Identification of CTEPH on Standard Computerised Tomography Pulmonary Angiography Performed in the Work-up of Suspected Pulmonary Embolism
Conditions: CTEPH, Pulmonary Embolism, Early Diagnosis
Sponsor: Leiden University Medical Center

 
 
 
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All fields are required, an incomplete form will be returned to the submitter.  If a field is not completed, please note the 
reason.  
 
Proposed Study Title 
Study Title: 
 Unmasking and unravelling of a silent killer: early detection of CTEPH 
Document date 
 10-06-2016 
Clinical Trial number 
NCT03083093 
Principal Investigator Contact Information 
Name:  
 Dr. F.A. Klok/Prof. Dr. M.V. Huisman 
Title: 
  
Address 1 
 Leiden University Medical Center, Room C-7-68 
Address 2 
 Albinusdreef 2 
City, ST, Zip 
 2300RC Leiden, the Netherlands 
Phone/Fax: 
 +31-71-529 8127 
E-mail: 
 f.a.klok@LUMC.nl/m.v.huisman@LUMC.nl 
Institution Contact Information 
Name:  
 Leiden University Medical Center, Department of Medicine 
Address 1 
 Albinusdreef 2 
Address 2 
  
City, ST, Zip 
 2300RC Leiden, the Netherlands 
Phone/Fax: 
  
website 
 www.LUMC.nl 
Contracting Information (if applicable) 
Name:  
 J. de Graaf 
Phone/Fax: 
  
E-mail: 
 J.de_Graaf@lumc.nl 
Study Information 
Indication 
 Pulmonary embolism / chronic thromboembolic pulmonary hypertension 
Phase: 
 n.a. 
Number of Subjects: 
100 patients 

 
 
 
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Background and Rationale  
• 
Provide background on unanswered question(s) the study is attempting to answer (do not exceed one page) 
The ultimate consequence of hemodynamic compromise and persistent pulmonary perfusion defects after acute PE is 
chronic thromboembolic pulmonary hypertension (CTEPH), which is a lethal condition unless a timely diagnosis is 
followed by adequate treatment [1-5]. The exact incidence of CTEPH after PE is estimated to be 3.5-5.5% in patients 
without major cardiovascular of malignant comorbidity, within the first 2 years after the PE diagnosis [1-7]. Its 
pathophysiology has not been fully elucidated yet, although it has been established that the increased arterial resistance 
is caused by chronic obstruction of pulmonary arterial vessels by organised thromboembolic material as well as from 
vascular remodelling in small unobstructed vessels [2,3] CTEPH is the only potentially curable cause of pulmonary 
hypertension. Pulmonary endarterectomy (PEA) is the surgical procedure which removes the obstructing thromboembolic 
material, resulting in significant improvements and in many cases normalisation in pulmonary artery pressure and right 
ventricular function [1-3]. Early diagnosis of CTEPH is essential, since especially when detected at an early stage, 
CTEPH may be cured by pulmonary endarterectomy while delay in diagnosis may be associated with irreversible 
secondary pulmonary vascular remodelling and right heart failure, leading to worse prognosis, higher perioperative 
mortality and inoperable disease stages [1-8]. 
 
Early CTEPH diagnosis, however, has proven to be a major clinical challenge. First, there are no specific signs or 
symptoms of CTEPH and patients may remain asymptomatic for months to years although clinically significant pulmonary 
hypertension (PH) is already present [1,3]. On the other hand, 50% of patients report persistent dyspnea until years after 
acute PE, a symptom that may point to CTEPH but in most patients is due to deconditioning, death-space ventilation due 
to persistent thrombi or other cardiopulmonary comorbidities, and not to CTEPH [9]. Second, the exact incidence of 
CTEPH is unknown. Third, until now, no validated cost-effective screening tool is available, and the timing of screening is 
unknown. For instance, previous studies have shown that subjecting all patients who survived acute PE to transthoracic 
echocardiography, which is the recommended screening tool for suspected PH, has a low diagnostic yield, causes an 
excess of false positive findings that warrant additional diagnostic tests and is therefore not cost-effective [6,16]. Given 
these uncertainties, international guidelines do not provide a clear recommendation on the frequency and duration of 
medical follow-up after acute PE and even recommend against specific screening for CTEPH [6,7] Consequently, it has 
been established that the majority of CTEPH diagnoses nowadays still have a diagnostic delay 1.5 years, and in day-to-
day clinical practice, many patients with a prior history of PE and non-specific cardiopulmonary symptoms are subjected 
to unstandardized and inefficient diagnostic tests [4,9]. 
 
