Gaël Picart

M.D Philippe Robin

Cécile Tromeur

PhD, Charles Orione

M.S Leela Raj

BHSc Nicolas Ferrière

M.D Raphael Le Mao

PhD Pierre-Yves Le Roux

PhD Pierre-Yves Le Floch

M.D Catherine A Lemarié

PhD Michel Nonent

PhD Christophe Leroyer

PhD Marie Guegan

M.S Karine Lacut

PhD Pierre-Yves Salaün

PhD Francis Couturaud
email: francis.couturaud@chu-brest.fr

Predictors of residual pulmonary vascular obstruction after pulmonary embolism: Results from a prospective cohort study

Keywords: Pulmonary embolism, Ventilation/Perfusion lung scan, residual pulmonary vascular obstruction, follow-up

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Pulmonary embolism (PE) is the most severe clinical presentation of venous thromboembolism (VTE). [START_REF] Sanchez | Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l'adulte. Version courte[END_REF][START_REF] Delluc | Current incidence of venous thromboembolism and comparison with 1998: a community-based study in Western France[END_REF][START_REF] Andersson | Incidence of acute pulmonary embolism, related comorbidities and survival; analysis of a Swedish national cohort[END_REF] The main complications are recurrent VTE, fatal and non-fatal, and chronic thromboembolic pulmonary hypertension (CTEPH). Beyond the initial three to six months of anticoagulation, anticoagulant treatment is either pursued or not, based on the presence or the absence of clinical risk factors. When PE is provoked by a major transient risk factor (e.g. surgery), the risk of recurrent VTE is low (≤3%) and anticoagulation should not be prolonged. [START_REF] Sanchez | Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l'adulte. Version courte[END_REF] Conversely, in the absence of major transient risk factors, the risk of recurrence is high (no identifiable clinical risk factors) or intermediate (presence of minor risk factors).

Several randomized trials comparing different anticoagulation durations have demonstrated that extending anticoagulation up to 1 or 2 years was effective in these patients, but the benefit was lost after stopping anticoagulation. [START_REF] Khan | Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and metaanalysis[END_REF][START_REF] Couturaud | Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial[END_REF][START_REF] Prandoni | The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients[END_REF] Thus, current guidelines recommend indefinite anticoagulation. [START_REF] Sanchez | Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l'adulte. Version courte[END_REF][START_REF] Konstantinides | ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)[END_REF] However, as the risk of bleeding might outweigh the risk of recurrent VTE over time, it remains uncertain whose patients will really benefit from indefinite anticoagulation. Hence, identification of predictors for recurrence is a major issue. [START_REF] Sanchez | Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l'adulte. Version courte[END_REF][START_REF] Couturaud | Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial[END_REF][START_REF] Prandoni | The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients[END_REF][START_REF] Konstantinides | ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)[END_REF][START_REF] Lecumberri | Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism[END_REF][START_REF] Tromeur | Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial[END_REF] Recently, several studies found that residual pulmonary vascular obstruction (RPVO), assessed by ventilation/perfusion (V/Q) lung scan, was an independent predictor of recurrent VTE. [START_REF] Tromeur | Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial[END_REF][START_REF] Planquette | Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism. A single center cohort study[END_REF][START_REF] Pesavento | Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism[END_REF][START_REF] Wan | Residual pulmonary embolism as a predictor for recurrence after a first unprovoked episode: Results from the REVERSE cohort study[END_REF][START_REF] Becattini | Risk of recurrent venous thromboembolism after acute pulmonary embolism: Role of residual pulmonary obstruction and persistent right ventricular dysfunction. A meta-analysis[END_REF] However, V/Q lung scan is a costly examination, with unequal accessibility, and the radiation exposure remains to be considered. Consequently, establishing criteria for targeting patients at increased risk of RPVO, who may therefore benefit from a V/Q lung scan in the follow-up of a PE, is clinically relevant.

In a recent sub-analysis of the PADIS-PE randomized trial, we found that age≥65 years, chronic respiratory disease, initial pulmonary vascular obstruction (IPVO) at PE diagnosis and elevated Factor VIII were independent predictors of RPVO≥5% in a population of unprovoked PE. [START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF] Another study found that age and unprovoked PE were risk factor of RPVO. [START_REF] Sanchez | Perfusion defects after pulmonary embolism: risk factors and clinical significance[END_REF] In this prospective cohort study, we aimed to determine the prevalence of RPVO on V/Q lung scans performed at 3 to 24 months during the follow-up after an acute episode of PE, provoked or not. Secondary objective was to identify predictors for RPVO.

