-PE in the United States. Methods Adult patients newly diagnosed with acute PE (index date) without prior pulmonary hypertension (PH) were identified from a large US administrative healthcare claims database (01/2007-03/2018; > 150 million patients). Patients were required to be continuously enrolled in their healthcare plan for ≥12 months pre-index (i.e., baseline period) and post-index (i.e., observation period). CTEPH-related diagnoses, procedures, and surgeries were evaluated during the observation period. Results A total of 93,947 patients with acute PE were identified. Mean age was 65.4 years and 54.4% were females. Over an average follow-up of 3.3 years post-index, 75.3% of patients were seen for ‘shortness of breath’, of whom 93.6% had an electrocardiogram, 75.2% an echocardiography, and 57.4% a computed tomographic angiography. Specific to CTEPH screening, 18.0% had a ventilation-perfusion scan, 7.6% a pulmonary angiogram, 4.7% a right heart catheterization. Among the 93,947 patients, 14,510 (15.4%) had a diagnosis of PH documented after acute PE, and 284 (0.3%) had a CTEPH-related procedure (i.e., pulmonary endarterectomy [0.2%; n=193] or balloon pulmonary angioplasty [0.1%; n=97]). Conclusion Real-world evidence shows that patients are not systematically monitored for CTEPH using diagnostic procedures recommended by current guidelines which state. “it is recommended that high risk patients on anticoagulants, who have persistent shortness of breath post-PE, should be screened for CTEPH”. There is an ongoing need to better define the use of CTEPH diagnostic procedures in patients who have experienced acute PE as well as risk prediction tools to identify patients at high risk of developing CTEPH after PE.

Multicentre observational screening survey for the detection of CTEPH following pulmonary embolism.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe complication of pulmonary embolism. Its incidence following pulmonary embolism is debated. Active screening for CTEPH in patients with acute pulmonary embolism is yet to be recommended.This prospective, multicentre, observational study (Multicentre Observational Screening Survey for the Detection of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Following Pulmonary Embolism (INPUT on PE); ISRCTN61417303) included patients with acute pulmonary embolism from 11 centres in Switzerland from March 2009 to November 2016. Screening for possible CTEPH was performed at 6, 12 and 24 months using a stepwise algorithm that included a dyspnoea phone-based survey, transthoracic echocardiography, right heart catheterisation and radiological confirmation of CTEPH.Out of 1699 patients with pulmonary embolism, 508 patients were assessed for CTEPH screening over 2 years. CTEPH incidence following pulmonary embolism was 3.7 per 1000 patient-years, with a 2-year cumulative incidence of 0.79%. The Swiss pulmonary hypertension registry consulted in December 2016 did not report additional CTEPH cases in these patients. The survey yielded 100% sensitivity and 81.6% specificity. The second step echocardiography in newly dyspnoeic patients showed a negative predictive value of 100%.CTEPH is a rare but treatable disease. A simple and sensitive way for CTEPH screening in patients with acute pulmonary embolism is recommended.

Derivation of a clinical prediction score for chronic thromboembolic pulmonary hypertension after acute pulmonary embolism

Essentials Predicting chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism is hard. We studied 772 patients with pulmonary embolism who were followed for CTEPH (incidence 2.8%). Logistic regression analysis revealed 7 easily collectable clinical variables that combined predict CTEPH. Our score identifies patients at low (0.38%) or higher (10%) risk of CTEPH. Introduction Validated risk factors for the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE) are currently lacking. Methods This is a post hoc patient-level analysis of three large prospective cohorts with a total of 772 consecutive patients with acute PE, without major cardiopulmonary or malignant comorbidities. All underwent echocardiography after a median of 1.5 years. In cases with signs of pulmonary hypertension, additional diagnostic tests to confirm CTEPH were performed. Baseline demographics and clinical characteristics of the acute PE event were included in a multivariable regression analysis. Independent predictors were combined in a clinical prediction score. Results CTEPH was confirmed in 22 patients (2.8%) by right heart catheterization. Unprovoked PE, known hypothyroidism, symptom onset > 2 weeks before PE diagnosis, right ventricular dysfunction on computed tomography or echocardiography, known diabetes mellitus and thrombolytic therapy or embolectomy were independently associated with a CTEPH diagnosis during follow-up. The area under the receiver operating charateristic curve (AUC) of the prediction score including those six variables was 0.89 (95% confidence interval [CI] 0.84-0.94). Sensitivity analysis and bootstrap internal validation confirmed this AUC. Seventy-three per cent of patients were in the low-risk category (CTEPH incidence of 0.38%, 95% CI 0-1.5%) and 27% were in the high-risk category (CTEPH incidence of 10%, 95% CI 6.5-15%). Conclusion The 'CTEPH prediction score' allows for the identification of PE patients with a high risk of CTEPH diagnosis after PE. If externally validated, the score may guide targeting of CTEPH screening to at-risk patients.