While CTPA is the investigation of choice for the diagnosis of acute PE, planar V/Q lung scan remains the main imaging 
modality for CTEPH with a sensitivity and specificity of up to 97% [6]. Multidetector CTPA has nonetheless become an 
established imaging modality for confirming CTEPH although this investigation alone cannot exclude the disease [7,10]. 
CTPA characteristics of CTEPH include (calcified) eccentric wall-adherent filling defects, stenosis or obstruction (webs 
and bands) of pulmonary arteries with post-stenotic dilatation, dilatation of the pulmonary artery, right ventricular 
hypertrophy/dilatation, systemic collateral arterial supply (bronchial arterial collaterals towards pulmonary post-obstructive 
vessels) and mosaic lung perfusion pattern due to locally decreased perfusion [7,10,11]. Notably, most of these 

 
 
 
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characteristics may also be found in patients with acute PE. Especially the aspect of the thrombus and the presence of 
webs and bands may be helpful in differentiating CTEPH from acute PE with acute right ventricular overload (Figure 1).  
 
Figure 1: CTPA clearly visualizing large central blood clots in the pulmonary artery (left panel, red arrow) and right ventricular overload (middle panel, blue arrows) which may 
indicate both acute PE as well as CTEPH; Same CTPA with a very subtle indication of CTEPH by demonstrating an intraluminal web (right panel, yellow arrow) 
 
Increasing evidence supports our hypothesis that in many cases CTEPH is misclassified as acute PE. As stated above, 
this hypothesis is based on the observations that 1) 1 to 2 in 4 CTEPH patients do not have a clear history of PE or DVT, 
2) the pathophysiological mechanism of the transition of acute to chronic PE is unknown, 3) most thrombophilic conditions 
are not associated with CTEPH and 4) initial echocardiography and CT data at the time of an index PE suggest that a 
majority of patients who are later diagnosed with CTEPH, already had radiological signs of CTEPH at the time of the 
index PE diagnosis [1-3,7,12]. In clinical practice, radiologists who interpret CTPAs performed for diagnosing or ruling out 
acute PE are primarily focused on the diagnosis of acute PE and not on small subtle radiological patterns of CTEPH, 
although these may be present. 
 
At the division of Image processing (LKEB) of the LUMC, prototype software has been developed to automatically 
quantify the pulmonary vasculature from CT images. With this innovative CT analysis method, the vascular tree is 
detected by so-called “vesselness”-filtering and “graph cuts” [13-15], and subsequently the architecture of this vascular 
tree is quantified by measuring the diameter of each vessel segment and calculating the frequency of occurrence of each 
vessel calibre (Figure 2).  
 
 
 
 
 
 
 
 
 
 
Figure 2: Pulmonary vasculature quantification: analyses of pulmonary vasculature with distribution of vascular calibre. 
 
Since the pulmonary vasculature resembles a fractal, the fractal dimension can be calculated from this frequency 

 
 
 
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distribution to describe its shape. This fractal-based imaging biomarker can be used to detect vascular changes in 
CTEPH, since the proportion of detected small and large vessels and therefore the fractal dimension will change. Hence, 
this technique may help differentiating CTEPH from acute PE on standard CTPA images.  
Objectives 
• 
List the objectives to correspond directly with the listed hypotheses: 
Primary objective 
To identify the accuracy of routine CTPA for the distinction of CTEPH from acute PE.  
 
