Novel imaging approach using dual-layer CT to assess anticoagulant therapy efficacy in acute pulmonary embolism

Abstract

Background

To study the effects of direct oral anticoagulant (DOAC) treatment in patients with acute pulmonary embolism (PE), it is important to analyze iodine density perfusion maps by dual-layer spectral detector computed tomography (DLCT).

Purpose

To investigate whether the total lung iodine value (TLIV) obtained from CT pulmonary angiography (CTPA) using DLCT provides valuable insights for assessing treatment response in acute PE.

Material and Methods

We conducted a retrospective study enrolling individuals receiving DOAC therapy for acute PE. Using DLCT, lung CT imaging before contrast was performed, followed by two contrast phases (when the region of interest in the pulmonary artery exceeded 150 HU [pulmonary arterial phase (PAP)] and 60 s after the start of contrast administration). Changes in TLIV and TLIV/LV were assessed from pre-treatment to post-DOAC treatment in both greater clot resolution group (group 1) and lesser clot resolution group (group 2). In addition, a comparison of the iodine level ratio between PAP and 60 s (60s/PAP ratio) for TLIV and TLIV/LV before and after treatment was performed between the two groups.

Results

In total, 24 patients with acute PE were analyzed using DLCT before and after DOAC therapy. The TLIV (60s/PAP ratio; median 1.34, interquartile range [IQR]=1.18–1.72) of group 1 (n = 16) was significantly higher (P = 0.002) than the TLIV (60s/PAP ratio; median = 0.91, IQR = 0.79–0.99) of group 2 (n = 8).

Conclusion

Measuring the iodine maps of all lungs showed promise as the level of lung perfusion after DOAC treatment appeared to reflect the treatment effect in acute PE.

Keywords

Computed tomography pulmonary angiography dual-energy computed tomography anticoagulant therapy

Introduction

Pulmonary embolism (PE) is broadly classified into acute and chronic diseases. Acute PE is a fatal disease, and the number of patients with PE has increased (1). Rapid imaging is crucial, as timely intervention can significantly improve prognosis.

Surgical thrombectomy has been reported to be effective for acute PE with hemodynamic instability (2), while direct oral anticoagulants (DOAC) has been proven to be as effective for acute PE with hemodynamic stability (3). Fibrin is the primary component of thrombus, making anticoagulation therapy the standard treatment for PE. DOACs are the first-line treatment due to their efficacy, safety, and ease of use, outperforming conventional therapies such as heparin and warfarin (4).

Acute PE is typically diagnosed using ventilation/perfusion (V/P) scintigraphy (5); however, pulmonary perfusion imaging with iodine density during pulmonary arterial phase imaging has been shown to assess pulmonary blood flow distribution, comparable to scintigraphy with technetium^99m-labeled macroaggregated albumin (^99mTc-MAA) (6).

Dual-layer CT (DLCT), a form of dual-energy CT (DECT), collects multiple energy levels through spectroscopy from a continuous energy source at the CT detector. Computed tomography pulmonary angiography (CTPA) is the first-line diagnostic method for patients with suspected PE, with a sensitivity and specificity in the range of 96%–100% and 89%–98%, respectively (7). CTPA is recognized as an effective application of DECT, and iodine maps are considered the most valuable images produced (8,9). Although lung perfusion by CTPA has been evaluated in a single section using iodine maps (10), the significance of calculating iodine content across the entire lung field has not been discussed.

To study the effects of DOAC treatment in patients with acute PE, it is important to quantitatively and objectively analyze iodine density perfusion maps using DLCT before and after treatment. Most wedge-shaped perfusion defects are associated with PE; however, a small number of such defects may not be clearly identified on DECT (11).

The aim of the present study was to investigate whether the quantification of blood pool in the entire lung through iodine distribution (total lung iodine value [TLIV]) before and after DOAC treatment, as obtained from DLCT imaging parameters, reflects thrombolytic effects.