Evaluation and Management of Chronic Pulmonary Thromboembolic Disease

Pulmonary embolism (PE) is common and the majority of patients survive the acute event. Survivors are at increased risk for adverse outcomes, including persistent thrombi, recurrent embolism, chronic thromboembolic pulmonary hypertension (CTEPH), and death. Anticoagulation protects against recurrence, which has a high mortality rate. The recommended duration of anticoagulation for patients with reversible PE risk factors is 3 months. For patients with idiopathic PE or persistent risk factors, extended duration of anticoagulation is preferred, balanced with an individual patient's risk of hemorrhage, which in itself is a major cause of morbidity and mortality. Among patients with malignancy who develop venous thromboembolism (VTE), low-molecular-weight heparin is preferred over oral vitamin K antagonists in the first 6 months. Thereafter, anticoagulation should be continued indefinitely with either low-molecular-weight heparin or oral vitamin K antagonists. Inferior vena cava filters are not routinely recommended and should only be used in patients who have a contraindication to anticoagulation. Patients who have had VTE and with persistent or recurrent dyspnea should be evaluated for recurrence of VTE or development of CTEPH. Patients with recurrent VTE should be anticoagulated indefinitely. Routine screening for CTEPH in asymptomatic patients is not recommended. Echocardiography often provides the first indication of the presence of pulmonary hypertension. Once presence of CTEPH is established by right-sided heart catheterization and perfusion imaging (ie, ventilation/perfusion scintigraphy, computed tomography angiography, or pulmonary angiography), patients should be referred early to a center with expertise, as it is potentially surgically curable by pulmonary endarterectomy. Those who are deemed inoperable after being evaluated may gain symptomatic benefit from drugs approved for idiopathic pulmonary arterial hypertension. Lung transplantation may also be an option for patients who are not candidates for pulmonary endarterectomy.

Chronic pulmonary embolism in Klippel-Trenaunay syndrome

Klippel-Trenaunay syndrome (KTS) is characterized by vascular malformations and disturbed soft tissue or bony growth, involving one or more extremities. A high incidence of venous thromboembolism (VTE) has been reported in this disorder, along with cases of belated diagnosed chronic thromboembolic (CTE) pulmonary hypertension (CTEPH). We performed a cross-sectional study to investigate the prevalence of CTE in patients with KTS. Those from our KTS patient cohort willing to participate were examined with a sequential diagnostic workup including perfusion scintigraphy, computed tomography, and echocardiography. Of 68 patients, 48 patients participated in the study (median age 43 years; 29 [60%] were female). Eleven patients (23%) had an abnormal perfusion scan result, of whom computed tomographic scanning showed signs of CTE in two patients (4.2%; 95% confidence interval [CI] 1.2%-14%); both patients had a history of VTE. Echocardiography showed no signs of CTEPH in these patients. In total, 23 patients (48%; 95% CI 35%-62%) had a history of superficial vein thrombosis and 8 patients (17%; 95% CI 8.7%-30%) had a history of deep vein thrombosis or pulmonary embolism, which was associated with more shortness of breath. Echocardiography was only performed in patients with CTE. A large proportion of patients with KTS had a history of VTE. The prevalence of CTE in the total KTS cohort, however, appeared less alarming than previously assumed. Based on these results, we suggest that there is only a limited indication for CTEPH screening among patients with KTS. Nevertheless, awareness for CTEPH remains appropriate, especially among patients presenting with shortness of breath and a history of VTE.