Secondary objectives 
- 
To further develop the technique of automatic quantification of the pulmonary vasculature on CT scans, and correlate 
this fractal-based imaging biomarker to clinical features (CTEPH or not). 
- 
To study the incremental value of NT-proBNP, troponin, ECG reading and the CTEPH prediction rule [16] to the 
diagnostic criteria of the CT scan that are derived in the primary analysis. 
- 
To study the cost-effectiveness of additional extensive screening of CTPA images for the identified criteria for 
CTEPH. 
Hypothesis  
• 
List the clinical Hypotheses in order of priority: 
1. More careful reading (than the current standard) of standard CTPA performed in the clinical work-up of suspected PE 
will differentiate patients with acute PE from those with more chronic or acute on chronic PE, which could be an early 
sign of CTEPH. 
2. We further hypothesize that the novel imaging processing technique of “automatic quantification of the pulmonary 
vasculature” will greatly aid in differentiating acute PE from CTEPH. Furthermore, with this technique targeted, early 
and efficient/cost-effective screening for CTEPH may become possible.  
Study Design/Clinical Plan 
• 
Provide a concise overview stating the type of experimental design 
For the first part of the study, we will study 50 consecutive patients diagnosed with CTEPH after an initial episode of 
acute PE and referred to the VUmc (period 2016-2018), as well as 50 patients diagnosed with acute PE in the LUMC in 
whom CTEPH was ruled out 2 years after the PE diagnosis by sequential echocardiography as part of standard care, 
matched on the RV/LV ratio of the patients who developed CTEPH.  
 
Three experienced thorax radiologists with specific expertise on acute PE and CTEPH from LUMC (Dr. LJM Kroft), VUmc 
(Dr. L Meijboom) and AMC (Dr. LFM Beenen) will blindly assess the index CTPAs of the study population. The CTPA 
scans must be made on a 32-row detector (or more advanced) contemporary CT machines. The patients are matched on 
RV/LV ratio to force the radiologists to focus on the subtle aspects of the thrombi and the presence of webs and bands in 
the pulmonary arteries. In addition to the binominal judgement whether CTEPH signs are already present (or not), the 
presence of the standardised items will be scored by all 3 readers independently. 
After the first 20 scan assessments by all three reviewers, an evaluation will be performed to check for logistical or other 

 
 
 
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issues that need to be solved before the final 80 scans will be distributed. If the 2 patient groups are successfully 
identified, the relevant diagnostic criteria that allow for this distinction will be summarized in a practical protocol.  
 
For the evaluation of health economics, which will be supervised by an expert in this particular field, the mean time for the 
additional CTPA reading by the experts will be measured. In addition, using standard models and available data, the 
current diagnostic delay of CTEPH diagnosis and the associated costs and effects on quality of life will be assessed from 
the literature.  
 
The final part of the study focuses on the further development of software that qualifies the functional pulmonary 
vasculature. In order to make the imaging biomarker of automatic quantification of the pulmonary vasculature more 
sensitive and specific, additional research is needed. This additional image analysis would include the distinction between 
the arterial and venous tree and quantifying their separate contribution to the fractal dimension. The segmentation of the 
vascular trees could also form the basis for a more detailed detection and local quantification of the acute PE and 
CTEPH-specific patterns, like vascular webs and abrupt changes in vascular dimensions. With every further step of 
software development, the specificity and sensitivity of the imaging biomarkers for specific vascular pulmonary diseases 
will be tested based on available scans form the clinics. After the technique of automatic quantification of the pulmonary 
vasculature on CT scans has been sufficiently developed (sensitivity and specificity of distinction between acute PE and 
established CTEPH both >85%), all CT scans in the derivation and validation set of the radiological criteria described 
above will be analysed accordingly to assess for clinical correlation to compare the diagnostic accuracy of the software 
with that of the expert radiologists (and the incremental value of both). 
Treatment 
• 
List the clinical dosage/dosage form, route, and dose regimen: 
 
Treatment of the patients with acute PE and those with identified CTEPH will be according to international standards, and 
are not part of the study protocol. 
 
Collateral Research  
• 
Include biomarkers, PK, etc.  
 