Material and Methods

Patients

We investigated 56 patients with clinically and radiologically suspected PE who underwent detailed thrombotic and pulmonary perfusion assessments using DLCT. This retrospective single-center study included patients suspected of having acute PE who were referred to our hospital for CTPA between July 2021 and June 2022. Only patients who underwent CT imaging with DLCT before and after DOAC treatment were included. This study has obtained ethics approval (RK-210511-2), and informed consent was obtained from all patients. Consecutive patients who met the following criteria for contrast-enhanced CT for acute PE were included: (i) chest pain/breathing pain (+), ST elevation by cardiac infarction (−) on heart electrogram; (ii) elevated D-dimer (+) level on blood sampling; and (iii) right ventricular dysfunction findings, such as right ventricular enlargement and bowing or leftward shift of the interventricular septum on echocardiogram. Patients who did not undergo follow-up CT were excluded, as well as those with malignant tumors, pregnancy or recent childbirth, surgical operations, nephrotic syndrome, or other significant heart or lung diseases.

The choice of dose and duration of DOAC treatment was at the discretion of the treating physicians. Each DOAC for the treatment and prevention of VTE was administered as follows: rivaroxaban (15 mg twice daily), apixaban (10 mg twice daily for 1 week and 5 mg twice daily thereafter), and edoxaban (60 mg once daily) after the diagnosis of deep vein thrombosis (DVT) or PE. However, the initial dose of each DOAC is sometimes reduced at the discretion of the physician.

A total of 35 patients were examined according to the PE protocol (as shown below); however, 15 patients did not undergo CT imaging with DLCT to assess treatment efficacy. Ultimately, 24 patients were included in the analysis (6 men, 18 women; mean age = 67.5 years; age range = 27–86 years).

CT examination protocol (PE protocol)

The DLCT scanner (IQon Elite Spectral CT, version 4.7.7; Philips Healthcare, Best, the Netherlands), scanning parameters, and contrast agent injection protocols are listed in Table 1. The CT contrast agent (ioversol 350, Optiray; Guerbet, Issy-les-Moulineaux, France) was intravenously injected at 2.5 mL/s via an antecubital vein. Using DLCT, lung imaging was performed before contrast administration and at two post-contrast phases as part of the PE protocol. The first was the pulmonary arterial phase (PAP), triggered when the region of interest (ROI) in the pulmonary artery exceeded 150 HU using a bolus tracking system. The second was a delayed phase acquired 60 s after the start of contrast injection, covering both the lungs and abdomen. A third scan, from the lungs to the lower legs, was performed 210 s after contrast administration to assess for DVT. All image data were transferred to a workstation (IntelliSpace Portal; ISP Release 11; Philips Healthcare) for evaluation of pulmonary perfusion in the coronal plane.

Table 1.

Scanning parameters and agent injection protocols.

Platform	IQon spectral CT
Tube voltage (KVp)	120
Tube current (mAs)	AEC
Helical pitch	0.891
Detector collimation (mm)	64 × 0.625
Rotation time (s)	0.27
Iodine dose (mg /kg)	600
Bolus tracking trigger (HU)	150
Scan delay (s)	25 / 50 / 160
Injection duration (s)	30
Fractional dose (mgI/kg/s)	20
Image reconstruction	Spectral level 3
iDOSE	Level 2 (5-mm slice), level 3 (1-mm slice)
Slice thickness (mm)	5, 1 (spectral image; 1 mm)

AEC, auto exposure control; CT, computed tomography.