Methods

Cohort Design and population

This study is based on our previously described single-center prospective cohort of patients with VTE. [START_REF] Delluc | Association of common genetic variations and idiopathic venous thromboembolism: Results from EDITh, a hospital-based case-control study[END_REF] Since January 1 st 1992, consecutive patients who had been hospitalized or referred to Brest University Hospital outpatient VTE clinic for management of symptomatic VTE were included if they were 18 years old or older and were able to sign the written consent. After inclusion, all cases were followed up without scheduled stopping date.

Patients were managed according to current guidelines and physician's experience.

Identification of study population

In the present analysis, patients were eligible if they had a symptomatic acute PE (with or without associated DVT) and if they underwent a planned V/Q lung scan at 3 to 24 months (90 to 745 days) during the follow-up after PE diagnosis. The diagnosis of index PE was based on objective, standardized and validated criteria. [START_REF] Sanchez | Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l'adulte. Version courte[END_REF][START_REF] Konstantinides | ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)[END_REF] Symptomatic PE was confirmed if there was: (i) a high clinical probability and a high-probability ventilation-perfusion lung scan according to the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) criteria; or (ii) a positive computed tomography pulmonary angiography (CTPA) showing a central filling defect outlined by contrast material, or a complete occlusion in a segmental or more proximal pulmonary artery; or (iii) a proximal DVT evidenced by ultrasonography in a patient with symptoms of PE.

To identify all the subjects who underwent planar V/Q lung scan during their followup as intended, a search by the ICD-10 (International Classification of Diseases, tenth edition) code and keywords was conducted in the Brest University Hospital database and crossed with our cohort study database. All imaging tests were then collected from medical records, and, when available, were printed to establish the RPVO retrospectively.

Patients were excluded if they had: (i) an evaluation at 3 to 24 months with tomography V/Q lung scintigraphy, V/Q single photon emission computed tomography (SPECT) or CTPA instead of planar V/Q lung scan; (ii) a history of pneumonectomy; (iii) a diagnosis of recurrent PE at the time of V/Q lung scan assessment at 3 to 24 months; or (iiii) if the imaging was not available for printing.

Outcome

The main outcome was to determine the prevalence of RPVO 5% on V/Q lung scan performed 3 to 24 months after PE diagnosis. The cut-off of 5% was based on our previously published post-hoc analysis of the PADIS PE trial. [START_REF] Tromeur | Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial[END_REF] RPVO was calculated for each perfusion scan by an experienced and three independent nuclear medicine physicians (P.R., PY.LR. PY. S.), blinded to patients' characteristics and using the score previously described by Meyer et al (see supplement data). [START_REF] Meyer | Comparison of perfusion lung scanning and angiography in the estimation of vascular obstruction in acute pulmonary embolism[END_REF] For the main outcome, RPVO was assessed whether a CTEPH was diagnosed or not at the time of follow-up evaluation by V/Q lung scan. In our cohort, all patients with a suspicion of CTEPH were investigated according to international recommendations and CTEPH was confirmed by a reference team specialized in pulmonary hypertension. In a sensitivity analysis, patients with CTEPH were excluded (see statistic section).

The identification of potential risk factors for the primary outcome (RPVO 5% with or without CTEPH) was based on the following predefined and prospectively collected data at the time of index PE and during follow-up: demographics, risk factors for VTE, comorbid conditions and therapeutic management of VTE. Chronic respiratory failure was defined by oxygen partial pressure inferior to 60 mmHg on two occasions on arterial blood gaz. Index PE was classified as provoked by a major transient risk factor in the presence of at least one of the following: surgery, hospitalization longer than 3 days, leg trauma with immobilization (including plaster cast), estrogen-containing contraception, hormone replacement therapy or treatment for assisted reproduction, pregnancy or postpartum within the past 3 months and active cancer at the time of PE diagnosis. VTE was considered as unprovoked in the absence of these risk factors. [START_REF] Sanchez | Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l'adulte. Version courte[END_REF] In addition, when available, initial pulmonary vascular obstruction (IPVO) score at index PE was calculated either on CTPA imaging (using Qanadli score) (see supplement data) [START_REF] Qanadli | New CT index to quantify arterial obstruction in pulmonary embolism: comparison with angiographic index and echocardiography[END_REF] or on V/Q lung scan (using Meyer score) [START_REF] Meyer | Comparison of perfusion lung scanning and angiography in the estimation of vascular obstruction in acute pulmonary embolism[END_REF] .