In addition to the primary endpoints, we will test the incremental value of NT-proBNP, troponin, ECG reading and our 
CTEPH prediction rule [16] to the diagnostic criteria of the CT scan that are derived in the primary analysis. Specifically, 
we will evaluate an innovative (automated) method for ECG reading for determination of the electric vector and 
estimation of the probability of right ventricular overload [17]. This 3-dimensional ECG-vector cardiogram (VCG) analysis 
will likely significantly improve the diagnostic value of ECGs for CTEPH when compared to the current manual ECG 
assessment. The main diagnostic improvement will be for patients with very early stages of CTEPH because even a 
small increase in pulmonary artery pressure will result in right ventricular pressure overload that is associated with subtle 
but clearly measurable changes in the electrocardiographically derived ventricular gradient as expressed by the 
electrocardiographic vector. 
 

 
 
 
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Statistical Plans 
• 
Include justification for clinical sample size and primary hypothesis testing: 
For the first part of the study, all three readers will independently assess the CTPAs. The final diagnosis for each arm of 
interest based on an aggregate reading of the CTPA images (acute PE or CTEPH with/without (sub)-acute PE) will be 
based on a majority rule. The sensitivity of CTPA is determined by calculating the proportion of scans that are read as 
"positive for the CTEPH specific radiological pattern” in patients with confirmed CTEPH and the specificity is determined 
by calculating the proportion of scans that are read as "negative for the CTEPH specific radiological pattern" in patients 
without CTEPH. The corresponding exact 95% confidence intervals for each of the point estimates will be calculated. In 
addition to these estimates, sensitivity and specificity estimates with corresponding 95% confidence intervals will be 
calculated for the initial independent assessment of each of the three readers participating. For the interobserver 
agreement between the reviewers a kappa statistic will be assessed. According to established criteria, a kappa score 
above 0.8 is considered excellent reliability, a score between 0.6 and 0.8 is considered good reliability, a score between 
0.4 and 0.6 is considered moderate reliability and a score below 0.4 is considered poor reliability. 
 
If the sensitivity of the CTPA is >90% with at least good interobserver agreement, we will conclude CTEPH may be 
excluded based on CTPA images. If the specificity of the CTPA is >90% with at least good interobserver agreement, we 
will conclude that the radiological pattern of CTEPH on CTPA performed to diagnose acute PE is highly predictive of a 
future CTEPH diagnosis and thus relevant to report and translate to the further diagnostic and therapeutic management 
of the patient. We will translate our findings in a set of diagnostic criteria, which should be validated in a future 
prospective study. 
 
A sample size of 50 patients in each of 2 study groups was chosen because with this sample size and an expected 
specificity of greater than 90%, the 95% confidence intervals on the point estimates would have a bandwidth of 
approximately ±15%, ensuring that the point estimate was sufficiently accurate to make decisions about the 
appropriateness and safety of the proposed validation study. 
 
The economic evaluation will include a study-based cost-effectiveness analysis (CEA) and a model-based cost-utility 
analysis (CUA).Both analyses will use net-benefit analysis, comparing the additional diagnostic test (extensive reading of 
the CT’s for presence of subtle signs of CTEPH on top of standard acute PE reading) to a strategy without this test. The 
CEA will be performed from a short-term healthcare perspective, estimating additional diagnostic costs per additional 
early CTEPH diagnosis. The CUA will be performed from a long-term societal perspective, estimating costs per quality-
adjusted life year (QALY). In the CUA, the estimated diagnostic performance will be extrapolated to treatment decisions 
and patient outcome, using a Markov model to estimate the impact on health risks, survival, QALYs, health care and 
productivity costs. 
 
For the software developing part of the study, no specific statistical tests are required. The accuracy of the final 
mathematical model will be compared with the accuracy of the manual reading of the CT’s by the panel of expert 

 
 
 
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radiologist by receiver operating characteristic analysis, the incremental value of both by reclassification analysis. 
 