Imaging analysis

CT images were interpreted in consensus by two board-certified radiologists (H.U. and Y.N., with 4 and 12 years of experience in chest CT, respectively). After careful review of all available images and information presented in our study, we determined whether a thrombus was present in the pulmonary artery. Pulmonary perfusion imaging using iodine density imaging was performed on various cross-sections (shown in Fig. 1a as a coronal image), and areas with reduced perfusion due to PE were recognized. Spectral-based image data were analyzed to determine the total pulmonary iodine dose using the ISP workstation (Fig. 1b), allowing for differentiation between artificial iodine deficiency caused by contrast medium stagnation in the subclavian vein and true embolic iodine deficiency. Visual assessment of the areas with reduced perfusion, as well as quantitative TLIV values, were performed. Two radiologists studied the effect of reduction of pulmonary arterial thrombi after DOAC treatment, dividing them into greater clot resolution group (group 1) and lesser clot resolution group (group 2).

Fig. 1.

(a) The coronal section image of a patient with acute pe. The obtained image data were sent to a workstation (IntelliSpace Portal; ISP; Philips Electronics) to assess the pulmonary perfusion of the contrast agent in the coronal section, as shown. The arrows indicate a decrease in lung perfusion due to PE. (b) ISP displays the average iodine content of all lungs and lung volumes, and the product of the two was used to calculate the total lung iodine content. TLIV is defined as total lung volume × mean iodine density. PE, pulmonary embolism; TLIV, total lung iodine value.

Iodine density perfusion map of whole lung

The lung volume (total lung volume; the area where air is seen within the imaging area, including the bronchi) and mean TLIV were displayed in the ISP. Image analysis was performed by consensus reading by two radiologists aware of the PE of the patients.

Using our software, lung volumes were automatically segmented. To eliminate intrapulmonary vessels and contrast-related artifacts within the vessels in the patients, regions with CT attenuation values below −250 HU were extracted from the segmented lung volume (12). Based on spectral-based imaging data, spectral sub-segmentation was applied to these regions to automatically calculate their volume and mean iodine concentration. The total pulmonary iodine content was then derived as the product of volume and mean iodine concentration.

TLIV is defined as total lung volume × mean iodine density.

The ratio and the difference of 60 s after the start of contrast administration to PAP are defined as 60s/PAP and 60s-PAP of TLIV, respectively.

The treatment effects of DOAC were quantitatively evaluated by analyzing the iodine density perfusion map of the entire lung.

Statistical analysis

The Wilcoxon signed-rank test was used to compare the median values of the pre- and post-treatment parameters. The Mann–Whitney U-test was used to compare the median values of the parameters between the groups 1 and 2. Statistical significance was set at P <0.05. Analyses were performed using SPSS version 29.0 (IBM Corp., Armonk, NY, USA) and JMP Pro version 17.0.0 (SAS Institute Inc., Cary, NC, USA).

Results

Patients

This study included 39 patients with acute PE who underwent DOAC therapy; however, 15 patients were excluded for not undergoing CT imaging with DLCT to assess efficacy after DOAC treatment. Finally, 24 patients with acute PE were analyzed using DLCT before and after DOAC therapy. A flowchart illustrating the derivation of the final population from the enrolled patients is shown in Fig. 2. The D-dimer level before DOAC treatment was 12.7 µg/mL (range = 5.1–20.1 µg/mL), which decreased to 1.7 µg/mL (range = 1.0–4.3 µg/mL) after treatment (Table 2). The median CT time interval before and after DOAC therapy was 14 days (interquartile range [IQR] = 11.3–14.0).

Fig. 2.

A flowchart for study enrollment of patients with acute pulmonary embolism.

Table 2.

Patient characteristics.*

	Total (n = 24)	Group 1 (n = 16)	Group 2 (n = 8)	P value
Sex
Male	6 (25)	3 (18.8)	3 (37.5)
Female	18 (75)	13 (81.3)	5 (62.5)
Age (years)	67.5 (50.0–79.5)	73 (59.5–81.75)	56.0 (44.5–68.5)	0.11
Pre- and post-treatment CT scan interval (days)	14 (11.3–14.0)	14 (11.3–14.0)	13 (11.3–14.0)	0.70
Pre-treatment SpO2 (%)	96 (94–97)	96 (95–97)	94.5 (94.0–98.3)	0.32
Post-treatment SpO2 (%)	96 (96–99)	97 (95–99)	96 (95.3–98.3)	0.70
Pre-treatment D-dimer (μg/ml)	12.7 (5.1–20.1)	12.6 (4.7–17.9)	20.1 (10.9–27.8)	0.22
Post-treatment D-dimer (μg/ml)	1.7 (1.0–4.3)	1.7 (1.0–3.2)	2.0 (1.0–4.9)	0.41

Values are given as n (%) or median (IQR). Mann–Whitney U-test was used.