Statistical methods

The main analysis (first model) was conducted on the whole population included in the study where RPVO was available. A secondary analysis (second model) was conducted only on patients whose RPVO and IPVO were available. Lastly, two sensitivity analyses were performed: (1) after exclusion of patients with a documented CTEPH; and (2) on the study population for the risk factors of RPVO≥10%. For each model, an univariable analysis was performed in order to evaluate the association between each potential predictor and the occurrence of RPVO measured at 3 to 24 months after PE diagnosis. Proportion and p-values were calculated for each variable, using Chi-squared test or Student test when appropriate.

Variables were then included in multivariable models if they respected the following criteria: (1) a p-value<0.20 in univariable analysis, (2) a prevalence ≥3%, and (3) a clinical relevance. Discriminant threshold values of continuous variables were established based on clinical relevance and previous studies on RPVO, age and BMI. [START_REF] Tromeur | Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial[END_REF][START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF] For IPVO, it was based on the calculation of area under the curve (AUC) of receiver operating curve (ROC) and Youden index calculation. The multivariable analyses were then conducted using a logistic regression model. All tests were two-sided and a p-value less than 0.05 was considered statistically significant. Statistical analyses were performed using the R-studio software (R Development Core Team (2005). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL: http://www.Rproject.org.)

Results

Patients

On July 31 st 2018, among the 5449 included patients with VTE in the Brest cohort, 3056 had PE, of whom pulmonary imaging test during follow-up was available in 674 PE patients. Among those, 137 presented one or more exclusion criteria (Figure 1): 10 had CTPA and 55 had SPECT instead of V/Q lung scan during follow-up, 18 were recurrent PE at the time of V/Q lung scan during follow-up, 4 had pneumonectomy and 50 V/Q lung scans were not available for RPVO assessment. Finally, 537 patients were included in the main study analysis. For the secondary analysis, IPVO scores at the time of PE diagnosis were available for 256 patients.

Baseline characteristics of population and index PE (Table 1)

Mean (SD) age of the study population was 60.6 (16.9) years; women were 292 (54.4%).

Index PE was provoked in 182 patients (33.9%), in whom 30 had an active cancer and 152 had at least one major transient risk factor. At the acute phase of PE, 9 patients had thrombolysis (1.7%), initial anticoagulant therapy was direct oral anticoagulant in 82 (15.3%), vitamin K antagonist (VKA) (with initial heparin) in 420 (78.7%) and low-molecular weight heparin alone in 32 (6.0%). Regarding anticoagulation duration, 525 patients (98.3%) received anticoagulation for at least 3 months and 405 (75.8%) for at least 6 months. 419 patients (78.5%) were still on anticoagulant treatment at V/Q lung scan date, whereas 115 (21.5%) had stopped it. In the 256 patients with available IPVO at the time of PE diagnosis, IPVO was established on CTPA for 49 (18.4%) patients and on V/Q lung scans for 207 (81.6%).

Residual pulmonary vascular obstruction (RPVO) (

Assessment of predictors for RPVO≥5% 3 to 24 months from PE (primary outcome)

In the univariable analysis on the whole population (n=537), age and chronic respiratory failure were associated with a significant increased risk of RPVO ≥5% (Table 1), which was confirmed in multivariable analysis (OR 2.25 [95%CI, 1.45-3.52] and OR 3.19 [95%CI, 1.22-10.04], respectively) (Table 3).

Secondary outcome and sensitivity analyses

In the 256 patients with available IPVO at the time of PE diagnosis, mean (SD) IPVO and RPVO were 30.9% (21.7) and 10.5% (13.7), respectively (p<0.001). ROC analysis yielded the most discriminant value of IPVO according to RPVO ≥5% at 20% (AUC: 0.67, 95%CI, 0.61-0.74) (Figure 2). In univariable analysis, IPVO was found to be a significant risk factor for RPVO ≥5% (p<0.001) (Table 1). In multivariable analysis, age ≥65 years, unprovoked PE and IPVO ≥20% were found to be independent predictors for RPVO ≥5% (OR 2.78 [95%CI, 1.41-5.53], OR 2.11 [95% CI, 1.11-4.07] and OR 2.94 [95% CI, 1.68-

5.20], respectively) (Table 3).