REFERENCES 
1) Kim NH et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 2013:D92-D99; 2) Lang IM et al. 
Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur 
Respir J 2013;41:462-468; 3) Lang IM et al. Update on chronic thromboembolic pulmonary hypertension. Circulation 
2014;130:508-518; 4) Pepke-Zaba J et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an 
international prospective registry. Circulation 2011;124:1973-1981; 5) Klok FA et al. Patient outcomes after acute 
pulmonary embolism. A pooled survival analysis of different adverse events. Am J Respir Crit Care Med 2010;181:501-
506; 6) Konstantinides SV et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. 
Eur Heart J 2014;35:3033-3069k; 7) Galiè N et al. "2015 ESC/ERS Guidelines for the diagnosis and treatment of 
pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension. Eur Respir J 
2015;46:1855-6; 8) Lang IM et al. Factors associated with diagnosis and operability of chronic thromboembolic pulmonary 
hypertension. A case-control study. Thromb Haemost 2013;110:83-91; 9) Klok FA et al. Prevalence and potential 
determinants of exertional dyspnea after acute pulmonary embolism. Respir Med 2010;104:1744-1749; 10) Tunariu N et 
al. Ventilation-perfusion scintigraphy Is more sensitive than multidetector CTPA in detecting chronic thromboembolic 
pulmonary disease as a treatable cause of pulmonary hypertension. J Nucl Med 2007;48:680–684; 11) Doğan H et al. 
The role of computed tomography in the diagnosis of acute and chronic pulmonary embolism. Diagn Interv Radiol 
2015;21:307-316; 12) Guérin L et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute 
pulmonary embolism. Thromb Haemost 2014;112:598-605; 13) Xiao C et al. Transactions on Image Processing 
2013;22:174-88; 14) Xiao C et al. A strain energy filter for 3D vessel enhancement with application to pulmonary CT 
images. Med Image Anal 2011;15:112-24; 15) Zhai Z et al. International Society for Optics and Photonics; 2016, accepted 
for publication; 16) Klok FA et al. Derivation of a clinical prediction score for chronic thromboembolic pulmonary 
hypertension after acute pulmonary embolism. J Thromb Haemost 2016;14:121-8; 17) Kamphuis VP et al. 
Electrocardiographic detection of right ventricular pressure overload in patients with suspected pulmonary hypertension. J 
Electrocardiol 2014;47:175-82. 

 
 
 
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Budget Summary 
• 
Please be sure to complete budget template (excel document) 
Total Amount Requested: 
(Include overhead) 
Total amount €430k 
 
Personal costs 
- 
2 years PhD student (1.0FTE): €150k  
- 
1 year Post-doc (1.0FTE): €100k 
 
Material costs 
- 
100x CT scans (including blinding, distribution and post-hoc analysis by 3 
independent radiologists):  €80k 
- 
100x Biomarkers (inclusive storage; NT-proBNP and Troponin): €20k 
- 
100x ECG (including post hoc vector analysis): €20k 
- 
Software/Hardware for pulmonary vasculature quantification development: €50k 
 
Other costs 
- 
IRB costs: €1k 
- 
Publication costs: €3k 
- 
Travel costs scientific meetings PhD student and Post-doc: €6k 
 
Additional sources of 
funding required? (Yes/No) 
If Yes, please be specific. 
No 
Timelines and Study Plans 
Number of Sites: 
 3 
Site Names: 
LUMC Leiden, the Netherlands 
VUmc, Amsterdam, the Netherlands 
AMC, Amsterdam, the Netherlands 
Study Start Date: 
1-1-2017 
Study End Date: 
1-1-2019 
Number of Subjects: 
100 
First Patient In Date: 
N.A. 
Last Patient Out Date: 
N.A. 
Enrollment Period in 
Months: 
2 years 

 
 
 
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Publication Plan 
 
Where are you planning to 
submit for publication? 
(journals, etc): 
We aim to extract multiple publications from this project, which will be submitted to top 
ranked cardiology/pulmonology oriented journals, such as Circulation, Eur Heart J, Eur 
Resp J or Am J Resp Crit Care. 
Are you planning to present 
your data at a scientific 
meeting? 
We will submit the abstract to the ESC annual meetings and/or ERS annual 
meetings 
Please list your target date 
for submission of 
publication. 
1-6-2019 
 
Drug Supply Information 
 
Drug Supplies Required 
(Yes/No)?   
 No 
List Drug Supplies and 
Amount Required: 
Drug Name: NA 
Amount: NA 
List Drug Supplies and 
Amount Required: 
Drug Name: NA 
Amount: NA 
Placebo Required 
(Yes/No)? 
 No 
Additional Sources of Drug 
Supply (Yes/No).  If Yes, 
please specify 
 No