*Group 1, greater clot resolution. Group 2, lesser clot resolution.

Comparison of whole lung iodine levels before and after DOAC treatment

The mean iodine levels at pre-contrast, PAP, and 60 s were compared before and after DOAC treatment. Although there was no significant difference between pre-contrast and post-treatment at the pre-contrast phase (P = 0.07) (Fig. 3a) and the PAP phase (P = 0.49) (Fig. 3b), a significant difference was observed at 60 s (P = 0.04) (Fig. 3c). In addition, the 60s/PAP ratio for the TLIV (P = 0.09) (Fig. 3d) did not show a significant before and after difference in treatment.

Fig. 3.

(a–d) Box and whisker diagrams. The mean iodine levels pre-contrast, PAP, and 60 s were compared between pre- and post-treatment, and a significant difference at 60 s was observed (c). The mean iodine levels at (a) pre-contrast, (b) PAP, and (d) 60s/PAP ratios were not significantly different before and after treatment. PAP, pulmonary arterial phase; TLIV, total lung iodine value.

Comparison between groups 1 and 2

A total of 24 patients with acute PE were analyzed using DLCT before and after DOAC therapy. The TLIV (60s/PAP ratio; 1.34; IQR = 1.18–1.72) for group 1 (n = 16) was significantly (P = 0.002) higher compared to the TLIV (60s/PAP ratio; 0.91; IQR = 0.79–0.99) for group 2 (n = 8).

The 60s/PAP ratio of TLIV for group 1 (n = 16) was significantly higher (P = 0.001) than that of group 2 (n = 8) (0.91; IQR = 0.79–0.99). Between pre- and post-treatment, the TLIV ratio (60s/PAP) was significantly higher (P = 0.001) in group 1 compared to group 2 (Fig. 4a). The difference in TLIV between 60 s and PAP (60s—PAP) was also significantly (P = 0.001) higher in group 1 than in group 2 (Fig. 4b). However, the pre- and post-treatment ratios of TLIV at 60 s were not significantly different (P = 0.24) (Fig. 4c), and the difference in TLIV between pre- and post-treatment at 60 s was not significant (P = 0.19) (Fig. 4d).

Fig. 4.

Box and whisker diagrams of greater clot resolution (group 1) and lesser clot resolution (group 2). (a) Pre- and post-treatment ratios of the rate of increase in TLIV (60s/PAP) between groups 1 and 2. The pre- and post-treatment ratios of the rate of increase in TLIV (60s/PAP) were significantly higher (P = 0.002) in group 1 than in group 2. **P < 0.01 by Mann–Whitney U-test. (b) The difference (60s–PAP) in the pre- and post-treatment ratio in TLIV between groups 1 and 2. The difference (60s–PAP) in the pre- and post-treatment ratio in TLIV was significantly higher (P = 0.002) in group 1 than in group 2. **P < 0.01 by Mann–Whitney U-test. (c) Pre- and post-treatment ratios at 60 s for the TLIV between groups 1 and 2. Pre- and post-treatment ratios at 60 s for the TLIV were not significantly different (P = 0.2324) between groups 1 and 2. (d) The difference between pre- and post-treatment TLIV at 60 s between groups 1 and 2. The difference between pre- and post-treatment TLIV at 60 s is not significant (P = 0.1880). PAP, pulmonary arterial phase; TLIV, total lung iodine value.