Sensitivity analyses in which the 17 patients with CTEPH were excluded or outcome was defined by RPVO≥10% were consistent with our main and secondary analyses (see supplement data).

Discussion

In this large prospective study, based on 537 patients who had suffered from a symptomatic acute PE and who underwent a lung scan evaluation at 3 to 24 months during follow-up for reason other than recurrent PE, we found that age ≥65 years and chronic respiratory failure were independent predictors of persistent pulmonary vascular obstruction, as defined by RPVO≥5%. In the subgroup of 256 patients in which IPVO was available, age ≥65 years, IPVO≥20% and unprovoked PE were independent predictors of RPVO. These results were consistent across sensitivity analyses.

During a mean follow-up period of 8 months for acute PE, 51.8% of patients had RPVO≥5% and 35.6% had RPVO≥10% using planar V/Q lung scan. Despite heterogeneity in literature regarding the type of imaging assessment, time from PE diagnosis, population's characteristics or RPVO definition, this prevalence of perfusion sequelae is consistent with other studies that used planar V/Q lung scan, that is more accurate than CT scan for pulmonary vascular obstruction assessment. [START_REF] Planquette | Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism. A single center cohort study[END_REF][START_REF] Pesavento | Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism[END_REF][START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF][START_REF] Sanchez | Perfusion defects after pulmonary embolism: risk factors and clinical significance[END_REF][START_REF] Wartski | Incomplete recovery of lung perfusion after 3 months in patients with acute pulmonary embolism treated with antithrombotic agents[END_REF][START_REF] Chopard | Detection of Residual Pulmonary Vascular Obstruction by Ventilation-Perfusion Lung Scan Late After a First Pulmonary Embolism[END_REF][START_REF] Es J Van, Douma | Clot resolution after 3 weeks of anticoagulant treatment for pulmonary embolism: comparison of computed tomography and perfusion scintigraphy[END_REF][START_REF] Cosmi | Residual emboli on lung perfusion scan or multidetector computed tomography after a first episode of acute pulmonary embolism[END_REF][START_REF] Tunariu | Ventilation-Perfusion Scintigraphy Is More Sensitive than Multidetector CTPA in Detecting Chronic Thromboembolic Pulmonary Disease as a Treatable Cause of Pulmonary Hypertension[END_REF] We chose a threshold value of 5% for RPVO based on previous studies demonstrating that this cutoff was the most discriminant for predicting the risk of recurrent PE. [START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF] This cut-off has anatomical relevance as it reflects vascular obstruction of one pulmonary segment. [START_REF] Tromeur | Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial[END_REF][START_REF] Wan | Residual pulmonary embolism as a predictor for recurrence after a first unprovoked episode: Results from the REVERSE cohort study[END_REF][START_REF] Gottschalk | Ventilation-perfusion scintigraphy in the PIOPED study. Part II. Evaluation of the scintigraphic criteria and interpretations[END_REF] Among potential predictors for RPVO ≥5%, we confirmed that age of 65 years or older was the strongest, in the main as well as in the secondary and sensitivity analyses.