Discussion

This is the first report on CT monitoring of thrombus regression and measurement of total pulmonary iodine content after DOAC therapy using DLCT. Total lung iodine measurement is a highly objective and highly reproducible method compared to lung perfusion measurement using an arbitrary ROI in the lung field. The objective of this study was to evaluate the regression of pulmonary arterial thrombus by early CT examination after DOAC, with the total pulmonary iodine dose to the whole lung in groups 1 and 2. In patients with acute PE treated with DOAC, the rate of increase in total pulmonary iodine levels at PAP and 60 s after contrast injection was greater in group 1 compared to group 2. TLIV using DECT is an indicator that enables visualization and quantification of perfusion improvement after PE treatment and may contribute to the evaluation of treatment efficacy and optimization of DOAC administration.

Appropriate CT reconstruction significantly improves the visibility of small clots in the pulmonary artery. However, when a pulmonary artery thrombus dissolves at one site but remains at another, it becomes challenging to objectively analyze the rate of thrombus reduction. Our method of measuring the total pulmonary iodine content involved assessing the increase in pulmonary blood flow due to thrombus dissolution at a ratio of 60 s after contrast to PAP after contrast, reflecting the blood flow supplied from the pulmonary arteries to the pulmonary interstitium across the entire lung field.

Taking two-phase images—one at PAP, when there is a high concentration of contrast agent in the pulmonary arteries, and the other at 60 s, when the contrast agent is fully distributed in the pulmonary interstitium—can be valuable for understanding pulmonary hemodynamics.

Pulmonary perfusion scintigraphy is a widely used method for monitoring pulmonary blood flow using technetium^−99m macroaggregated albumin (^99mTc-MAA). Dissaux et al. (10) found that pulmonary perfusion scintigraphy and CTPA are equivalent assessing pulmonary perfusion. Based on a report by Hayashino et al. (13), CTPA has greater discriminatory power than pulmonary perfusion scintigraphy for diagnosing PE. Therefore, analyzing pulmonary perfusion and pulmonary arterial thrombus CTPA is practical for excluding PE in urgent clinical settings.

DLCT can reflect the redistribution of iodine in the lung parenchyma, which is consistent with the distribution of blood perfusion, because retrospective spectral image reconstruction is available after the examination is completed in patients with acute PE. Lung perfusion imaging with CTPA is better used to detect the number of emboli in the lung lobes, lung segments, and lung subsegments (14).

In our case series, patients received early anticoagulation therapy for acute PE. To investigate the effect of DOAC in patients with acute PE, we analyzed iodine density perfusion maps of the whole lung obtained from DLCT before and after treatment. When the total iodine content of all lungs was used to quantitatively evaluate the therapeutic effect of DOAC, the 60s/PAP ratio and the 60 s–PAP difference were found to be significantly higher in group 1 compared to group 2, by analyzing the iodine density perfusion maps in all lung fields.

We found it important to evaluate total lung iodine value from CTPA with DLCT in acute PE because setting the region of interest arbitrarily can lead to variations in measured pulmonary blood flow. To our knowledge, this is the first study to assess the total pulmonary iodine content using DLCT.

Pre- and post-treatment comparisons of total pulmonary iodine levels show a high 60s/PAP ratio and 60s–PAP difference if thrombolysis in the pulmonary artery was good and a low 60s/PAP ratio and 60s–PAP difference if thrombolysis was poor. Individual differences in pulmonary hemodynamics make it difficult to adequately assess the reduction in pulmonary perfusion due to PE simply by comparison at a certain time after contrast medium injection. Therefore, in our study, we used a blood flow ratio (60s/PAP ratio) at two time points after contrast enhancement. This method not only shows the thrombus in the pulmonary artery but also the rate and difference of increase in pulmonary blood flow between PAP and 60 s, making it a simple way to assess pulmonary perfusion.