Several studies reported age as a risk factor for RPVO, which is confirmed by our results. [START_REF] Planquette | Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism. A single center cohort study[END_REF][START_REF] Pesavento | Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism[END_REF][START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF][START_REF] Sanchez | Perfusion defects after pulmonary embolism: risk factors and clinical significance[END_REF][START_REF] Poli | Risk of recurrence in patients with pulmonary embolism: Predictive role of D-dimer and of residual perfusion defects on lung scintigraphy[END_REF] One potential explanation is that advancing age is correlated with more important inflammation as well as pulmonary and vascular deterioration. [START_REF] Fleg | Age-associated changes in cardiovascular structure and function: a fertile milieu for future disease[END_REF][START_REF] Kovacs | The aging lung[END_REF] The second important finding is the observation of a 3-fold increased risk of RPVO ≥5% in patients having IPVO ≥20% at PE diagnosis. This was observed on a subgroup of patients whose IPVO was available and a selection bias leading to over-or under-estimation could not be excluded. However, the baseline characteristics of this sample were very similar to that of the overall study population, especially regarding comorbid conditions, PE risk factors, initial management and prevalence of RPVO (supplementary Table S1), which is in agreement with other studies [START_REF] Planquette | Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism. A single center cohort study[END_REF][START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF][START_REF] Sanchez | Perfusion defects after pulmonary embolism: risk factors and clinical significance[END_REF] . In addition, the 20% cutoff of IPVO, yielded by ROC curve analysis, is concordant with our previous study showing that 25% is the most discriminant threshold value. [START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF] Interestingly, we observed a trend towards an increased risk of RPVO ≥5% in patients with unprovoked PE as compared to those with PE provoked by a major transient risk factor. This result was also statistically significant when the analysis was restricted to patients with available IPVO at the time of PE diagnosis. Although this association was weak, it is supported by clinical and biochemical data. In a large prospective cohort study of 647 patients with acute PE, Pesavento et al found a statistically significant association between unprovoked PE and RPVO assessed by perfusion lung scan 6 months after an acute PE. [START_REF] Pesavento | Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism[END_REF] In addition, there is evidence that patients with unprovoked VTE are more likely to have an underlying thrombophilia, which might increase the risk of unresolved PE. [START_REF] Couturaud | Factors that predict thrombosis in relatives of patients with venous thromboembolism[END_REF] Nevertheless, further trials are needed to confirm this observation.

In contrast to others, some potential risk factors were not associated with RPVO. First, results about chronic respiratory diseases were not consistent across models. In our prospective cohort, chronic pulmonary disease was actually defined as chronic respiratory failure, which does not include common respiratory conditions such as non-severe COPD or asthma. In addition, the prevalence of this condition was very low. However, when excluding patients with chronic respiratory failure, results on other predictors were unchanged (data not shown). Furthermore, the impact of chronic respiratory disease on RPVO might not be negligible, not only because of the functional impairment of the respiratory system but also by intrinsic characteristics. In our large double-blind randomized trial PADIS-PE, we previously found that chronic respiratory disease was an independent predictor for RPVO. [START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF] Indeed, several publications suggest that moderate to severe COPD is associated with an increased thrombotic risk due to increased levels of proinflammatory cytokines, notably interleukin-6, that increase thrombogenicity of endothelial surface and coagulation cascade induction. [START_REF] Bertoletti | Clinical Presentation and Outcome of Venous Thromboembolism in COPD[END_REF][START_REF] Voelkel | Pulmonary Vascular Involvement in Chronic Pulmonary Disease[END_REF][START_REF] Vaidyula | Circulating Tissue Factor Procoagulant Activity is Elevated in Stable Moderate to Severe Chronic Obstructive Pulmonary Disease[END_REF][START_REF] Jankowski | Activated Factor XI and Tissue Factor in Chronic Obstructive Pulmonary Disease: Links with Inflammation and Thrombin Generation[END_REF] Second, personal history of previous PE and presence of cancer were not associated with an increased risk of RPVO. This is likely due to a selection bias as patients with such past history may have been proposed more often indefinite anticoagulation.

Our findings may have important implications for daily clinical practice and for future clinical research studies. The underlying question of the study was to identify which patients would benefit from a V/Q lung scan during their follow-up after an acute episode of PE. This imaging test may have an important weight, when faced both to the question of optimal anticoagulation duration and follow-up modalities. First, there is evidence that RPVO is an important predictor of recurrent VTE. [START_REF] Tromeur | Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial[END_REF][START_REF] Planquette | Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism. A single center cohort study[END_REF][START_REF] Pesavento | Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism[END_REF][START_REF] Wan | Residual pulmonary embolism as a predictor for recurrence after a first unprovoked episode: Results from the REVERSE cohort study[END_REF] Second, V/Q lung scan is a key test for the detection and the diagnosis of CTEPH, in association with transthoracic echocardiography and right heart catheterization. Third, it has been shown that about one third of patients with an acute PE will have persistent dyspnea and physical performances and quality of life alteration, mostly related to residual pulmonary vascular obstruction. [START_REF] Sanchez | Perfusion defects after pulmonary embolism: risk factors and clinical significance[END_REF][START_REF] Klok | The post-PE syndrome: a new concept for chronic complications of pulmonary embolism[END_REF] In this setting, recent international guidelines emphasized on the necessity to provide an integrated model of patient care including searching for the entire spectrum of post-PE symptoms and functional limitations. [START_REF] Sanchez | Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l'adulte. Version courte[END_REF][START_REF] Khan | Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and metaanalysis[END_REF][START_REF] Held | Functional Characterization of Patients with Chronic Thromboembolic Disease[END_REF][START_REF] Claeys | Impaired Cardiac Reserve and Abnormal Vascular Load Limit Exercise Capacity in Chronic Thromboembolic Disease[END_REF][START_REF] Kahn | Functional and Exercise Limitations After a First Episode of Pulmonary Embolism[END_REF][START_REF] Fernandes | From Acute to Chronic Thromboembolic Disease[END_REF] Thus, screening for RPVO using lung scan reassessment around 3 to 6 months from an acute PE may be part of risk/benefit balance for continuing anticoagulation and may detect patients who require a close follow-up and complementary tests to detect chronic thromboembolic disease or CTEPH. However, V/Q lung scan cannot be proposed to every patient after PE, for reasons such as cost, radiation exposure or accessibility. [START_REF] Konstantinides | ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)[END_REF] Although validation studies are needed, particularly in patients with persistent dyspnea, our results, based on a selected population, provide evidence to help identifying patients at risk of RPVO in clinical practice.

Our work has several strengths: (1) it is one of the largest prospective cohort on this scientific area; (2) enrolment of patients was prospective with objectively diagnosed and adjudicated symptomatic PE and long term follow-up; (3) the main outcome (i.e. RPVO) was measured by experienced physicians blinded to patients' characteristics; and (4), results were consistent across models and sensitivity analyses. Some limitations should be underlined. First, the inclusion method of the overall population, based on patients who underwent V/Q lung scan in their follow-up, might have led to selection bias. Hence, V/Q lung scan for the screening of RPVO may have been used mostly in severe patients or in case of persistent dyspnea despite anticoagulation months after an acute PE. However, baseline characteristics, as well as results, were consistent with other studies in which V/Q lung scan was systematically performed for every patient, including a randomized trial. [START_REF] Pesavento | Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism[END_REF][START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF][START_REF] Sanchez | Perfusion defects after pulmonary embolism: risk factors and clinical significance[END_REF] Second, one could argue that inclusion of CTEPH patients in the analysis might invalid conclusions because of a potentially different pathophysiology with chronic thrombo-embolic disease. However, in practice, V/Q lung scan at distance of acute PE is often performed in patients who remain symptomatic despite anticoagulation, whether CTEPH is suspected or not. Furthermore, proven CTEPH diagnoses represented a small sample of our population (17 patients (3.3%)) and the impact was negligible: when excluding patients with documented CTEPH, the results were unchanged and consistent across all statistical models (Supplementary Table S2-S3, Figure S1). Finally, we were unable to include biological data in the analysis, such as elevated Factor VIII or antiphospholipid antibodies. [START_REF] Raj | Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial[END_REF][START_REF] Fernandes | From Acute to Chronic Thromboembolic Disease[END_REF]

CONCLUSION

In summary, in this selected population of patients with an acute PE, we found that age ≥65 year and IPVO≥20% at diagnosis were independent predictors of RPVO≥5%, assessed with V/Q lung scan performed between 3 to 24 months after symptomatic PE. We also observed a trend towards an increased risk of RPVO in patients with unprovoked PE.

These results reinforce previous findings and have the potential to help clinicians targeting patients at risk of RPVO in the follow-up of an acute PE. However, it remains to be confirmed in dedicated clinical trials.

Orione declares he has no conflict of interest related to this research. Ms. Raj

Figure 1 .Figure 2 .

 12 Figure 1. Flow chart

Table 3 )

 3 Mean (SD) time from index PE to lung scan evaluation was 8.1 (4.3) months. Median

	(IQR) RPVO was 5.00% (0.00 -15.75). During follow-up, 278 patients (51.8%) had
	RPVO≥5% (main outcome) and 191 (35.6%) had RPVO≥10%. CTEPH was diagnosed in 17
	patients (3.3%) through follow-up.