In PAP, we believe that measuring the high concentration of contrast agent retained in the subclavian vein during the PAP may increase iodine concentration within the lungs. The analysis software used extracts substances with CT values in the range of −1250 HU to −250 HU. Therefore, arteries and veins within the imaging range, including the subclavian vein with high CT values, are not extracted. As a result, it is expected that this approach not only avoids influencing the increase in iodine concentration within the lungs but also removes venous vessels and contrast agent artifacts.

The present study has some limitations. First, it was performed at a single center, and the number of patients was relatively small. A multicenter study with a larger number of patients is recommended to confirm these results. Second, our study had a patient selection bias because of the heterogeneity of acute PE etiologies. A prospective multicenter study with a unified etiology is recommended. Third, this study did not obtain cardiac function parameters such as echocardiographic data, and therefore we cannot exclude the potential influence of cardiac function on the observed decrease in iodine perfusion. Further studies incorporating indicators of cardiac function, such as echocardiography, are needed to evaluate the potential impact of cardiac function on iodine perfusion measurements.

In conclusion, it is important to evaluate TLIV using CTPA with DLCT in acute PE before and after DOAC treatment because total lung iodine measurement is a highly objective and highly reproducible method, and the amount of perfusion in all lungs after DOAC treatment suggests a reflection of the treatment effect of acute PE.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MO reports grants and personal fees from Guerbet (grant 2022-DEV-AM-AR-0038 G.0109) and Japanese Grants-in-Aid for Scientific Research (22K07730).

ORCID iDs

Masahiro Okada

Ryoji Aoki

Yasuo Okumura

References

Kucher

Rossi

De Rosa

, et al. Massive pulmonary embolism. Circulation 2006;113:577–582.

Shiomi

Kiyama

Shimizu

, et al. Surgical embolectomy for high-risk acute pulmonary embolism is standard therapy. Interact Cardiovasc Thorac Surg 2017;25:297–301.

Büller

Prins

Lensin

, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–1297.

Bauersachs

Berkowitz

Brenner

, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–2510.

Mortensen

Gutte

. SPECT/CT and pulmonary embolism. Eur J Nucl Med Mol Imaging 2014;41:S81–S90.

Thieme

Becker

Hacker

, et al. Dual energy CT for the assessment of lung perfusion–correlation to scintigraphy. Eur J Radiol 2008;68:369–374.

Stein

Fowler

Goodman

, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006;354:2317–2327.

Cai

Feng

Qiu

, et al. Iodine distribution map in dual-energy computed tomography pulmonary artery imaging with rapid kVp switching for the diagnostic analysis and quantitative evaluation of acute pulmonary embolism. Acad Radiol 2015;22:743–751.

Rajiah

. Dual-Energy computed tomography in thoracic imaging-current practices and utility: survey of the society of thoracic radiology. J Thorac Imaging 2020;35:W43–w50.

10.

Dissaux

Le Floch

Robin

, et al. Pulmonary perfusion by iodine subtraction maps CT angiography in acute pulmonary embolism: comparison with pulmonary perfusion SPECT (PASEP trial). Eur Radiol 2020;30:4857–4864.

11.

Bauer

Kerl

Weber

, et al. Lung perfusion analysis with dual energy CT in patients with suspected pulmonary embolism–influence of window settings on the diagnosis of underlying pathologies of perfusion defects. Eur J Radiol 2011;80:e476–e482.

12.

Müller

Lim

Eichinger

, et al. Influence of fissure integrity on quantitative CT and emphysema distribution in emphysema-type COPD using a dedicated COPD software. Eur J Radiol 2017;95:293–299.

13.

Hayashino

Goto

Noguchi

, et al. Ventilation-perfusion scanning and helical CT in suspected pulmonary embolism: meta-analysis of diagnostic performance. Radiology 2005;234:740–748.

14.

Zhang

Cai

Liu

, et al. Value of dual-energy lung perfusion imaging using a dual-source CT system for the pulmonary embolism. Open Life Sci 2018;13:107–111.