Table 1 . Baseline characteristics and risk factors for residual pulmonary vascular obstruction ≥5% in univariable analysis

 1 declares she has no conflict of interest related to this research. Dr. Ferrieres declares he has no conflict of interest related to this research. Dr. Le Mao declares he has no conflict of interest related to this research. Dr. Le Roux declares he has no conflict of interest related to this research. Dr. Le Floch declares he has no conflict of interest related to this research. Ms. Lemarie declares she has no conflict of interest related to this research. Dr. Nonent declares he has no conflict of interest related to this research. Ms Guegan declares she has no conflict of interest related to this research. Dr. Le Roux declares he has no conflict of interest related to this research. Dr Leroyer reports having received research grant support from Pfizer and fees for board memberships or symposia from Bayer and Astra Zeneca and having received travel support from Bayer, Daiichi Sankyo, Leo Pharma, Intermune and Actelion. Dr. Lacut reports having received personal fees from Bayer-Health Care, Bristol-Myers Squibb and Boehringer Ingelheim. Dr. Salaun declares he has no conflict of interest related to this research. Dr. Couturaud reports having received research grant support from Pfizer and fees for board memberships or symposia from Bayer, Bristol-Myers Squibb/Pfizer and Astra Zeneca and having received travel support from Bayer, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Boehringer Ingelheim, Leo Pharma, Intermune and Actelion. No other potential conflict of interest relevant to this article was reported.

	Overall
	N =537

Table 2 . Residual pulmonary vascular obstruction

 2

	Time from PE to lung scan (months), median (IQR))	6.36 (5.78 -9.39)
	RPVO (%), median (IQR)	5.00 (0.00 -15.8)
	RPVO ≥5%, n (%)	278 (51.8)
	RPVO ≥10%, n (%)	191 (35.6)
	CTEPH n (%) (NA=16/537)	17 (3.3)
	PE: Pulmonary embolism; IQR: Interquartile range; RPVO: residual pulmonary vascular obstruction; CTEPH:
	Chronic thromboembolic pulmonary hypertension
	Number of missing data are reported as NA: Not available

Table 3 . Risk factors for residual pulmonary vascular obstruction ≥5% in univariable analysis

 3 Pulmonary embolism; DVT: Deep vein thrombosis; DOAC: Direct oral anticoagulant; VKA: Vitamin K antagonists; LMWH: Low molecular weight heparin, UFH: Unfractionated heparin # A heparin treatment was initiated concomitantly to VKA until reaching targeted International Randomized Ratio * % related to number of females + These variables were integrated into multivariate analysis § This P-value was calculated for the distribution of three variables: Unprovoked / Provoked by active cancer / Provoked by a major transient factor

	RPVO <5% N=259	RPVO ≥5% N=278	p-value

Data are presented as n (%) or mean (Standard Deviation, SD). Number of missing data are reported as NA: Not available BMI: Body mass index; OR: Odds Ratio, CI: Confidence interval; IPVO: initial pulmonary vascular obstruction; VTE: Venous thromboembolism; PE:

Table 4 . Risk factors for residual pulmonary vascular obstruction ≥ 5% in multivariable analysis

 4

	First model: overall	Second model: population
	population,		with available IPVO
	N=537		N=256
	OR (95% CI)	p-value	OR (95% CI)	p-value

OR: Odds Ratio, CI: Confidence interval; IPVO: Initial pulmonary vascular obstruction; VTE: Venous thromboembolism; PE: Pulmonary embolism; DVT: Deep vein thrombosis. Ref: reference NA = Not applicable

Study concept and design: F. Couturaud, G. Picart, L. Raj, R. Le Mao, C. Tromeur,. Acquisition of data: M. Guégan. Statistical analysis: G. Picart, C. Orione, F. Couturaud. Analysis and interpretation of data: All. Drafting of the manuscript: F. Couturaud, G. Picart, P. Robin, Tromeur, PY. Salaun Critical revision of the manuscript for important intellectual content:All. Final approval of the manuscript: All. Obtaining funding: F. Couturaud. Administrative, technical, or material support: F. Couturaud, P. Robin, PY. Salaun, C. Lemarie, M. Nonent, C. Leroyer. Study supervision: F. Couturaud.

Funding/Support: The study was supported by grants from the "Programme Hospitalier de Recherche Clinique" (French Department of Health) and Foundation "Archipel Santé" and the sponsor was the University Hospital of Brest.

Role of the funding source:

The funding source was not involved in designing or conducting the study, collecting, managing, analyzing or interpreting the data, preparing, reviewing or approving the manuscript, or deciding to submit this for publication.

Author contributions: Dr Couturaud had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest disclosures: